Endovascular Recanalization of Chronically Occluded Native Arteries After Failed Bypass Surgery in Patients with Critical Ischemia.

PubMed

Yin, Minyi; Wang, Wei; Huang, Xintian; Hong, Biao; Liu, Xiaobing; Li, Weimin; Lu, Xinwu; Lu, Min; Jiang, Mier

2015-12-01

The study aimed to evaluate the feasibility, safety, and outcome of endovascular recanalization of native chronic total occlusions (CTO) in patients with critical limb ischemia (CLI) and lower extremities bypass graft failure. A retrospective review of CLI patients with failed lower limb grafts (>30 days after surgery) that underwent recanalization of native CTO was conducted in two institutions from January 2010 to June 2014. Twenty-eight patients (28 limbs) were included in the study, and all had limited surgical revascularization options. Demographics, procedural data, technical success, complications, vessel patency, limb salvage rates, and survival rates were analyzed. The mean follow-up period was 12.8 months. The technical success rate was 92.9% (26/28 limbs). The combined ipsilateral antegrade-retrograde approach was performed in nine limbs (32.1%). Major periprocedural (<30 days) complications included two myocardial infarctions (7.1%) and two stent thromboses (7.1%), resulting in one amputation. The ankle brachial index before discharge was significantly improved after recanalization (0.78 ± 0.08 vs. 0.31 ± 0.10, p < 0.01). The primary, assisted primary, and secondary patency rates at 12 months were 52.2, 65.8, and 82.2%, respectively. The limb salvage rate and amputation-free survival rate at 12 months were 91.6 and 87.0%, respectively. Endovascular recanalization of native CTO in patients with graft failure-related CLI is a feasible, safe, and effective procedure, with reasonable technical success, vessel patency, and limb salvage rates. The technique should be attempted before amputation in patients with limited surgical revascularization options.

Predictive scoring model of mortality after surgical or endovascular revascularization in patients with critical limb ischemia.

PubMed

Shiraki, Tatsuya; Iida, Osamu; Takahara, Mitsuyoshi; Okamoto, Shin; Kitano, Ikurou; Tsuji, Yoshihiko; Terashi, Hiroto; Uematsu, Masaaki

2014-08-01

The latest guideline points to life expectancy of <2 years as the main determinant in revascularization modality selection (bypass surgery [BSX] or endovascular therapy [EVT]) in patients with critical limb ischemia (CLI). This study examined predictors and a predictive scoring model of 2-year mortality after revascularization. We performed Cox proportional hazards regression analysis of data in a retrospective database, the Bypass and Endovascular therapy Against Critical limb ischemia from Hyogo (BEACH) registry, of 459 consecutive CLI patients who underwent revascularization (396 EVT and 63 BSX cases between January 2007 and December 2011) to determine predictors of 2-year mortality. The predictive performance of the score was assessed with the area under the time-dependent receiver operating characteristic curve. Of 459 CLI patients (mean age, 72 ± 10 years; 64% male; 49% nonambulatory status, 68% diabetes mellitus, 47% on regular dialysis, and 18% rest pain and 82% tissue loss as treatment indication), 84 died within 2 years after revascularization. In a multivariate model, age >75 years (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.85), nonambulatory status (HR, 5.32; 95% CI, 2.96-9.56), regular dialysis (HR, 1.90; 95% CI, 1.10-3.26), and ejection fraction <50% (HR, 2.49; 95% CI, 1.48-4.20) were independent predictors of 2-year mortality. The area under the time-dependent receiver operating characteristic curve for the developed predictive BEACH score was 0.81 (95% CI, 0.76-0.86). Predictors of 2-year mortality after EVT or BSX in CLI patients included age >75 years, nonambulatory status, regular dialysis, and ejection fraction <50%. The BEACH score derived from these predictors allows risk stratification of CLI patients undergoing revascularization. Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Safety and efficacy of cell-based therapy on critical limb ischemia: A meta-analysis.

PubMed

Ai, Min; Yan, Chang-Fu; Xia, Fu-Chun; Zhou, Shuang-Lu; He, Jian; Li, Cui-Ping

2016-06-01

Critical limb ischemia (CLI) is a major health problem worldwide, affecting approximately 500-1000 people per million per annum. Cell-based therapy has given new hope for the treatment of limb ischemia. This study assessed the safety and efficacy of cellular therapy CLI treatment. We searched the PubMed, Embase and Cochrane databases through October 20, 2015, and selected the controlled trials with cell-based therapy for CLI treatment compared with cell-free treatment. We assessed the results by meta-analysis using a variety of outcome measures, as well as the association of mononuclear cell dosage with treatment effect by dose-response meta-analysis. Twenty-five trials were included. For the primary evaluation index, cell-based therapy significantly reduced the rate of major amputation (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.32-0.60, P = 0.000) and significantly increased the rate of amputation-free survival (OR 2.80, 95% CI 1.70-4.61, P = 0.000). Trial sequence analysis indicated that optimal sample size (n = 3374) is needed to detect a plausible treatment effect in all-cause mortality. Cell-based therapy significantly improves ankle brachial index, increases the rate of ulcer healing, increases the transcutaneous pressure of oxygen, reduces limb pain and improves movement ability. Subgroup analysis indicated heterogeneity is caused by type of control, design bias and transplant route. In the dose-response analysis, there was no significant correlation between cell dosage and the therapeutic effect. Cell-based therapy has a significant therapeutic effect on CLI, but randomized double-blind placebo-controlled trials are needed to improve the credibility of this conclusion. Assessment of all-cause mortality also requires a larger sample size to arrive at a strong conclusion. In dose-response analysis, increasing the dosage of cell injections does not significantly improve the therapeutic effects of cell-based therapy. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Independence and mobility after infrainguinal lower limb bypass surgery for critical limb ischemia.

PubMed

Ambler, Graeme K; Dapaah, Andrew; Al Zuhir, Naail; Hayes, Paul D; Gohel, Manjit S; Boyle, Jonathan R; Varty, Kevin; Coughlin, Patrick A

2014-04-01

Critical limb ischemia (CLI) is a common condition associated with high levels of morbidity and mortality. Most work to date has focused on surgeon-oriented outcomes such as patency, but there is increasing interest in patient-oriented outcomes such as mobility and independence. This study was conducted to determine the effect of infrainguinal lower limb bypass surgery (LLBS) on postoperative mobility in a United Kingdom tertiary vascular surgery unit and to investigate causes and consequences of poor postoperative mobility. We collected data on all patients undergoing LLBS for CLI at our institution during a 3-year period and analyzed potential factors that correlated with poor postoperative mobility. During the study period, 93 index LLBS procedures were performed for patients with CLI. Median length of stay was 11 days (interquartile range, 11 days). The 12-month rates of graft patency, major amputation, and mortality were 75%, 9%, and 6%, respectively. Rates of dependence increased fourfold during the first postoperative year, from 5% preoperatively to 21% at 12 months. Predictors of poor postoperative mobility were female sex (P = .04) and poor postoperative mobility (P < .001), initially and at the 12-month follow-up. Patients with poor postoperative mobility had significantly prolonged hospital length of stay (15 vs 8 days; P < .001). Patients undergoing LLBS for CLI suffer significantly impaired postoperative mobility, and this is associated with prolonged hospital stay, irrespective of successful revascularization. Further work is needed to better predict patients who will benefit from revascularization and in whom a nonoperative strategy is optimal. Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Outcomes of Critical Limb Ischemia in Hemodialysis Patients After Distal Bypass Surgery　- Poor Limb Prognosis With Stage 4 Wound, Ischemia, and Foot Infection (WIfI).

PubMed

Hoshina, Katsuyuki; Yamamoto, Kota; Miyata, Tetsuro; Watanabe, Toshiaki

2016-10-25

Distal bypass is the first-line treatment for patients with critical limb ischemia (CLI). In Japanese high-volume centers, approximately half of these patients are on hemodialysis (HD). We have treated such patients first with bypass using a multidisciplinary perioperative strategy. We reveal the recent characteristics of patients who underwent distal bypass and the surgical outcomes in Japan, especially focusing on the foot conditions by using the wound, ischemia, and foot infection (WIfI) classification.Methods and Results:The 152 patients underwent distal bypass in a tertiary center hospital, and we compared patients on HD (HD group) to those not on HD (non-HD group). There were significant differences between the 2 groups in the overall survival, major adverse cardiac event-free survival and amputation-free survival (AFS) rates (P<0.0001). The procedural outcomes were analyzed via primary and secondary patency, and there was no difference. In the subanalysis of limb status using WIfI stage, the AFS rate of the HD group was significantly worse than that of the non-HD group for WIfI stage 4 patients. The life and limb prognoses of patients with CLI and HD were worse than those of non-HD patients. There was no difference in surgical outcomes suggested by the graft patency rates between the 2 groups. AFS in WIfI stage 4 was significantly worse in the HD group, which indicated the importance of preoperative limb status. (Circ J 2016; 80: 2382-2387).

Three-Year Outcomes of Surgical Versus Endovascular Revascularization for Critical Limb Ischemia

PubMed Central

Takahara, Mitsuyoshi; Soga, Yoshimitsu; Kodama, Akio; Terashi, Hiroto; Azuma, Nobuyoshi

2017-01-01

Background— The aim of this study was to compare clinical outcomes between surgical reconstruction and endovascular therapy (EVT) for critical limb ischemia (CLI) in today’s real-world settings. Methods and Results— This multicenter, prospective, observational study registered and followed 548 Japanese CLI patients. The registration was in advance of revascularization; 197 patients were scheduled to receive surgical reconstruction, and the remaining 351 were scheduled to receive EVT. The primary end point was 3-year amputation-free survival, compared between the 2 treatments in an intention-to-treat manner, using propensity score matching. Interaction analysis was additionally performed to explore which subgroups had better outcomes with surgical reconstruction or EVT. After propensity score matching, the 3-year amputation-free survival was not significantly different between the 2 groups (52% [95% confidence interval, 43%–60%] and 52% [95% confidence interval, 44–60%]; P=0.26). Subsequent interaction analysis identified (1) Wound, Ischemia, and foot Infection (WIfI) classification W-3, (2) fI-2/3, (3) history of ipsilateral minor amputation, (4) history of revascularization after CLI onset, and (5) bilateral CLI as the factors more favorable for surgical reconstruction, whereas (1) diabetes mellitus, (2) renal failure, (3) anemia, (4) history of nonadherence to cardiovascular risk management, and (5) contralateral major amputation were as those less favorable for surgical reconstruction. Conclusions— The 3-year amputation-free survival was not different between surgical reconstruction and EVT in the overall CLI population. The subsequent interaction analysis suggested that there would be a subgroup more suited for surgical reconstruction and another benefiting more from EVT. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000007050. PMID:29246911

Critical Limb Ischemia (CLI)

MedlinePlus

... re human: Search ©2017 Vascular Cures is a tax-exempt, nonprofit organization tax ID#: 94-2825216 as described in the Section ... 3) of the Internal Revenue Code. Donations are tax deductible. 274 Redwood Shores Parkway, #717, Redwood City, ...

The relationship between medical expenses and the severity of peripheral arterial disease in Japan.

PubMed

Seo, Akihiko; Yamamoto, Kota; Akai, Atsushi; Akagi, Daisuke; Takayama, Toshio; Hoshina, Katsuyuki

2018-02-02

The main objective is to examine whether the severity of peripheral arterial disease (PAD) affects the expenses and hospital stay of the patients who undergo bypass surgery below the inguinal ligament for PAD. Eighty consecutive patients who underwent infrainguinal bypass surgery for PAD between January 2012 and December 2014 were included in the study. Patients were divided into groups according to their critical limb ischemia (CLI) symptoms and the Wound, Ischemia, and Foot Infection (WIfI) classification. As endpoints, we assessed the duration of postoperative hospital stay and expenses during hospitalization. CLI was a significant factor for longer hospital stay and increased medical expenses (p = 0.009 and p = 0.001). In the patients with CLI, significant factors for longer hospital stay and increased medical expenses were (1) history of distal bypass (p = 0.33 and p = 0.003, respectively) and stage 4 local lower limb status in WIfI classification (p = 0.0007 and p = 0.053). PAD severity was associated with prolonged postoperative hospital stay and increased medical expenses. The presence or absence of CLI and its severity according to the WIfI classification correlated with medical expenses and hospital stay duration between the milder and severe groups.

Impact of lesion location on procedural and acute angiographic outcomes in patients with critical limb ischemia treated for peripheral artery disease with orbital atherectomy: A CONFIRM registries subanalysis.

PubMed

Lee, Michael S; Mustapha, Jihad; Beasley, Robert; Chopra, Paramjit; Das, Tony; Adams, George L

2016-02-15

This analysis compares the procedural and acute angiographic outcomes in patients with critical limb ischemia (CLI) treated with orbital atherectomy in above-the-knee (ATK)/popliteal (POP) lesions versus below-the-knee (BTK) lesions. Lesion location affects the procedural outcomes and the opportunity for limb salvage in patients with CLI suffering from peripheral artery disease (PAD). The CONFIRM registry series was analyzed and includes 1109 real-world patients (1544 lesions) suffering from CLI treated with orbital atherectomy. The rates of dissection, perforation, slow flow, vessel closure, spasm, embolism, and thrombus formation were compared between CLI patients with ATK/POP lesions and BTK lesions. Patients with ATK/POP lesions had a higher final residual stenosis (10 vs. 9%; P = 0.004) and use of more adjunctive therapies (e.g. balloons and stents; 1.3 vs. 1.1%; P < 0.001) compared to patients with BTK lesions. Patients with BTK had higher incidence of perforation (1.5 vs. 0.2%; P = 0.005), slow flow (7.7 vs. 5.0%; P = 0.03) and spasm (10.3 vs. 4.2%; P < 0.001) but lower incidence of embolism (0.4 vs. 5.1%; P < 0.001). Plaque modification with orbital atherectomy was successful in CLI patients regardless of lesion location. BTK lesions were associated with increased rates of perforation, slow flow and spasm which may be explained by more challenging procedural characteristics in these patients such as smaller vessel size and tortuosity. The higher incidence of emboli in ATK/POP lesions is most likely attributed to the higher prevalence of severe calcium observed in this cohort. © 2015 Wiley Periodicals, Inc.

Radiotracer Imaging Allows for Noninvasive Detection and Quantification of Abnormalities in Angiosome Foot Perfusion in Diabetic Patients With Critical Limb Ischemia and Nonhealing Wounds

PubMed Central

Alvelo, Jessica L.; Papademetris, Xenophon; Mena-Hurtado, Carlos; Jeon, Sangchoon; Sumpio, Bauer E.; Sinusas, Albert J.

2018-01-01

Background: Single photon emission computed tomography (SPECT)/computed tomography (CT) imaging allows for assessment of skeletal muscle microvascular perfusion but has not been quantitatively assessed in angiosomes, or 3-dimensional vascular territories, of the foot. This study assessed and compared resting angiosome foot perfusion between healthy subjects and diabetic patients with critical limb ischemia (CLI). Additionally, the relationship between SPECT/CT imaging and the ankle–brachial index—a standard tool for evaluating peripheral artery disease—was assessed. Methods and Results: Healthy subjects (n=9) and diabetic patients with CLI and nonhealing ulcers (n=42) underwent SPECT/CT perfusion imaging of the feet. CT images were segmented into angiosomes for quantification of relative radiotracer uptake, expressed as standardized uptake values. Standardized uptake values were assessed in ulcerated angiosomes of patients with CLI and compared with whole-foot standardized uptake values in healthy subjects. Serial SPECT/CT imaging was performed to assess uptake kinetics of technetium-99m-tetrofosmin. The relationship between angiosome perfusion and ankle–brachial index was assessed via correlational analysis. Resting perfusion was significantly lower in CLI versus healthy subjects (P=0.0007). Intraclass correlation coefficients of 0.95 (healthy) and 0.93 (CLI) demonstrated excellent agreement between serial perfusion measurements. Correlational analysis, including healthy and CLI subjects, demonstrated a significant relationship between ankle–brachial index and SPECT/CT (P=0.01); however, this relationship was not significant for diabetic CLI patients only (P=0.2). Conclusions: SPECT/CT imaging assesses regional foot perfusion and detects abnormalities in microvascular perfusion that may be undetectable by conventional ankle–brachial index in patients with diabetes mellitus. SPECT/CT may provide a novel approach for evaluating responses to targeted therapies. PMID:29748311

Superiority of Transcutaneous Oxygen Tension Measurements in Predicting Limb Salvage After Below-the-Knee Angioplasty: A Prospective Trial in Diabetic Patients With Critical Limb Ischemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Redlich, Ulf; Xiong, Yan Y.; Pech, Maciej

2011-04-15

Purpose: To assess postprocedural angiograms, the ankle-brachial index (ABI), and transcutaneous oxygen tension (TcPO{sub 2}) to predict outcome after infrageniculate angioplasty (PTA) in diabetic patients with critical limb ischemia (CLI) scheduled for amputation. Materials and Methods: PTA was performed in 28 diabetic patients with CLI confined to infrapopliteal vessels. We recorded patency of crural vessels, including the vascular supply of the foot as well as the ABI and TcPO{sub 2} of the foot. Results: Technical success rate was 92.9% (n = 26), and limb-salvage rate at 12 months was 60.7% (n = 17). The number of patent straight vessels abovemore » and below the level of the malleoli increased significantly in patients avoiding amputation. Amputation was unnecessary in 88.2% (n = 15) patients when patency of at least one tibial artery was achieved. In 72.7% (n = 8) of patients, patency of the peroneal artery alone was not sufficient for limb salvage. ABI was of no predictive value for limb salvage. TcPO{sub 2} values increased significantly only in patients not requiring amputation (P = 0.015). In patients with only one tibial artery supplying the foot or only a patent peroneal artery in postprocedural angiograms, TcPO{sub 2} was capable of reliably predicting the outcome. Conclusion: Below-the-knee PTA as an isolated part of therapy was effective to prevent major amputation in more than a half of diabetic patients with CLI. TcPO{sub 2} was a valid predictor for limb salvage, even when angiographic outcome criteria failed.« less

Midterm Outcomes From a Pilot Study of Percutaneous Deep Vein Arterialization for the Treatment of No-Option Critical Limb Ischemia.

PubMed

Kum, Steven; Tan, Yih Kai; Schreve, Michiel A; Ferraresi, Roberto; Varcoe, Ramon L; Schmidt, Andrej; Scheinert, Dierk; Mustapha, Jihad A; Lim, Darryl M; Ho, Derek; Tang, Tjun Y; Alexandrescu, Vlad-Adrian; Mutirangura, Pramook

2017-10-01

To report the initial clinical experience with percutaneous deep vein arterialization (PDVA) to treat critical limb ischemia (CLI) via the creation of an arteriovenous fistula. Seven patients (median age 85 years; 5 women) with CLI and no traditional endovascular or surgical revascularization options (no-option CLI) were recruited in a pilot study to determine the safety of PDVA. All patients were diabetic; 4 had Rutherford category 6 ischemia. Six were classified at high risk of amputation based on the Society for Vascular Surgery WIfI (wound, ischemia, and foot infection) classification. The primary safety endpoints were major adverse limb events and major adverse coronary events through 30 days and serious adverse events through 6 months. Secondary objectives included clinical efficacy based on outcome measures including thermal measurement, transcutaneous partial pressure of oxygen (TcPO 2 ), clinical improvement at 6 months, and wound healing. The primary safety endpoints were achieved in 100% of patients, with no deaths, above-the-ankle amputations, or major reinterventions at 30 days. The technical success rate was 100%. Two myocardial infarctions occurred within 30 days, each with minor clinical consequences. All patients demonstrated symptomatic improvement with formation of granulation tissue, resolution of rest pain, or both. Complete wound healing was achieved in 4 of 7 patients and 5 of 7 patients at 6 and 12 months, respectively, with a median healing time of 4.6 months (95% confidence interval 84-192). Median postprocedure peak TcPO 2 was 61 mm Hg compared to a preprocedure level of 8 mm Hg (p=0.046). At the time of wound healing, 4 of 5 of patients achieved TcPO 2 levels of >40 mm Hg. There were 2 major amputations, 1 above the knee after PDVA thrombosis and 1 below the knee for infection. Three patients died of causes unrelated to the procedure or study device at 6, 7, and 8 months, respectively. Limb salvage was 71% at 12 months. PDVA is an innovative approach for treating no-option CLI and represents an alternative option for the "desert foot," potentially avoiding major amputation. Our results demonstrate its safety and feasibility, with promising early clinical results in this small cohort.

Wound Blush Obtainment Is the Most Important Angiographic Endpoint for Wound Healing.

PubMed

Utsunomiya, Makoto; Takahara, Mitsuyoshi; Iida, Osamu; Yamauchi, Yasutaka; Kawasaki, Daizo; Yokoi, Yoshiaki; Soga, Yoshimistu; Ohura, Norihiko; Nakamura, Masato

2017-01-23

This study aimed to assess the optimal angiographic endpoint of endovascular therapy (EVT) for wound healing. Several reports have demonstrated acceptable patency and limb salvage rates following infrapopliteal interventions for the treatment of critical limb ischemia (CLI). However, the optimal angiographic endpoint of EVT remains unclear. We conducted a subanalysis of the prospective multicenter OLIVE (Endovascular Treatment for Infrainguinal Vessels in Patients with Critical Limb Ischemia) registry investigation assessing patients who received infrainguinal EVT for CLI. We analyzed data from 185 limbs with ischemic ulcerations classified as Rutherford class 5 or 6, managed with EVT alone (i.e., not undergoing bypass surgery). The wound healing rate after EVT was estimated by the Kaplan-Meier method. The association between final angiographic data and wound healing was assessed employing a Cox proportional hazards model. The overall wound healing rate was 73.5%. The probabilities of wound healing in patients with wound blush obtainment was significantly higher than that of those without wound blush (79.6% vs. 46.5%; p = 0.01). In the multivariate analysis, wound blush obtainment was an independent predictor of wound healing. The presence of wound blush after EVT is significantly associated with wound healing. Wound blush as an angiographic endpoint for EVT may serve as a novel predictor of wound healing in patients with CLI. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Allogeneic transplantation of programmable cells of monocytic origin (PCMO) improves angiogenesis and tissue recovery in critical limb ischemia (CLI): a translational approach.

PubMed

Berndt, Rouven; Hummitzsch, Lars; Heß, Katharina; Albrecht, Martin; Zitta, Karina; Rusch, Rene; Sarras, Beke; Bayer, Andreas; Cremer, Jochen; Faendrich, Fred; Groß, Justus

2018-04-27

Employing growth factor-induced partial reprogramming in vitro, peripheral human blood monocytes can acquire a state of plasticity along with expression of various markers of pluripotency. These so-called programmable cells of monocytic origin (PCMO) hold great promise in regenerative therapies. The aim of this translational study was to explore and exploit the functional properties of PCMO for allogeneic cell transplantation therapy in critical limb ischemia (CLI). Using our previously described differentiation protocol, murine and human monocytes were differentiated into PCMO. We examined paracrine secretion of pro-angiogenic and tissue recovery-associated proteins under hypoxia and induction of angiogenesis by PCMO in vitro. Allogeneic cell transplantation of PCMO was performed in a hind limb ischemia mouse model in comparison to cell transplantation of native monocytes and a placebo group. Moreover, we analyzed retrospectively four healing attempts with PCMO in patients with peripheral artery disease (PAD; Rutherford classification, stage 5 and 6). Statistical analysis was performed by using one-way ANOVA, Tukey's test or the Student's t test, p < 0.05. Cell culture experiments revealed good resilience of PCMO under hypoxia, enhanced paracrine release of pro-angiogenic and tissue recovery-associated proteins and induction of angiogenesis in vitro by PCMO. Animal experiments demonstrated significantly enhanced SO 2 saturation, blood flow, neoangiogenesis and tissue recovery after treatment with PCMO compared to treatment with native monocytes and placebo. Finally, first therapeutic application of PCMO in humans demonstrated increased vascular collaterals and improved wound healing in patients with chronic CLI without exaggerated immune response, malignant processes or extended infection after 12 months. In all patients minor and/or major amputations of the lower extremity could be avoided. In summary, PCMO improve angiogenesis and tissue recovery in chronic ischemic muscle and first clinical results promise to provide an effective and safe treatment of CLI.

Neutrophil-to-lymphocyte ratio is effective prognostic indicator for post-amputation patients with critical limb ischemia

PubMed Central

Wang, Qi; Liu, Han; Sun, Siqiao; Cheng, Zhihua; Zhang, Yang; Sun, Xiwei; Wang, Zhongying; Wang, Shuai

2017-01-01

Objectives: To confirm whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are indicators for the prognosis of post-amputation patients with critical limb ischemia (CLI). Methods: In this retrospective observational study a total 270 post-amputation patients with CLI were included between January 2010 and December 2014 in the First Hospital of Jilin University, Changchun, China. The neutrophil and lymphocyte counts were recorded before amputations. Neutrophil-to-lymphocyte ratio was calculated and NLR ≥8.08 was defined as elevated. Logistic regression analysis was conducted to test the prognostic value. Results: According to the statistical analysis, it was indicated that NLR ≥8.08 (odds ratio [OR] 26.228, 95% confidence interval [CI]: 5.801-118.583, p<0.001), PLR ≥237.14 (OR: 3.464, 95% CI: 1.289-9.308, p=0.014) and coronary heart disease (OR: 2.739, 95% CI: 1.060-7.082, p=0.038) were the independent prognostic indicators for the patients. Conclusion: Neutrophil-to-lymphocyte ratio, PLR, and coronary heart disease are independent prognostic indicators for post-amputation patients with CLI. PMID:28042626

Decision-Making in Critical Limb Ischemia: A Markov Simulation.

PubMed

Deutsch, Aaron J; Jain, C Charles; Blumenthal, Kimberly G; Dickinson, Mark W; Neilan, Anne M

2017-11-01

Critical limb ischemia (CLI) is a feared complication of peripheral vascular disease that often requires surgical management and may require amputation of the affected limb. We developed a decision model to inform clinical management for a 63-year-old woman with CLI and multiple medical comorbidities, including advanced heart failure and diabetes. We developed a Markov decision model to evaluate 4 strategies: amputation, surgical bypass, endovascular therapy (e.g. stent or revascularization), and medical management. We measured the impact of parameter uncertainty using 1-way, 2-way, and multiway sensitivity analyses. In the base case, endovascular therapy yielded similar discounted quality-adjusted life months (26.50 QALMs) compared with surgical bypass (26.34 QALMs). Both endovascular and surgical therapies were superior to amputation (18.83 QALMs) and medical management (11.08 QALMs). This finding was robust to a wide range of periprocedural mortality weights and was most sensitive to long-term mortality associated with endovascular and surgical therapies. Utility weights were not stratified by patient comorbidities; nonetheless, our conclusion was robust to a range of utility weight values. For a patient with CLI, endovascular therapy and surgical bypass provided comparable clinical outcomes. However, this finding was sensitive to long-term mortality rates associated with each procedure. Both endovascular and surgical therapies were superior to amputation or medical management in a range of scenarios. Copyright © 2017 Elsevier Inc. All rights reserved.

Ghrelin Promotes Functional Angiogenesis in a Mouse Model of Critical Limb Ischemia Through Activation of Proangiogenic MicroRNAs.

PubMed

Katare, Rajesh; Rawal, Shruti; Munasinghe, Pujika Emani; Tsuchimochi, Hirotsugu; Inagaki, Tadakatsu; Fujii, Yutaka; Dixit, Parul; Umetani, Keiji; Kangawa, Kenji; Shirai, Mikiyasu; Schwenke, Daryl O

2016-02-01

Current therapeutic strategies for the treatment of critical limb ischemia (CLI) have only limited success. Recent in vitro evidence in the literature, using cell lines, proposes that the peptide hormone ghrelin may have angiogenic properties. In this study, we aim to investigate if ghrelin could promote postischemic angiogenesis in a mouse model of CLI and, further, identify the mechanistic pathway(s) that underpin ghrelin's proangiogenic properties. CLI was induced in male CD1 mice by femoral artery ligation. Animals were then randomized to receive either vehicle or acylated ghrelin (150 μg/kg sc) for 14 consecutive days. Subsequently, synchrotron radiation microangiography was used to assess hindlimb perfusion. Subsequent tissue samples were collected for molecular and histological analysis. Ghrelin treatment markedly improved limb perfusion by promoting the generation of new capillaries and arterioles (internal diameter less than 50 μm) within the ischemic hindlimb that were both structurally and functionally normal; evident by robust endothelium-dependent vasodilatory responses to acetylcholine. Molecular analysis revealed that ghrelin's angiogenic properties were linked to activation of prosurvival Akt/vascular endothelial growth factor/Bcl-2 signaling cascade, thus reducing the apoptotic cell death and subsequent fibrosis. Further, ghrelin treatment activated proangiogenic (miR-126 and miR-132) and antifibrotic (miR-30a) microRNAs (miRs) while inhibiting antiangiogenic (miR-92a and miR-206) miRs. Importantly, in vitro knockdown of key proangiogenic miRs (miR-126 and miR-132) inhibited the angiogenic potential of ghrelin. These results therefore suggest that clinical use of ghrelin for the early treatment of CLI may be a promising and potent inducer of reparative vascularization through modulation of key molecular factors.

Comparative effectiveness of peripheral vascular intervention versus surgical bypass for critical limb ischemia in the Vascular Study Group of Greater New York.

PubMed

Meltzer, Andrew J; Sedrakyan, Art; Isaacs, Abby; Connolly, Peter H; Schneider, Darren B

2016-11-01

In this study, the effectiveness of peripheral vascular intervention (PVI) was compared with surgical bypass grafting (BPG) for critical limb ischemia (CLI) in the Vascular Study Group of Greater New York (VSGGNY). Patients undergoing BPG or PVI for CLI at VSGGNY centers (2011-2013) were included. The Society for Vascular Surgery objective performance goals for CLI were used to directly compare the safety and effectiveness of PVI and BPG. Propensity score matching was used for risk-adjusted comparisons of PVI with BPG. A total of 414 patients (268 PVI, 146 BPG) were treated for tissue loss (69%) or rest pain (31%). Patients undergoing PVI were more likely to have tissue loss (74.6% vs 57.5%; P < .001) and comorbidities such as diabetes (69.3% vs 57.5%; P = .02), heart failure (22% vs 13.7%; P = .04), and severe renal disease (13.1% vs 4.1%; P = .004). No significant differences were found between the groups across a panel of safety objective performance goals. In unadjusted analyses at 1 year, BPG was associated with higher rates of freedom from reintervention, amputation, or restenosis (90.4% vs 81.7%; P = .02) and freedom from reintervention or amputation (92.5% vs 85.8%, P = .045). After propensity score matching, PVI was associated with improved freedom from major adverse limb events and postoperative death at 1 year (95.6% vs 88.5%; P < .05). By unadjusted comparison, early reintervention and restenosis are more prevalent with PVI. However, risk-adjusted comparison underscores the safety and effectiveness of PVI in the treatment of CLI. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Cool excimer laser-assisted angioplasty (CELA) and tibial balloon angioplasty (TBA) in management of infragenicular arterial occlusion in critical lower limb ischemia (CLI).

PubMed

Sultan, Sherif; Tawfick, Wael; Hynes, Niamh

2013-04-01

We aim to compare cool excimer laser-assisted angioplasty (CELA) versus tibial balloon angioplasty (TBA) in patients with critical limb ischemia (CLI) with tibial artery occlusive disease. The primary end point is sustained clinical improvement (SCI) and amputation-free survival (AFS). The secondary end points are binary restenosis, target extremity revascularization (TER), and cost-effectiveness. From June 2005 to October 2010, 1506 patients were referred with peripheral vascular disease and 572 with CLI. A total of 80 patients underwent 89 endovascular revascularizations (EVRs) for tibial occlusions, 47 using TBA and 42 using CELA. All patients were Rutherford category 4 to 6. Three-year SCI was enhanced with CELA (81%) compared to TBA (63.8%; P = .013). Three-year AFS significantly improved with CELA (95.2%) versus TBA (89.4%; P = .0165). Three-year freedom from TER was significantly improved with CELA (92.9%) versus 78.7% TBA (P = .026). Three-year freedom from MACE was comparable in both the groups (P = .455). Patients with CELA had significantly improved quality time without symptoms of disease or toxicity of treatment (Q-TWiST) at 3 years (10.5 months; P = .048) with incremental cost of €2073.19 per quality-adjusted life year gained. Tibial EVR provides exceptional outcome in CLI. The CELA has superior SCI, AFS, and freedom from TER, with improved Q-TWiST and cost-effectiveness.

[The physiopathology of critical ischemia of the lower limbs].

PubMed

Novo, S; Abrignani, M G; Liquori, M; Sangiorgi, G B; Strano, A

1993-10-01

Peripheral obstructive arterial disease (POAD) of the lower limbs is the third main complication of atherosclerosis, after coronary artery disease and cerebrovascular disease. In 15-20% of cases POAD have an unfavourable evolution toward critical leg ischemia (CLI). This clinical condition is characterized by the onset of rest pain and/or trophic cutaneous lesions until gangrene appears. In some cases amputation is needed. The pathophysiological, clinical and therapeutic aspects of CLI were recently discussed in two Consensus Conferences held in Berlin in 1989 and in Rudesheim in 1991, with the elaboration of a final draft published on circulation. CLI appears when peripheral perfusion critically decreases due to macro and microcirculatory alterations. Atherosclerotic plaque is the primum movens, but often there are more plaques in sequence along the ilio-femoro-popliteal axis. The pathophysiological and clinical consequences are more severe if the stenosis is haemodynamically important, after a rapid progression of plaque growth or when thrombotic complications develop. The reduction in distal perfusion induces troubles in the microcirculation and an embalancement between the microvascular defense system (MDS) and the microvascular flow regulating system (MFRS) with endothelial dysfunction, platelet and leucocytes activation, worsening of blood viscosity due to the increase in fibrinogen levels and to the red cells deformability changes, activation of coagulation and impairment of fibrinolysis. So, a vicious circle appears with further worsening of distal perfusion and onset of trophic lesions. A further worsening of CLI can derive from local recurrent infections particularly frequent in diabetic patients.

Revascularization for critical limb ischemia using the SpiderFX embolic protection device in the below-the-knee circulation: initial results.

PubMed

Ward, Thomas J; Piechowiak, Rachel L; Patel, Rahul S; Fischman, Aaron M; Nowakowski, F Scott; Kim, Edward; Ellozy, Sharif H; Faries, Peter L; Lookstein, Robert A

2014-10-01

To examine the safety and efficacy of the SpiderFX embolic protection device (EPD) in the below-the-knee (BTK) circulation in patients with critical limb ischemia (CLI). A single-center retrospective review was performed to identify patients with CLI and single-vessel runoff in whom the SpiderFX EPD was used in the BTK circulation. Technical success and device-related complications were the primary endpoints. Retrieval of macroscopic debris in the EPD, 1-year freedom from major adverse limb events (MALEs), and 30-day perioperative death were also evaluated. A major amputation, surgical bypass, endovascular thrombectomy, or endovascular thrombolysis was considered a MALE. Thirty-six patients (21 men; mean age, 75.8 y) treated between 2008 and 2013 had endovascular revascularization with use of the SpiderFX EPD in the BTK circulation. The SpiderFX EPD was successfully deployed in all cases; the technical success rate of revascularization was 100%. Two minor and zero major complications were observed related to the SpiderFX. Two MALEs, a major amputation and a subsequent surgical bypass, were observed in the cohort. All MALEs occurred within 1 year of treatment (1-y freedom from MALE rate, 90%). Debris was retrieved in the SpiderFX device in 47% of patients. The use of the SpiderFX EPD in the BTK circulation in patients with CLI is safe and frequently retrieves debris. Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.

Neutrophil-to-Lymphocyte Ratio and Its Association with Critical Limb Ischemia in PAOD Patients

PubMed Central

Gary, Thomas; Pichler, Martin; Belaj, Klara; Hafner, Franz; Gerger, Armin; Froehlich, Harald; Eller, Philipp; Pilger, Ernst; Brodmann, Marianne

2013-01-01

Background The Neutrophil-to-Lymphocyte ratio (NLR) is an easy to perform test from the white blood cell count. An increase in NLR has been associated with vascular endpoints reflecting inflammation in atherosclerotic lesions. Atherosclerosis is a global threat and vascular endpoints, like myocardial infarction or critical limb ischemia (CLI), are a leading cause of death in industrialized countries. We therefore investigated NLR and its association with CLI and other vascular endpoints in peripheral arterial occlusive disease (PAOD) patients. Methods and Findings We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. NLR was calculated and the cohort was divided into tertiles according to the NLR. An optimal cut-off value for the continuous NLR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI significantly increased with an increase in NLR. As an optimal cut-off a NLR of 3.95 was identified. Two groups were categorized, one containing 1441 patients (NLR≤3.95) and a second group with 680 patients (NLR>3.95). CLI was more frequent in NLR>3.95 patients (330(48.5%)) compared to NLR≤3.95 patients (350(24.3%)) (p<0.001), as were prior myocardial infarction (48(7.0%) vs. 47(3.3%), p<0.001) and stroke (73(10.7) vs. 98(6.8%), p<0.001). Regarding other inflammatory parameters, C-reactive protein (median 5.6 mg/l (2.3–19.1) vs. median 3 mg/l (1.5–5.5)) and fibrinogen (median 412 mg/dl (345.5–507.5) vs. 344 mg/dl (308–403.5)) also significantly differed in the two patient groups (both p<0.001). A NLR>3.95 was associated with an OR of 2.5 (95%CI 2.3–2.7) for CLI even after adjustment for other vascular risk factors. Conclusions An increased NLR is significantly associated with patients at high risk for CLI and other vascular endpoints. The NLR is an easy to perform test, which could be used to highlight patients at high risk for vascular endpoints. PMID:23457609

Outcomes of Critical Limb Ischemia in an Urban, Safety Net Hospital Population with High WIfI Amputation Scores

PubMed Central

Ward, Robert; Dunn, Joie; Clavijo, Leonardo; Shavelle, David; Rowe, Vincent; Woo, Karen

2017-01-01

Background Patients presenting to a public hospital with critical limb ischemia (CLI) typically have advanced disease with significant comorbidities. The purpose of this study was to assess the influence of revascularization on 1-year amputation rate of CLI patients presenting to Los Angeles County USC Medical Center, classified according to the Society for Vascular Surgery Wound, Ischemia and foot Infection (WIfI). Methods A retrospective review of patients who presented to a public hospital with CLI from February 2010 to July 2014 was performed. Patients were classified according to the WIfI system. Only patients with complete data who survived at least 12 months after presentation were included. Results Ninety-three patients with 98 affected limbs were included. The mean age was 62.8 years. Eighty-two patients (84%) had hypertension and 71 (72%) had diabetes. Fifty (57.5%) limbs had Trans-Atlantic Inter-Society Consensus (TASC) C or D femoral–popliteal lesions and 82 (98%) had significant infrapopliteal disease. The majority had moderate or high WIfI amputation and revascularization scores. Eighty-four (86%) limbs underwent open, endovascular, or hybrid revascularization. Overall, one year major amputation (OYMA) rate was 26.5%. In limbs with high WIfI amputation score, the OYMA was 34.5%: 21.4% in those who were revascularized and 57% in those who were not. On univariable analysis, factors associated with increased risk of OYMA were nonrevascularization (P = 0.005), hyperlipidemia (P = 0.06), hemodialysis (P = 0.005), gangrene (P = 0.02), ulcer classification (P = 0.05), WIfI amputation score (P = 0.026), and WIfI wound grade (P = 0.04). On multivariable analysis, increasing WIfI amputation score (odds ratio [OR] 1.84, 95% confidence interval [CI] 1.0–3.39) was associated with increased risk of OYMA while revascularization (OR 0.24, 95% CI 0.07–0.80) was associated with decreased risk of OYMA. Conclusions The OYMA rates in this population were consistent with those predicted by the WIfI classification system. In this population, revascularization significantly reduced the risk of amputation. Comorbidities including diabetes mellitus and TASC classification did not moderate the association of WIfI amputation score with risk of 1-year major amputation. PMID:27546850

Outcomes of Critical Limb Ischemia in an Urban, Safety Net Hospital Population with High WIfI Amputation Scores.

PubMed

Ward, Robert; Dunn, Joie; Clavijo, Leonardo; Shavelle, David; Rowe, Vincent; Woo, Karen

2017-01-01

Patients presenting to a public hospital with critical limb ischemia (CLI) typically have advanced disease with significant comorbidities. The purpose of this study was to assess the influence of revascularization on 1-year amputation rate of CLI patients presenting to Los Angeles County USC Medical Center, classified according to the Society for Vascular Surgery Wound, Ischemia and foot Infection (WIfI). A retrospective review of patients who presented to a public hospital with CLI from February 2010 to July 2014 was performed. Patients were classified according to the WIfI system. Only patients with complete data who survived at least 12 months after presentation were included. Ninety-three patients with 98 affected limbs were included. The mean age was 62.8 years. Eighty-two patients (84%) had hypertension and 71 (72%) had diabetes. Fifty (57.5%) limbs had Trans-Atlantic Inter-Society Consensus (TASC) C or D femoral-popliteal lesions and 82 (98%) had significant infrapopliteal disease. The majority had moderate or high WIfI amputation and revascularization scores. Eighty-four (86%) limbs underwent open, endovascular, or hybrid revascularization. Overall, one year major amputation (OYMA) rate was 26.5%. In limbs with high WIfI amputation score, the OYMA was 34.5%: 21.4% in those who were revascularized and 57% in those who were not. On univariable analysis, factors associated with increased risk of OYMA were nonrevascularization (P = 0.005), hyperlipidemia (P = 0.06), hemodialysis (P = 0.005), gangrene (P = 0.02), ulcer classification (P = 0.05), WIfI amputation score (P = 0.026), and WIfI wound grade (P = 0.04). On multivariable analysis, increasing WIfI amputation score (odds ratio [OR] 1.84, 95% confidence interval [CI] 1.0-3.39) was associated with increased risk of OYMA while revascularization (OR 0.24, 95% CI 0.07-0.80) was associated with decreased risk of OYMA. The OYMA rates in this population were consistent with those predicted by the WIfI classification system. In this population, revascularization significantly reduced the risk of amputation. Comorbidities including diabetes mellitus and TASC classification did not moderate the association of WIfI amputation score with risk of 1-year major amputation. Published by Elsevier Inc.

Gender related Long-term Differences after Open Infrainguinal Surgery for Critical Limb Ischemia.

PubMed

Lejay, A; Schaeffer, M; Georg, Y; Lucereau, B; Roussin, M; Girsowicz, E; Delay, C; Schwein, A; Thaveau, F; Geny, B; Chakfe, N

2015-10-01

The role of gender on long-term infrainguinal open surgery outcomes still remains uncertain in critical limb ischemia patients. The aim of this study is to evaluate the gender-specific differences in patient characteristics and long-term clinical outcomes in terms of survival, primary patency and limb salvage among patients undergoing infrainguinal open surgery for CLI. All consecutive patients undergoing infrainguinal open surgery for critical limb ischemia between 2003 and 2012 were included. Survival, limb salvage and primary patency rates were assessed. Independent outcome determinants were identified by the Cox proportional hazard ratio using age and gender as adjustment factors. 584 patients (269 women and 315 men, mean age 76 and 71 years respectively) underwent 658 infrainguinal open surgery (313 in women and 345 in men). Survival rate at 6 years was lower among women compared to men with 53.5% vs 70.9% (p < 0.001). The same applied to primary patency (35.9% vs 52.4%, p < 0.001) and limb salvage (54.3% vs 81.1%, p < 0.001) at 6 years. Female-gender was an independent factor predicting death (hazard ratio 1.50), thrombosis (hazard ratio 2.37) and limb loss (hazard ratio 7.05) in age and gender-adjusted analysis. Gender-related disparity in critical limb ischemia open surgical revascularization outcomes still remains. Copyright © 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Gene therapy for therapeutic angiogenesis in peripheral arterial disease - a systematic review and meta-analysis of randomized, controlled trials.

PubMed

Hammer, Alexandra; Steiner, Sabine

2013-09-01

Beyond pharmacological, endovascular and surgical treatment strategies for peripheral arterial disease (PAD), therapeutic angiogenesis has been advocated to relieve symptoms and support limb salvage, in particular in patients with critical limb ischemia. We aimed to systematically review randomized controlled trials (RCTs) of gene therapy in PAD. A systematic search of electronic databases was performed to identify RCTs studying local administration of pro-angiogenic growth factors (VEGF, FGF, HGF, Del-1, HIF-1alpha) using plasmid or viral gene transfer by intra-arterial or intra-muscular injections. Outcomes of interest comprised all-cause mortality, amputations, ulcer healing, walking distance and ankle-brachial index. If feasible, standard meta-analysis should be performed with subgroup analysis for claudicants and patients with critical limb ischemia (CLI). The systematic search yielded 12 RCTs for analysis from 1163 citations. In total, 1494 patients (29 % females) were included with the majority suffering from CLI (64 %). Various endpoints were improved by single studies, but none by a majority of studies. Meta-analysis showed neither a significant benefit nor harm for gene therapy when synthesizing data for all-cause mortality (OR 0.88, 95 % CI 0.62 - 1.26) amputations (OR 0.64, 95 % CI 0.31 - 1.31) or ulcer healing (OR 1.79, 95 % CI 0.8 - 4.01). No differences were seen between patients with intermittent claudication or CLI. Despite promising results in single studies, no clear benefit could be identified for gene therapy in PAD patients, irrespective of disease severity.

Wound healing of critical limb ischemia with tissue loss in patients on hemodialysis.

PubMed

Honda, Yohsuke; Hirano, Keisuke; Yamawaki, Masahiro; Mori, Shinsuke; Shirai, Shigemitsu; Makino, Kenji; Tokuda, Takahiro; Takama, Takuro; Tsutumi, Masakazu; Sakamoto, Yasunari; Takimura, Hideyuki; Kobayashi, Norihiro; Araki, Motoharu; Ito, Yoshiaki

2017-06-01

We assessed wound healing in patients on hemodialysis (HD) with critical limb ischemia (CLI). This study enrolled 267 patients (including 120 patients on HD and 147 patients not on HD) who underwent endovascular therapy (EVT) for CLI. The primary endpoint was wound-healing rate at two years. Secondary endpoints were time to wound healing, wound recurrence rate, and limb salvage at two years. The percentage of male and young patients was higher in the HD patients ( p < 0.01). A lower patency of the pedal arch after EVT was observed frequently in HD patients ( p < 0.01). The wound-healing rate was significantly lower in HD patients (79.5% vs. 92.4%, p < 0.001). Time to wound healing was significantly longer in HD patients (median 132 days vs. 82 days, p = 0.005). Wound recurrence was observed more frequently in HD patients (25.0% vs. 10.2%, p = 0.007). Limb salvage (72.8% vs. 86.4%, p = 0.002) was significantly lower in HD patients. In a cox proportional hazard model, HD was an independent predictor of wound healing (risk ratio (RR), 0.46; 95% confidence interval (CI), 0.33-0.62; p < 0.001) and wound recurrence (RR, 1.58; 95% CI, 1.11-2.22; p = 0.01). HD was independently associated with lower and delayed wound healing, and wound recurrence.

Platelet-to-Lymphocyte Ratio: A Novel Marker for Critical Limb Ischemia in Peripheral Arterial Occlusive Disease Patients

PubMed Central

Gary, Thomas; Pichler, Martin; Belaj, Klara; Hafner, Franz; Gerger, Armin; Froehlich, Harald; Eller, Philipp; Rief, Peter; Hackl, Gerald; Pilger, Ernst; Brodmann, Marianne

2013-01-01

Background Platelet-to-Lymphocyte Ratio (PLR) is an easily applicable blood test. An elevated PLR has been associated with poor prognosis in patients with different oncologic disorder. As platelets play a key role in atherosclerosis and atherothrombosis, we investigated PLR and its association with critical limb ischemia (CLI) and other vascular endpoints in peripheral arterial occlusive disease (PAOD) patients. Methods and Findings We evaluated 2121 PAOD patients treated at our institution from 2005 to 2010. PLR was calculated and the cohort was categorized into tertiles according to the PLR. An optimal cut-off value for the continuous PLR was calculated by applying a receiver operating curve analysis to discriminate between CLI and non-CLI. In our cohort occurrence of CLI significantly increased with an increase in PLR. As an optimal cut-off value, a PLR of 150 was identified. Two groups were categorized, one containing 1228 patients (PLR≤150) and a second group with 893 patients (PLR>150). CLI was more frequent in PLR>150 patients (410(45.9%)) compared to PLR≤150 patients (270(22.0%)) (p<0.001), as was prior myocardial infarction (51(5.7%) vs. 42(3.5%), p = 0.02). Regarding inflammatory parameters, C-reactive protein (median 7.0 mg/l (3.0–24.25) vs. median 5.0 mg/l (2.0–10.0)) and fibrinogen (median 457 mg/dl (359.0–583.0) vs. 372 mg/dl (317.25–455.75)) also significantly differed in the two patient groups (both p<0.001). Finally, a PLR>150 was associated with an OR of 1.9 (95%CI 1.7–2.1) for CLI even after adjustment for other well-established vascular risk factors. Conclusions An increased PLR is significantly associated with patients at high risk for CLI and other cardiovascular endpoints. The PLR is a broadly available and cheap marker, which could be used to highlight patients at high risk for vascular endpoints. PMID:23844064

Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product.

PubMed

MacAskill, Mark G; Saif, Jaimy; Condie, Alison; Jansen, Maurits A; MacGillivray, Thomas J; Tavares, Adriana A S; Fleisinger, Lucija; Spencer, Helen L; Besnier, Marie; Martin, Ernesto; Biglino, Giovanni; Newby, David E; Hadoke, Patrick W F; Mountford, Joanne C; Emanueli, Costanza; Baker, Andrew H

2018-03-28

Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC-ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31 + /CD144 + ), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Saving the limb in diabetic patients with ischemic foot lesions complicated by acute infection.

PubMed

Clerici, Giacomo; Faglia, Ezio

2014-12-01

Ischemia and infection are the most important factors affecting the prognosis of foot ulcerations in diabetic patients. To improve the outcome of these patients, it is necessary to aggressively treat 2 important pathologies--namely, occlusive arterial disease affecting the tibial and femoral arteries and infection of the ischemic diabetic foot. Each of these 2 conditions may lead to major limb amputation, and the presence of both critical limb ischemia (CLI) and acute deep infection is a major risk factor for lower-extremity amputation. Thus, the management of diabetic foot ulcers requires specific therapeutic approaches that vary significantly depending on whether foot lesions are complicated by infection and/or ischemia. A multidisciplinary team approach is the key to successful treatment of a diabetic foot ulcer: ischemic diabetic foot ulcers complicated by acute deep infection pose serious treatment challenges because high levels of skill, organization, accuracy, and timing of intervention are required to maximize the chances of limb salvage: these complex issues are better managed by a multidisciplinary clinical group. © The Author(s) 2014.

Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review.

PubMed

Benoit, Eric; O'Donnell, Thomas F; Patel, Amit N

2013-01-01

Researchers have accumulated a decade of experience with autologous cell therapy in the treatment of critical limb ischemia (CLI). We conducted a systematic review of clinical trials in the literature to determine the safety and efficacy of cell therapy in CLI. We searched the literature for clinical trials of autologous cell therapy in CLI, including observational series of five or more patients to accrue a large pool of patients for safety analysis. Safety analysis included evaluation of death, cancer, unregulated angiogenesis, and procedural adverse events such as bleeding. Efficacy analysis included the clinical endpoints amputation and death as well as functional and surrogate endpoints. We identified 45 clinical trials, including seven RCTs, and 1,272 patients who received cell therapy. The overall adverse event rate was low (4.2%). Cell therapy patients did not have a higher mortality rate than control patients and demonstrated no increase in cancer incidence when analyzed against population rates. With regard to efficacy, cell therapy patients had a significantly lower amputation rate than control patients (OR 0.36, p = 0.0004). Cell therapy also demonstrated efficacy in a variety of functional and surrogate outcomes. Clinical trials differed in the proportion of patients with risk factors for clinical outcomes, and these influenced rates of amputation and death. Cell therapy presents a favorable safety profile with a low adverse event rate and no increase in severe events such as mortality and cancer and treatment with cell therapy decreases the risk of amputation. Cell therapy has a positive benefit-to-risk ratio in CLI and may be a valuable treatment option, particularly for those challenging patients who cannot undergo arterial reconstruction.

Characteristics and clinical outcomes of repeat endovascular therapy after infrapopliteal balloon angioplasty in patients with critical limb ischemia.

PubMed

Kobayashi, Norihiro; Hirano, Keisuke; Yamawaki, Masahiro; Araki, Motoharu; Sakai, Tsuyoshi; Sakamoto, Yasunari; Mori, Shinsuke; Tsutsumi, Masakazu; Honda, Yohsuke; Tokuda, Takahiro; Makino, Kenji; Shirai, Shigemitsu; Ito, Yoshiaki

2018-02-15

We clarified characteristics and clinical outcomes of critical limb ischemia (CLI) patients who underwent repeat endovascular therapy (EVT) for infrapopliteal lesions. High restenosis rate after infrapopliteal EVT remains a major concern. Patients with CLI who underwent EVT between April 2007 and February 2014, were divided into the following three groups according to how often EVT was repeated: Group A, no repeat of EVT; Group B, EVT repeated once/twice; and Group C, EVT repeated ≥3 times. Wound healing rates at 1 year were 93.9% in Group A, 77.1% in Group B, and 27.3% in Group C (P < 0.001). Limb salvage rates at 3 years were 93.0, 88.5, and 57.1%, respectively (P = 0.001). Amputation-free survival rates at 3 years were 60.8, 51.2, and 29.2%, respectively (P = 0.019). Multivariate analysis revealed that hemodialysis (OR 3.413, 95% CI 1.263-9.225, P = 0.016), low ejection fraction (OR 7.758, 1.049-57.360, P = 0.045), and clinical stage assessed by SVS WIfI (OR 2.440, 1.417-4.203, P = 0.001) were independent predictors of repeat EVT. The rate of requirement for repeat EVT significantly increased as clinical stage became more severe (repeat EVT rate: 0% in CS 1, 28.6% in CS 2, 34.0% in CS 3, and 45.7% in CS 4, P < 0.001). The clinical outcomes of CLI patients requiring repeat EVT three or more times were poor. The SVS WIfI clinical stage may be useful to predict the necessity of repeat EVT. © 2017 Wiley Periodicals, Inc.

Therapeutic Angiogenesis by Gene Therapy for Critical Limb Ischemia: Choice of Biological Agent.

PubMed

Sanada, Fumihiro; Taniyama, Yoshiaki; Azuma, Junya; Yuka, Ikeda-Iwabe; Kanbara, Yasuhiro; Iwabayashi, Masaaki; Rakugi, Hiromi; Morishita, Ryuichi

2014-04-01

Peripheral artery disease (PAD) is caused by atherosclerosis, hardening and narrowing arteries over time due to buildup of fatty deposit in vascular bed called plaque. Severe blockage of an artery of the lower extremity markedly reduce blood flow, resulting in critical limb ischemia (CLI) manifested by a variety of clinical syndromes including rest pain in the feet or toes, ulcer and gangrene with infection. Despite significant advances in clinical care and interventions for revascularization, patients with CLI remain at high risk for amputation and cardiovascular death. To overcome this unmet need, therapeutic angiogenesis using angiogenic growth factors has evolved in an attempt to increase blood flow in ischemic limb. Initial animal studies and phase I clinical trials with vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF) demonstrated promising results, inspiring scientists to progress forward. However, more rigorous phase II and III clinical trials have failed to demonstrate beneficial effects of these angiogenic growth factors to date. Recently, two multicenter, double-blind, placebo-controlled clinical trials in Japan (phase III) and US (phase II) demonstrated that hepatocyte growth factor (HGF) gene therapy for CLI significant improved primary end points and tissue oxygenation up to two years in comparison to placebo. These clinical results implicate a distinct action of HGF on cellular processes involved in vascular remodeling under pathological condition. This review presents data from phase I-III clinical trials of therapeutic angiogenesis by gene therapy in patients with PAD. Further, we discuss the potential explanation for the success or failure of clinical trials in the context of the biological mechanisms underlying angiogenesis and vascular remodeling, including cellular senescence, inflammation, and tissue fibrosis.

Transpopliteal stenting of femoral occlusions in patients with critical limb ischemia using a 4-French system.

PubMed

Spreen, Marlon; Vink, Ted; Knippenberg, Bob; Reekers, Jim; van Dijk, Lukas; Wever, Jan; van Eps, Randolph; van Overhagen, Hans

2014-08-01

In many patients with critical limb ischemia (CLI), transfemoral endovascular recanalization is the preferred treatment. Transpopliteal treatment may be used in patients with inaccessible groins. This retrospective study regards transpopliteal stenting of superficial femoral artery (SFA) occlusions using a 4F system. Eleven patients (4 male and 7 female [mean age 77 years]) underwent 12 attempts of transpopliteal recanalization of long SFA occlusions (Trans-Atlantic InterSociety Consensus B through D). All patients had CLI (Rutherford 4 to 6) and were nonoperable due to poor general condition. Indications for transpopliteal access were proximal/flush SFA occlusions (n = 5), failure of antegrade recanalization (n = 4), infected femoral-femoral crossover bypass (n = 2), and occlusion of both the native SFA and the femoral-popliteal bypass (n = 1). The popliteal artery was punctured under ultrasound guidance. Occlusions were recanalized subintimally, and 4F compatible stents were implanted. Technical success rate (<30 % residual stenosis) was achieved in 83 % of cases. In two patients, stent dislocation occurred while the sheath was removed. One arteriovenous fistula was successfully treated with additional stenting. During 6-month follow-up, there were no major amputations, and three patients died from nonrelated causes. Fifty percent of patients alive after 6 months improved to Rutherford score ≤3. The duplex restenosis (>50 %) rate at 6 months was 50 %. Transpopliteal primary stenting of complex SFA lesions in CLI for a temporary bypass is now technically feasible using a 4F system. Technical results are promising. Clinical results after 6 months are acceptable when taking into consideration that this approach may be the last option for limb salvage.

Cost-effectiveness in the contemporary management of critical limb ischemia with tissue loss.

PubMed

Barshes, Neal R; Chambers, James D; Cohen, Joshua; Belkin, Michael

2012-10-01

The care of patients with critical limb ischemia (CLI) and tissue loss is notoriously challenging and expensive. We evaluated the cost-effectiveness of various management strategies to identify those that would optimize value to patients. A probabilistic Markov model was used to create a detailed simulation of patient-oriented outcomes, including clinical events, wound healing, functional outcomes, and quality-adjusted life-years (QALYs) after various management strategies in a CLI patient cohort during a 10-year period. Direct and indirect cost estimates for these strategies were obtained using transition cost-accounting methodology. Incremental cost-effectiveness ratios (ICERs), in 2009 U.S. dollars per QALYs, were calculated compared with the most conservative management strategy of local wound care with amputation as needed. With an ICER of $47,735/QALY, an initial surgical bypass with subsequent endovascular revision(s) as needed was the most cost-effective alternative to local wound care alone. Endovascular-first management strategies achieved comparable clinical outcomes but at higher cost (ICERs ≥$101,702/QALY); however, endovascular management did become cost-effective when the initial foot wound closure rate was >37% or when procedural costs were decreased by >42%. Primary amputation was dominated (less effectiveness and more costly than wound care alone). Contemporary clinical effectiveness and cost estimates show an initial surgical bypass is the most cost-effective alternative to local wound care alone for CLI with tissue loss and can be supported even in a cost-averse health care environment. Copyright © 2012. Published by Mosby, Inc.

'Real angiosome' assessment from peripheral tissue perfusion using tissue oxygen saturation foot-mapping in patients with critical limb ischemia.

PubMed

Kagaya, Y; Ohura, N; Suga, H; Eto, H; Takushima, A; Harii, K

2014-04-01

The "tissue oxygen saturation (StO2) foot-mapping" method was developed using a non-invasive near-infrared tissue oximeter monitor to classify the foot regions as ischemic and non-ischemic areas. The purpose of this study was to evaluate StO2 foot-mapping as a reliable method to detect ischemic areas in the feet of patients with critical limb ischemia (CLI), and to compare the results with assessments from the angiosome model. The foot areas of 20 CLI patients and 20 healthy controls were classified into four regions: (1) 0 ≤ StO2 < 30%, (2) 30 ≤ StO2 < 50%, (3) 50 ≤ StO2 < 70%, and (4) 70 ≤ StO2 ≤ 100% to perform StO2 foot-mapping. Each area occupancy rate was compared between the two groups, and the threshold StO2 value for detecting ischemia was set. Next, the locations of ulcers (in 16 patients) were compared to the predicted ischemic regions by the StO2 foot-mapping and by the angiosome model and angiography. In regions (1) and (2) (StO2 < 50%), the area occupancy rate was significantly higher in the CLI group and almost zero in the control group, so that the threshold StO2 value for detecting ischemia was set at 50%. The locations of ulcers were compatible with StO2 foot-mapping in 87.5% of the cases (14/16), while they were compatible with the assessment from the angiosome model in 68.8% of the cases (11/16). This study suggests that StO2 foot-mapping can successfully and non-invasively detect ischemic areas in the peripheral tissue of the foot, and also more appropriately than the assessment provided by the angiosome model. StO2 foot-mapping can be used to evaluate the real angiosome: the real distribution of the peripheral tissue perfusion in the CLI patient's foot, which is determined by the peripheral microvascular blood flow, rather than the main arterial blood flow. Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

One-Year Outcomes Following Directional Atherectomy of Infrapopliteal Artery Lesions: Subgroup Results of the Prospective, Multicenter DEFINITIVE LE Trial.

PubMed

Rastan, Aljoscha; McKinsey, James F; Garcia, Lawrence A; Rocha-Singh, Krishna J; Jaff, Michael R; Noory, Elias; Zeller, Thomas

2015-12-01

To report a subgroup analysis of the prospective, multicenter, single-arm DEFINITIVE LE trial to assess the effectiveness of directional atherectomy for the treatment of infrapopliteal artery lesions at 1 year. In the DEFINITIVE LE trial, follow-up assessments occurred up to 1 year postprocedure. Of the 800 patients enrolled, 145 subjects with 189 infrapopliteal lesions met the criteria for this analysis. Seventy (48.3%) and 75 (51.7%) patients were suffering critical limb ischemia (CLI) and intermittent claudication, respectively; 68.3% (99/145) had diabetes. The mean lesion length was 58±44 mm (all lesions); 20.2% were occluded. The primary endpoint for patients with claudication was duplex ultrasound-derived primary patency, while for subjects with CLI it was freedom from major amputation of the target limb at 1 year. Endpoints and adverse events were independently assessed. Procedure success (≤30% residual stenosis) was achieved in 84% of treated lesions. The 1-year primary patency rate was 84% (claudicants 89.6% and CLI patients 78%, p=0.11), and the freedom from major amputation rate was 97.1% (claudicants 100% and CLI 93.8%, p=0.03). In both claudication and CLI patients, significant improvements in Rutherford category and objective measures of walking distance and quality of life were seen at 1 year in comparison to baseline. This study demonstrates that directional atherectomy in infrapopliteal arteries results in promising technical and clinical results at 1 year for claudicant as well as CLI patients. © The Author(s) 2015.

Endovascular Procedures in Treatment of Infrapopliteal Arterial Occlusive Disease: Single Center Experience With 69 Infrapopliteal Procedures.

PubMed

Janko, Pasternak J; Nebojsa, Budakov B; Andrej, Petres V

2018-03-01

Peripheral arterial occlusive disease (PAD) includes acute and chronic disorders of the blood supply as a result of obstruction of blood flow in the arteries of the limb. Treatment of PAD can be conservative, surgical and endovascular. Percutaneous transluminal angioplasty with or without stenting has become a recognized method, which is increasingly used in treatment of arterial occlusive disease. This study aimed to determine early results of endovascular treatment of critical limb ischemia (CLI) patients with infrapopliteal lesions. The study included 69 patients (46 men; mean age 65 years, range 38-84) with CLI (class 4 to 6 according to Rutherford). The primary study endpoints were absence of major amputation of the target limb at 6 months and occurance of local and systemic complications specifically related to use of endovascular treatment. Major amputation was avoided in 61 patients. Through 6 months, 6 patients underwent additional revascularization. One local complication (clinicaly significant dissection of popliteal artery) occurred, and it was resolved by stent implantation. There were no cases of systemic complications and death during the follow-up period. Rates of major amputation were 12.3% for diabetics versus 8.3% for non-diabetics. Our data showed that endovascular treatment of infrapopliteal disease is an effective and safe treatment in patients experiencing CLI, provides high limb preservation and low complication rates. Study outcomes support endovascular treatment as a primary option for patients experiencing CLI due to below the knee (BTK) occlusive disease. © 2018 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Survival benefits of revascularization in patients with critical limb ischemia and renal insufficiency.

PubMed

Ortmann, Jana; Gahl, Brigitta; Diehm, Nicolas; Dick, Florian; Traupe, Tobias; Baumgartner, Iris

2012-09-01

Evidence for the best treatment strategy for patients with critical limb ischemia (CLI) at different stages of renal insufficiency (RI) is rare. Therefore, we determined the benefit of revascularization vs medical therapy (MT) only in CLI patients with different levels of RI. This intention-to-treat cohort study with follow-up at 2, 6, and 12 months was conducted in a consecutive series of 351 patients with CLI. Revascularization by surgical (78 patients) or endovascular techniques (191 patients) was performed in 269 patients. MT as first-line therapy was administered in 82 patients. Patients were grouped according to glomerular filtration rate (GFR), estimated with the Modification of Diet in Renal Disease equation, into absent/mild RI (estimated GFR [eGFR], ≥ 60 mL/min/1.73 m(2)), moderate RI (eGFR, 30-59 mL/min/1.73 m(2)), and severe RI (eGFR, <30 mL/min/1.73 m(2) or dialysis). Primary outcome measures were overall and amputation-free survival. Cox regression models adjusted for baseline characteristics after Kaplan-Meier survival estimates were performed. The mean age differed significantly between groups (P < .001), and patients with absent/mild RI were more often men (P < .001) or smokers (P < .001) and less often hypertensive (P < .001). Risk factor adjustment showed that revascularized CLI patients with absent/mild RI had a longer amputation-free survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.26-0.82; P = .008), higher limb salvage (HR, 0.29; 95% CI, 0.17-0.91; P < .029), and better clinical success than MT patients (HR, 0.33; 95% CI, 0.17-0.65; P = .001). The moderate RI group benefited from revascularization in overall survival (HR, 0.51; 95% CI, 0.26-0.99; P = .049), amputation-free survival (HR, 0.51; 95% CI, 0.29-0.90; P = .020), and clinical success (HR, 0.42; 95% CI, 0.22-0.80; P = .008). A beneficial effect on overall survival was found even in patients with severe RI when revascularized (HR, 0.33; 95% CI, 0.12-0.91; P = .032 vs MT). Patients with CLI may benefit from revascularization compared with MT alone at all levels of renal impairment. Thus, revascularization should not be withheld in CLI patients at any level of RI. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

One-Year Outcomes Following Directional Atherectomy of Popliteal Artery Lesions: Subgroup Analysis of the Prospective, Multicenter DEFINITIVE LE Trial

PubMed Central

Rastan, Aljoscha; McKinsey, James F.; Garcia, Lawrence A.; Rocha-Singh, Krishna J.; Jaff, Michael R.; Harlin, Stuart; Kamat, Suraj; Janzer, Sean; Zeller, Thomas

2017-01-01

Purpose: To report the effectiveness of directional atherectomy for the treatment of popliteal artery occlusive disease. Methods: This subset of the prospective, multicenter, single-arm DEFINITIVE LE trial included 158 patients (mean age 72.0±10.9 years; 82 men) who underwent directional atherectomy in 162 popliteal artery lesions between 2009 and 2011. Forty-eight (30.4%) patients were suffering from critical limb ischemia (CLI). The mean lesion length was 5.8±3.9 cm; 38 (23.5%) arteries were occluded. The primary outcome measure for patients with intermittent claudication (IC) was duplex ultrasound–defined primary patency at 1 year; the outcome for subjects with CLI was freedom from major amputation of the target limb at 1 year. Outcomes and adverse events were independently assessed. Results: Procedure success (≤30% residual stenosis) was achieved in 84.4% of treated lesions; adjunctive stenting was required in 6 (3.7%) of the 162 lesions. The 1-year primary patency rate was 75.0% (IC patients 78.2% and CLI patients 67.5%, p=0.118). The freedom from major amputation in both cohorts was 100%. In both IC and CLI patients, significant improvements were demonstrated at 1 year in the Rutherford category, walking distance, and quality of life in comparison to baseline. Conclusion: This study indicates that directional atherectomy in popliteal arteries leads to favorable technical and clinical results at 1 year for claudicant as well as CLI patients. PMID:29117818

One-Year Outcomes Following Directional Atherectomy of Popliteal Artery Lesions: Subgroup Analysis of the Prospective, Multicenter DEFINITIVE LE Trial.

PubMed

Rastan, Aljoscha; McKinsey, James F; Garcia, Lawrence A; Rocha-Singh, Krishna J; Jaff, Michael R; Harlin, Stuart; Kamat, Suraj; Janzer, Sean; Zeller, Thomas

2018-02-01

To report the effectiveness of directional atherectomy for the treatment of popliteal artery occlusive disease. This subset of the prospective, multicenter, single-arm DEFINITIVE LE trial included 158 patients (mean age 72.0±10.9 years; 82 men) who underwent directional atherectomy in 162 popliteal artery lesions between 2009 and 2011. Forty-eight (30.4%) patients were suffering from critical limb ischemia (CLI). The mean lesion length was 5.8±3.9 cm; 38 (23.5%) arteries were occluded. The primary outcome measure for patients with intermittent claudication (IC) was duplex ultrasound-defined primary patency at 1 year; the outcome for subjects with CLI was freedom from major amputation of the target limb at 1 year. Outcomes and adverse events were independently assessed. Procedure success (≤30% residual stenosis) was achieved in 84.4% of treated lesions; adjunctive stenting was required in 6 (3.7%) of the 162 lesions. The 1-year primary patency rate was 75.0% (IC patients 78.2% and CLI patients 67.5%, p=0.118). The freedom from major amputation in both cohorts was 100%. In both IC and CLI patients, significant improvements were demonstrated at 1 year in the Rutherford category, walking distance, and quality of life in comparison to baseline. This study indicates that directional atherectomy in popliteal arteries leads to favorable technical and clinical results at 1 year for claudicant as well as CLI patients.

Mid-Term Outcomes of Endovascular Treatment for TASC-II D Femoropopliteal Occlusive Disease with Critical Limb Ischemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Torres-Blanco, Álvaro, E-mail: atorres658@yahoo.es; Edo-Fleta, Gemma; Gómez-Palonés, Francisco

2016-03-15

PurposeThe purpose of the study was to assess the safety and midterm effectiveness of endovascular treatment in Trans-Atlantic Inter-Society Consensus II (TASC-II) D femoropopliteal occlusions in patients with critical limb ischemia (CLI).MethodsPatients with CLI who underwent endovascular treatment for TASC-D de novo femoropopliteal occlusive disease between September 2008 and December 2013 were selected. Data included anatomic features, pre- and postprocedure ankle-brachial index, duplex ultrasound, and periprocedural complications. Sustained clinical improvement, limb salvage rate, freedom from target lesion revascularization (TLR), and freedom from target extremity revascularization (TER) were assessed by Kaplan–Meier estimation and predictors of restenosis/occlusion with Cox analysis.ResultsThirty-two patients underwentmore » treatment of 35 TASC-D occlusions. Mean age was 76 ± 9. Mean lesion length was 23 ± 5 cm. Twenty-eight limbs (80 %) presented tissue loss. Seventeen limbs underwent treatment by stent, 13 by stent-graft, and 5 by angioplasty. Mean follow-up was 29 ± 20 months. Seven patients required major amputation and six patients died during follow-up. Eighteen endovascular and three surgical TLR procedures were performed due to restenosis or occlusion. Estimated freedom from TLR and TER rates at 2 years were 41 and 76 %, whereas estimated primary and secondary patency rates were 41 and 79 %, respectively.ConclusionsEndovascular treatment for TASC II D lesions is safe and offers satisfying outcomes. This patient subset would benefit from a minimally invasive approach. Follow-up is advisable due to a high rate of restenosis. Further follow-up is necessary to know the long-term efficacy of these procedures.« less

Gram-scale production of plasmid pUDK-HGF with current good manufacturing practices for gene therapy of critical limb ischemia.

PubMed

Hu, ChunSheng; Cheng, XiaoChen; Lu, YuXin; Wu, ZuZe; Zhang, QingLin

2016-11-16

The demand of a plasmid encoding human hepatocyte growth factor gene (pUDK-HGF) in large quantities at high purity and concentration has increased for gene therapy of critical limb ischemia (CLI) in clinical trials. In this article, we produced pUDK-HGF in compliance with current good manufacturing practices at gram scale. The process included a 50-L batch fermentation, continuous alkaline lysis, and integrated three-step chromatography on Sepharose 6 Fast Flow, PlasmidSelect Xtra, and Source 15Q. The production process has been scaled up to yield 4.24 ± 0.41 g of pharmaceutical pUDK-HGF from 1.0 kg bacterial cell paste and the overall yield reached range from 58.37 to 66.70%. The final pUDK-HGF product exhibited high purity with supercoiled percentage of > 95.8% and undetectable residual RNA, contaminated protein, and bacterial endotoxin. The phase I clinical study indicates that intramuscular injection of pUDK-HGF is safe, well tolerated, and may provide symptomatic relief to CLI patients. These results show that our manufacturing process of pUDK-HGF is efficient in producing pharmaceutical-grade plasmid DNA and is safe for clinical applications.

Conservative management of distal leg necrosis in lung transplant recipients.

PubMed

Aigner, F; Husmann, M; Huber, L C; Benden, C; Schuurmans, M M

2017-05-01

Critical limb ischemia (CLI) with distal leg necrosis in lung transplant recipients (LTR) is associated with a high risk for systemic infection and sepsis. Optimal management of CLI has not been defined so far in LTR. In immunocompetent individuals with leg necrosis, surgical amputation would be indicated and standard care. We report on the outcome of four conservatively managed LTR with distal leg necrosis due to peripheral arterial disease (PAD) with medial calcification of the distal limb vessels. Time interval from lung transplantation to CLI ranged from four years (n = 1) to more than a decade (n = 3). In all cases a multimodal therapy with heparin, acetylsalicylic acid, iloprost and antibiotic therapy was performed, in addition to a trial of catheter-based revascularization. Surgical amputation of necrosis was not undertaken due to fear of wound healing difficulties under long-term immunosuppression and impaired tissue perfusion. Intensive wound care and selective debridement were performed. Two patients developed progressive gangrene followed by auto-amputation during a follow-up of 43 and 49 months with continued ambulation and two patients died of unrelated causes 9 and 12 months after diagnosis of CLI. In conclusion, we report a conservative treatment strategy for distal leg necrosis in LTR without surgical amputation and recommend this approach based on our experience. Copyright © 2017 Tissue Viability Society. Published by Elsevier Ltd. All rights reserved.

Combination of autologous transplantation of G-CSF-mobilized peripheral blood mononuclear cells and Panax notoginseng saponins in the treatment of unreconstructable critical limb ischemia.

PubMed

Wang, Xiuchun; Jiang, Liping; Wang, Xuemei; Yin, Fengling; Li, Guixin; Feng, Xueqiang; Wang, Kai; Sun, Shunji

2014-08-01

The aim of this study is to explore the efficacy and safety of the combination of autologous transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (PBMNCs) and Panax notoginseng saponins (PNS) in the treatment of unreconstructable critical limb ischemia (CLI). We performed an open-label, parallel-group, single-center, randomized clinical trial in this study. A total of 52 patients were enrolled and randomly divided into 2 groups (the PBMNC + PNS group and the PBMNC group) in a 1:1 ratio. Evaluation variables, including changes in the ankle-brachial index (ABI) of ischemic limbs, ulcer area, severity of rest pain, transcutaneous oxygen pressure (T(C)PO2), and 6-min walk distance from baseline to week 8 and 16, as well as angiographic scores for new collateral vessel formation at week 16, were used to compare the benefits of these 2 treatment approaches. After 16 weeks of treatment, improvement in ABI, T(C)PO2, and 6-min walk distance was significantly better in the PBMNC + PNS group. In addition, the combination of PBMNC transplantation and PNS administration yielded a greater reduction in ulcer area and severity of rest pain than did PBMNC transplantation alone. The proportion of patients experiencing any adverse event was similar between both treatment groups. Adverse events caused by PBMNC transplantation or PNS were generally mild and no serious adverse events occurred throughout the entire period of study. A combination of PNS and PBMNC transplantation appears to be a safe and effective treatment for patients with unreconstructable CLI. This combination may have great potential advantages in comparison with PBMNC transplantation alone and might constitute a novel therapeutic option for unreconstructable CLI. Copyright © 2014 Elsevier Inc. All rights reserved.

[Cost and cost-effectiveness in the treatment of peripheral arterial occlusion disease - what is proven?].

PubMed

Torsello, G; Bisdas, T; Debus, S; Grundmann, R T

2015-02-01

This overview comments on the health-care relevance of peripheral arterial occlusive disease (PAOD) in patients with intermittent claudication (IC) and critical limb ischaemia (CLI). We evaluated different treatment modalities in terms of cost-effectiveness. For the literature review, the Medline database (PubMed) was searched under the key words "critical limb ischemia AND cost", "critical limb ischemia AND economy", "peripheral arterial disease AND cost", "peripheral arterial disease AND economy". In the years 2005 to 2009, the hospitalisations of patients with PAOD rose disproportionately in Germany by 20 %, to 483,961 hospital admissions. By comparison, hospital admissions altogether increased by only 8 %. The average in-patient costs were estimated to be approximately € 5000 per PAOD-patient - a rather conservative estimate. For the patient with IC the economic data position is clear, supervised exercise training is by far the most cost-effective treatment option, followed by percutaneous transluminal angioplasty (PTA) and finally the peripheral bypass. In accordance with the guidelines of the UK, the latter is therefore indicated only if PTA fails or is technically not possible. In patients with CLI, the situation is not obvious. Indeed, a short-term economic advantage can be calculated for the PTA, the long-term comparison of both methods, however, is impossible due to insufficient data. In addition, the risk factors for the patient have to be included in the calculation. This was indeed demonstrated in the short-term, but could not be analysed in the long-term follow-up. The issue of greater cost-effectiveness of open or endovascular treatment in patients with CLI is uncertain, the studies and patient populations are too heterogeneous. Further studies are urgently needed to structure the sequence of the various treatment options in guidelines and clinical pathways. Georg Thieme Verlag KG Stuttgart · New York.

Prevalence and severity of peripheral arterial disease among patient with heel pressure ulcer: a retrospective study of 42 patients.

PubMed

Tisserand, Guillaume; Zenati, Nora; Seinturier, Christophe; Blaise, Sophie; Pernod, Gilles

2017-09-01

Heel pressure ulcer is a major complication in elderly hospitalized patients. The association with peripheral arterial disease (PAD) which is also a frequent disease in this population is poorly known. The aim of this study was to assess the prevalence of PAD and critical limb ischemia (CLI) in patients with heel pressure ulcer. Patients referred to the vascular medicine department for heel pressure ulcer from October 2014 to June 2015 were included in the study. The assessment of peripheral arterial disease was made with the results of ankle brachial index and/or doppler ultra sound of lower limb arteries. Toe systolic pressure and transcutaneous pressure (TcPO2) were also recorded, and the diagnosis of critical limb ischemia was made according to the TASC 2 criteria. The population was composed with 42 patients (women 43%, men 57%). The mean age was 81±11 years. Heel pressures ulcers were diagnosed in the following situations: lower limb fracture (31%), acute medical illness (21%), multiple chronic conditions (28%) and critical care unit hospitalization (7%). A peripheral arterial disease was present in 31 patients (73%), and a critical limb ischemia in 7 patients. For 18 patients, PAD was not known in their past medical history, and this was the case of 5 patients among those with critical limb ischemia. A revascularization was performed in 12 patients, and 5 patients undergo a lower limb amputation. 12 patients were died at 3 months. PAD is frequent among patients with heel pressure ulcer, and is often unknown. The functional and vital prognostic are poor, and the results of our study emphasize the importance of screening PAD in the evaluation of heel pressure ulcer risk.

Treating peripheral arterial disease percutaneously with atherectomy.

PubMed

Schwartz, Bryan G; Kloner, Robert A; Burstein, Steven; Economides, Christina; Mayeda, Guy S

2012-06-01

To determine clinical outcomes of patients who underwent percutaneous revascularization (PR) with multiple devices. PR cases at a private, tertiary referral hospital were reviewed retrospectively. Limb salvage and patency rates were calculated by the Kaplan Meier method. Historical and procedural factors were analyzed by multivariate Cox proportional hazards models. We identified 66 patients and 87 limbs with 261 lesions, including 38 patients with critical limb ischemia (CLI) (51 limbs, 171 lesions). PR incorporated multiple devices (2.0 ± 1.2 devices/lesion, 2.4 ± 1.6 devices/procedure), including balloon angioplasty (57%), excisional atherectomy (54%), orbital atherectomy (44%), and stenting (13%). Last imaged patency was at 18 ± 13 months and last clinical follow-up was 22 ± 12 months. Thirty-five of 87 limbs had ≥1 repeat PR. In 51 limbs with CLI, limb salvage was 75% at 3 years. Independent predictors of amputation were higher creatinine (P=.01; hazard ratio [HR], 1.4), Rutherford category (P=.03; HR, 3.5), and history of coronary artery bypass graft (CABG) (P=.03; HR, 8.9). Overall patency remained 75% through 3 years. Loss of patency or primary patency (patency without repeat PR) was predicted by higher creatinine, Rutherford category, chronic total occlusion, history of CABG, female gender, current and past smoking. Use of excisional atherectomy maintained overall patency (P=.01; HR, 0.36). An aggressive approach to PR with frequent use of atherectomy resulted in high rates of limb salvage and patency. Smoking cessation and excisional atherectomy may improve patency rates.

Endovascular Management of the Arteria Profunda Femoralis: Long-Term Angiographic and Clinical Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karnabatidis, Dimitrios, E-mail: karnaby@med.upatras.gr; Spiliopoulos, Stavros; Pastromas, Georgios

2012-10-15

Purpose: This study was designed to investigate the long-term angiographic and clinical outcomes of percutaneous transluminal angioplasty (PTA) of the arteria profunda femoralis (PFA), in a series of patients suffering from critical limb ischemia (CLI) or severe intermittent claudication (IC). Methods: Our department's database was searched to identify patients who underwent PTA or bail-out stenting of the PFA. Among the study's inclusion criteria were Rutherford categories 3-6 and {>=}70% stenosis of the PFA. Only de novo stenotic lesions were assessed. Primary endpoints were technical success, angiographic lesion primary patency, angiographic binary in-lesion restenosis, and target lesion recanalization (TLR) rates. Secondarymore » endpoints included patient survival, limb salvage, and complication rates. Patient's baseline demographics, lesion, and procedural details were analyzed. Results: Between 2001 and 2011, 20 consecutive patients (17 males) with a mean age of 73 {+-} 9 (range 53-87) years underwent PTA or bail-out stenting in 23 PFA lesions. Critical limb ischemia was the indication in eight of 20 patients (40%). The mean lesion length was 31 {+-} 9.5 mm. The procedural technical success was 100% (23/23), whereas mean time angiographic and clinical follow-up was 26.8 {+-} 24.6 months. According to the Kaplan-Meier analysis, primary patency and binary restenosis rate were 95 and 86.1% respectively up to 8 years follow-up. No TLR procedures were performed. The 8-year patient survival and limb salvage rates were 87.5 and 84.7% respectively. Conclusions: PTA or stenting of focal, stenotic, PFA lesions, in patients suffering from CLI or IC, exhibit high long-term primary patency rates, as well as low binary restenosis and TLR rates. Large, multicenter studies are required to validate these results.« less

Predictors of failure and success of tibial interventions for critical limb ischemia.

PubMed

Fernandez, Nathan; McEnaney, Ryan; Marone, Luke K; Rhee, Robert Y; Leers, Steven; Makaroun, Michel; Chaer, Rabih A

2010-10-01

The efficacy of tibial artery endovascular intervention (TAEI) for critical limb ischemia (CLI) and particularly for wound healing is not fully defined. The purpose of this study is to determine predictors of failure and success for TAEI in the setting of CLI. All TAEI for tissue loss or rest pain (Rutherford classes 4, 5, and 6) from 2004 to 2008 were retrospectively reviewed. Clinical outcomes and patency rates were analyzed by multivariable Cox proportional hazards regression and life table analysis. One hundred twenty-three limbs in 111 patients (62% male, mean age 74) were treated. Sixty-seven percent of patients were diabetics, 55% had renal insufficiency, and 21% required hemodialysis. One hundred two limbs (83%) exhibited tissue loss; all others had ischemic rest pain. All patients underwent tibial angioplasty (PTA). Tibial excimer laser atherectomy was performed in 14% of the patients. Interventions were performed on multiple tibial vessels in 20% of limbs. Isolated tibial procedures were performed on 50 limbs (41%), while 73 patients had concurrent ipsilateral superficial femoral artery or popliteal interventions. The mean distal popliteal and tibial runoff score improved from 11.8 ± 3.6 to 6.7 ± 1.6 (P < .001), and the mean ankle-brachial index increased from 0.61 ± 0.26 to 0.85 ± 0.22 (P < .001). Surgical bypass was required in seven patients (6%). The mean follow up was 6.8 ± 6.6 months, while the 1-year primary, primary-assisted, and secondary patency rates were 33%, 50%, and 56% respectively. Limb salvage rate at 1 year was 75%. Factors found to be associated with impaired limb salvage included renal insufficiency (hazard ratio [HR] = 5.7; P = .03) and the need for pedal intervention (HR = 13.75; P = .04). TAEI in an isolated peroneal artery (odds ratio = 7.80; P = .01) was associated with impaired wound healing, whereas multilevel intervention (HR = 2.1; P = .009) and tibial laser atherectomy (HR = 3.1; P = .01) were predictors of wound healing. In patients with tissue loss, 41% achieved complete closure (mean time to healing, 10.7 ± 7.4 months), and 39% exhibited partial wound healing (mean follow up, 4.4 ± 4.8 months) at last follow up. Diabetes, smoking, statin therapy, and revascularization of > 1 tibial vessel had no impact on limb salvage or wound healing. Re-intervention rate was 50% at 1 year. TAEI is an effective treatment for CLI with acceptable limb salvage and wound healing rates, but requires a high rate of reintervention. Patients with renal failure, pedal disease, or isolated peroneal runoff have poor outcomes with TAEI and should be considered for surgical bypass. Copyright © 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reekers, Jim A., E-mail: j.a.reekers@amc.uva.nl; Koelemay, Mark J. W., E-mail: m.j.koelemaij@amc.uva.nl; Marquering, Henk A., E-mail: h.a.marquering@amc.uva.nl

PurposeTo report on the first clinical experience with perfusion angiography (PA) of the foot in patients with chronic critical limb ischemia.Materials and MethodsPA is a post-processing software algorithm and no extra digital subtraction angiography (DSA) has to be performed for this analysis. The data used to test the feasibility of PA were obtained from a consecutive group of 89 patients with CLI who were treated with standard below the knee angioplasty and 12 separate patients who were not suitable for endovascular revascularization.ResultsMotion artifacts in the dataset of the DSA made post-procedural analysis impossible in 10 % intervention. In the majority ofmore » patients (59/68) PA showed an increase in volume flow in the foot after successful angioplasty of the crural vessels. However, in 9/68 patients no increase was seen after successful angioplasty. With the use of a local administered competitive α-adrenergic receptor antagonist, it is also possible to test and quantify the capillary resistance index which is a parameter for the remaining functionality of the microcirculation in CLI patients.ConclusionPA might be used as a new endpoint for lower limb revascularization and can also be used to test the functionality the microcirculation to identify sub-types of patients with CLI. Clinical evaluation and standardization of PA is mandatory before introduction in daily practice.« less

The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design.

PubMed

Benoit, Eric; O'Donnell, Thomas F; Iafrati, Mark D; Asher, Enrico; Bandyk, Dennis F; Hallett, John W; Lumsden, Alan B; Pearl, Gregory J; Roddy, Sean P; Vijayaraghavan, Krishnaswami; Patel, Amit N

2011-09-27

Autologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI). One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP), which is usually combined with mortality for AMP-free survival (AFS). Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control) of 48 patients treated with site of service obtained bone marrow cells (BMAC) as well as a systematic review of the literature. Cells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood). Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss. Fifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6%) and those with tissue loss (46.7%), irrespective of treatment group, was significant (p = 0.0029). In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337). The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067). Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain. BMAC shows promise in improving AMP-free survival if the trends in this pilot study are validated in a larger pivotal trial. The difference in amp rate between Rutherford 4 & 5 patients suggests that these patients should be stratified in future RCTs.

Nanoscale strategies: treatment for peripheral vascular disease and critical limb ischemia.

PubMed

Tu, Chengyi; Das, Subhamoy; Baker, Aaron B; Zoldan, Janeta; Suggs, Laura J

2015-01-01

Peripheral vascular disease (PVD) is one of the most prevalent vascular diseases in the U.S. afflicting an estimated 8 million people. Obstruction of peripheral arteries leads to insufficient nutrients and oxygen supply to extremities, which, if not treated properly, can potentially give rise to a severe condition called critical limb ischemia (CLI). CLI is associated with extremely high morbidities and mortalities. Conventional treatments such as angioplasty, atherectomy, stent implantation and bypass surgery have achieved some success in treating localized macrovascular disease but are limited by their invasiveness. An emerging alternative is the use of growth factor (delivered as genes or proteins) and cell therapy for PVD treatment. By delivering growth factors or cells to the ischemic tissue, one can stimulate the regeneration of functional vasculature network locally, re-perfuse the ischemic tissue, and thus salvage the limb. Here we review recent advance in nanomaterials, and discuss how their application can improve and facilitate growth factor or cell therapies. Specifically, nanoparticles (NPs) can serve as drug carrier and target to ischemic tissues and achieve localized and sustained release of pro-angiogenic proteins. As nonviral vectors, NPs can greatly enhance the transfection of target cells with pro-angiogenic genes with relatively fewer safety concern. Further, NPs may also be used in combination with cell therapy to enhance cell retention, cell survival and secretion of angiogenic factors. Lastly, nano/micro fibrous vascular grafts can be engineered to better mimic the structure and composition of native vessels, and hopefully overcome many complications/limitations associated with conventional synthetic grafts.

Contemporary management of critical lower limb ischemia in TASC D lesions with subintimal angioplasty in femoro-popliteal lesions, tibial angioplasty and sequential compression biomechanical device for infra-inguinal arterial occlusion. Experience and quality of life outcome learned over 25 years.

PubMed

Sultan, S; Hynes, N

2014-12-01

Patients with end-stage critical limb ischemia (CLI) survive on borrowed time and amputation is inevitable if an aggressive management stratagem is not instigated. Our primary aim was to equate effectiveness of subintimal angioplasty (SIA) and tibial balloon angioplasty (TBA) in sustaining clinical improvement and amputation free survival (AFS) in patients with CLI TASD II D. Moreover, patients with severe CLI, who were not suitable for revascularization and who were offered therapy with a sequential compression biomechanical device (SCBD) were scrutinised as part of a comprehensive lower limb salvage program. From 2002-2012, 5876 patients were referred with peripheral vascular disease (PVD); 987 presented with CLI and 798 had intervention; 189 patients presenting with CLI were not candidates for revascularisation, out of which 171 were offered SCBD. We formed a prospective observational group study of 441 patient who had TASC D disease. All of these patients presented as emergencies and were allocated to the next available treatment list. Duplex ultrasound arterial mapping (DUAM) was the sole preoperative investigation tool in 92% of all cases. Of the 441 patients studied, 190 patients (206 procedures) has SIA for TASC D femero-popliteal occlusions, 80 patients (89 procedures) had TBA and cool eximer laser angioplasty (CELA) for tibial artery occlusions and 171 patients with severe CLI were not suitable for revascularization and joined the SCBD program. Mean age (SIA 73±13 years vs. TBA/CELA 74±8 years vs. SCBD 75±13 years), and comorbidity severity scores (P>0.05) were similar between groups. Perioperative mortality within the SIA group was 1.6% vs. 0% within the TBA group and 0.6% in SCBD. Length of hospital stay within the TBA group was 3.8±2 days vs. SIA 14±16 days, P<0.0001. The 5-year freedom from major adverse events (MAE) for the SIA group was 68% that was comparable to the results obtained for both the TBA group; 59%, and SCBD group: 62.5% (P=0.1935). Five-year freedom from target lesion revascularization was 85.9% within the SIA group and 79% within the TBA group. A sustained clinical improvement was seen in 82.8% of primary SIA and 68% of TBA, which mimics the outcome of SCBD at 68% at one year. A total of 83% SCBD patients had no rest pain within one week of starting the program and gangrene remained dry and non-progressive. Ulceration healed in all but 12 patients. There were no device-related complications. Limb salvage was 94% at 5 years. All-cause survival was 69%. Quality time spent without symptoms of disease or toxicity of treatment (Q-TWiST) was 24.7 months for SIA and 8.5 months for TBA and was 38.13 for SCBD for a total of 708 months of usage. Cost per quality adjusted-life years (QALY) for SIA was € 5662.79, € 12,935.18 for TBA and € 2943.56 for SCBD. All treatment pathways augmented patient-specific Q-TWiST with substantial cost reduction. SIA, TBA and SCBD expand AFS and symptom-free survival. All treatment modalities are minimally invasive and allow for a high patient turnover without compromising limb salvage, once they are performed by experienced vascular surgeons in high deliberate practice volume centers.

Costs of Real-Life Endovascular Treatment of Critical Limb Ischemia: Report from Poland-A European Union Country with a Low-Budget Health Care System.

PubMed

Krzanowski, Marek; Drelicharz, Lukasz; Belowski, Andrzej; Partyka, Lukasz; Sumek-Brandys, Barbara; Ramakrishnan, Piravin Kumar; Nizankowski, Rafal

2016-02-01

To analyze the costs of inhospital, percutaneous treatment of patients with critical limb ischemia (CLI) carried out in Poland, a European Union country with a low-budget national health system. A retrospective analysis of prospectively collected data on all patients admitted to a tertiary care hospital for endovascular treatment of CLI over 1 year. A single, large volume, tertiary angiology center located in Southern Poland. CLI patients due to aortoiliac, femoropopliteal, or infrapopliteal arterial stenoses or occlusions with indications for first-line endovascular therapy or similar patients who refused open surgical procedure despite having primary indications for vascular surgery. Direct stenting using bare-metal stents was the primary mode of treatment for lesions located within the aortoiliac and femoropopliteal arterial segments. Plain old balloon angioplasty (POBA) was the second most commonly used technique. For below-the-knee arteries, POBA was the mainstay of treatment, which was occasionally supported by drug-eluting stent angioplasty. Directional atherectomy, scoring balloon angioplasty, or local fibrinolysis was used infrequently. Drug-eluting balloon percutaneous transluminal angioplasty was not used. The main outcome measures were the mean reimbursement of costs provided by the Polish National Health Fund (NHF) for inhospital treatment of patients for whom endovascular procedures were performed as initial treatment for CLI and the inhospital costs of endovascular treatment calculated by the caregiver in the 2 years since the first procedure. The average total number of days spent in hospital, amputation-free survival (AFS), overall survival (OS), and limb salvage rate (LSR) according to a life-table method were also calculated for the 2 years. In the first year, there were 496 endovascular and 15 surgical hospitalizations for revascularization procedures to treat 340 limbs in 327 patients, with a further 53 revascularization procedures in the second year. There were an additional 90 hospitalizations over the first year and 38 over the second year for CLI-associated cardiovascular comorbidities. The mean reimbursement for hospitalizations of patients included into observation, provided by the NHF, was $4901.94 per patient for the first year and $833.57 per patient alive to the second year. The mean cost of hospitalization for percutaneous revascularization treatment was $3804.25 per patient for the first year and $3340.30 per patient requiring revascularization within the second year. All costs were calculated in constant 2011 USD. The average total number of days spent in hospital was 8.4 days for the first year and 1.97 days per patient alive to the second year. At 1 and 2 years, the AFS was 76.8% and 66.6%, the OS was 86.5% and 77.3%, and the LSR was 89.4% and 86%, respectively. Endovascular therapy using the currently available techniques can be performed in almost all patients suffering from CLI at relatively low costs, and satisfactory results can be obtained. Physicians play a pivotal role in ensuring quality of treatment and the reduction of treatment cost in these patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Combined Retrograde-Antegrade Arterial Recanalization Through Collateral Vessels: Redefinition of the Technique for Below-the-Knee Arteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Graziani, L., E-mail: langrazi@tin.it; Morelli, L. G.

2011-02-15

The effectiveness of below-the-knee PTA to obtain successful revascularization in patients with critical limb ischemia (CLI) has been well established, and many centers have adopted endovascular intervention as the first-line treatment in patients with chronic lower-extremity disease. The well-known complex and multilevel arterial disease in patients with CLI have lead to interventionists to continuously implement different technologies and techniques. The aim of the present study was to standardize and redefine a technique characterized for combined retrograde-antegrade recanalization of a native leg artery through a collateral arterial branch by using a single access. This concept has been well described in coronarymore » arteries and recently in pelvic and tibial arteries.« less

Autologous Bone Marrow Mononuclear Cell Therapy is Safe and Promotes Amputation Free Survival in Patients with Critical Limb Ischemia

PubMed Central

Murphy, Michael P.; Lawson, Jeffrey H.; Rapp, Brian M.; Dalsing, Michael C.; Klein, Janet; Wilson, Michael G.; Hutchins, Gary D.; March, Keith L.

2011-01-01

Objective The purpose of this phase I open label non-randomized trial was to assess the safety and efficacy of autologous bone marrow mononuclear cell (ABMNC) therapy in promoting amputation free survival (AFS) in patients with critical limb ischemia (CLI). Methods Between September 2005 and March 2009 twenty-nine patients (30 limbs), with a median age of 66 (range 23–84) (14 male,15 female) with CLI were enrolled . Twentyone limbs presented with rest pain (RP), six with RP and ulceration, and three with ulcer only. All patients were not candidates for surgical bypass due to absence of a patent artery below the knee and/or endovascular approaches to improving perfusion was not possible as determined by an independent vascular surgeon. Patients were treated with an average dose of 1.7 ± 0.7 × 109 ABMNC injected intramuscularly in the index limb distal to the anterior tibial tuberosity. The primary safety endpoint was accumulation of serious adverse events and the primary efficacy endpoint was AFS at one year. Secondary endpoints at 12 weeks post-treatment were changes in first toe pressure (FTP), toe-brachial index (TBI), ankle-brachial index (ABI), and transcutaneous oxygen measurements (TcPO2). Perfusion of the index limb was measured with PET-CT with intra-arterial infusion of H2O15. Rest pain (RP), using a 10-cm visual analog scale, quality of life using the VascuQuol questionnaire, and ulcer healing were assessed at each follow-up interval. Subpopulations of endothelial progenitor cells were quantified prior to ABMNC administration using immunocytochemistry and fluorescent activated cell sorting. Results There were two serious adverse events however there no procedure related deaths. Amputation-free survival at one-year was 86.3%. There was a significant increase in FTP (10.2+ 6.2 mmHg, P=.02) and TBI (0.10± 0.05, P=.02) and a trend in improvement in ABI (0.08±0.04, P=.73). Perfusion Index by PET-CT H2O15 increased by 19.3 ± 3.1 and RP decreased significantly by 2.2 ± 0.6 cm. (P=.02). The VascuQol questionnaire demonstrated significant improvement in QOL and three of 9 ulcers (33%) healed completely. KDR+ but not CD34+ or CD133+ subpopulations of ABMNC were associated with improvement in limb perfusion. Conclusion This phase I study has demonstrated safety and the AFS rates suggest efficacy of ABMNC in promoting limb salvage in “no option” CLI. Based on these results we plan to test the concept that ABMNCs improve AFS at one year in a phase III randomized, double-blinded multicenter trial. PMID:21514773

Lower extremity revascularization using directional atherectomy: 12-month prospective results of the DEFINITIVE LE study.

PubMed

McKinsey, James F; Zeller, Thomas; Rocha-Singh, Krishna J; Jaff, Michael R; Garcia, Lawrence A

2014-08-01

The aim of this study was to assess the safety and effectiveness of directional atherectomy (DA) for endovascular treatment of peripheral arterial disease (PAD) in infrainguinal arteries in patients with claudication or critical limb ischemia. To date, no prospective, multicenter, independently-adjudicated study has evaluated the effectiveness and durability of DA in the treatment of PAD. Previous DA studies have not been prospectively powered to evaluate any differences in outcomes in patients with and without diabetes. DEFINITIVE LE (Determination of EFfectiveness of the SilverHawk(®) PerIpheral Plaque ExcisioN System (SIlverHawk Device) for the Treatment of Infrainguinal VEssels / Lower Extremities) prospectively enrolled subjects at 47 multinational centers with an infrainguinal lesion length up to 20 cm. Primary endpoints were defined as primary patency at 12 months for claudicants and freedom from major unplanned amputation for critical limb ischemia (CLI) subjects. A pre-specified statistical hypothesis evaluated noninferiority of primary patency in diabetic versus nondiabetic claudicants. Independent angiographic and sonographic core laboratories assessed outcomes, and events were adjudicated by a clinical events committee. A total of 800 subjects were enrolled. The 12-month primary patency was 78% (95% confidence interval: 74.0% to 80.6%) in claudicants, with a 77% rate in the diabetic subgroup versus 78% in the nondiabetic subgroup (noninferior, p < 0.001). The rate of freedom from major unplanned amputation of the target limb at 12 months in CLI subjects was 95% (95% confidence interval: 90.7% to 97.4%). Periprocedural adverse events included embolization (3.8%), perforation (5.3%), and abrupt closure (2.0%). The bail-out stent rate was 3.2%. The DEFINITIVE LE study demonstrated that DA is a safe and effective treatment modality at 12 months for a diverse patient population with either claudication or CLI. Furthermore, DA was shown to be noninferior for treating PAD in patients with diabetes compared with those without diabetes. (Study of SilverHawk/TurboHawk in Lower Extremity Vessels [DEFINITIVE LE]; NCT00883246). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

tPA-MMP-9 Axis Plays a Pivotal Role in Mobilization of Endothelial Progenitor Cells from Bone Marrow to Circulation and Ischemic Region for Angiogenesis

PubMed Central

Day, Yuan-Ji

2016-01-01

We examined the role of tissue plasminogen activator- (tPA-) matrix metalloproteinase- (MMP-) 9 in mobilizing endothelial progenitor cells (EPCs) from bone marrow to circulation and critical limb ischemia (CLI) region. Male C57BL/6J mice having been irradiated were categorized into wild-type mice (WT) receiving WT bone marrow cell (BMC) transfusion (group 1), WT mice receiving MMP-9 knockout (MMP-9−/−) BMC (group 2), MMP-9−/− receiving MMP-9−/− BMC (group 3), and MMP-9−/− receiving WT BMC (group 4), each of which was subdivided into sham control (SC), CLI, SC-tPA, and CLI-tPA. In groups 1 and 4, by post-CLI 18 h and day 14, circulating EPC (C-kit+/CD31+, Sca-1+/KDR+) levels were highest in CLI-tPA subgroup. In groups 2 and 3, EPC levels did not differ among all subgroups. The EPC levels in bone marrow were higher in groups 2 and 3 than those in groups 1 and 4. By day 14, in animals with CLI, expression levels of proangiogenic factors (CXCR4, SDF-1α, and VEGF) showed similar trends as circulating EPC levels. Moreover, the number of infiltrated neutrophils and macrophages in quadriceps was higher in groups 1 and 4 than groups in 2 and 3. In conclusion, tPA-MMP-9 axis plays a crucial role in EPC mobilization and angiogenesis in experimental CLI. PMID:27610138

One Year Primary Patency of Infrapopliteal Angioplasty Using Drug- Eluting Balloons: Single Center Experience at King Hussein Medical Center

PubMed Central

Haddad, Sizeph Edward; Shishani, Jan Mohammad; Qtaish, Izzeddin; Rawashdeh, Mohammad Abdelmajeed; Qtaishat, Belal Saleh

2017-01-01

Objective: Conventional percutaneous transluminal angioplasty (PTA) for long lesions in the below-the-knee (BTK) arteries in patients presenting with critical limb ischemia (CLI) has high restenosis rates at 1 year. Our goal is to evaluate whether paclitaxel drug-eluting balloons (DEB) have higher 1 year primary patency rates compared to conventional PTA. Methods: This is a single-center, prospective, randomized trial that was conducted from June 2013 to December 2015. The aim of the study was to compare 1 year primary patency rates of DEB and PTA in BTK arteries in CLI patients. Inclusion criteria were patients presenting with CLI (Rutherford class 4 or greater), stenosis or occlusion ≥30 mm of at least one tibial artery, and agreement to 12-month evaluation. Exclusion criteria were life expectancy <1 year, allergy to paclitaxel, and contraindication to combined antiplatelet treatment. Follow-up was performed by clinical assessment, ankle brachial pressure index, Doppler ultrasound imaging, and conventional angiogram if indicated. Primary end point was 1 year primary patency, and secondary end points were target lesion revascularization (TLR) and major amputation. Statistical analysis was performed using Fischer's exact test. Results: Ninety-three patients with 106 lesions in the BTK arteries were enrolled in this study. One year primary patency was achieved in 26 (65%) and seven (17%) in the DEB and PTA groups (P = 0.006), respectively. TLR was performed in nine lesions (23%) and 29 lesions (71%) in DEB and PTA groups (P = 0.009), respectively. Major amputations occurred in one limb (2%) and two limbs (4%) in DEB and PTA groups (P = 0.6), respectively. Conclusion: Paclitaxel DEB has significantly higher 1 year primary patency rate associated with significantly less TLR than conventional PTA, following endovascular recanalization of BTK arteries in patients presenting with CLI. PMID:28852581

Outcomes of Infrainguinal Revascularizations with Endovascular First Strategy in Critical Limb Ischemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jens, Sjoerd, E-mail: s.jens@amc.uva.nl; Conijn, Anne P., E-mail: a.p.conijn@amc.uva.nl; Frans, Franceline A., E-mail: f.a.frans@amc.uva.nl

PurposeThis study was designed to study the outcome of infrainguinal revascularization in patients with critical limb ischemia (CLI) in an institution with a preference towards endovascular intervention first in patients with poor condition, unfavourable anatomy for surgery, no venous material for bypass, and old age.MethodsA prospective, observational cohort study was conducted between May 2007 and May 2010 in patients presenting with CLI. At baseline, the optimal treatment was selected, i.e., endovascular or surgical treatment. In case of uncertainty about the preferred treatment, a multidisciplinary team (MDT) was consulted. Primary endpoints were quality of life and functional status 6 and 12 monthsmore » after initial intervention, assessed by the VascuQol and AMC Linear Disability Score questionnaires, respectively.ResultsIn total, 113 patients were included; 86 had an endovascular intervention and 27 had surgery. During follow-up, 41 % underwent an additional ipsilateral revascularisation procedure. For the total population, and endovascular and surgery subgroups, the VascuQol sum scores improved after 6 and 12 months (p < 0.01 for all outcomes) compared with baseline. The functional status improved (p = 0.043) after 12 months compared with baseline for the total population. Functional status of the surgery subgroup improved significantly after 6 (p = 0.031) and 12 (p = 0.044) months, but not that of the endovascular subgroup.ConclusionsOverall, the strategy of performing endovascular treatment first in patients with poor condition, unfavourable anatomy for surgery, no venous material for bypass, and old age has comparable or even slightly better results compared with the BASIL trial and other cohort studies. All vascular groups should discuss whether their treatment strategy should be directed at treating CLI patients preferably endovascular first and consider implementing an MDT to optimize patient outcomes.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jens, Sjoerd, E-mail: s.jens@amc.uva.nl; Marquering, Henk A., E-mail: h.a.marquering@amc.uva.nl; Koelemay, Mark J. W., E-mail: m.j.koelemaij@amc.uva.nl

ObjectiveTo study the feasibility of 2D perfusion imaging in critical limb ischemia (CLI).Methods/ResultsPerfusion angiography is a new technology which was tested in 18 patients with CLI of the foot. A standardized protocol was used with a catheter placed at the mid-part of the popliteal artery, and a total of 9 cc of non-ionic iodinated contrast material was injected at a rate of 3 cc/sec. The technology is based on early cardiology research where iodinated contrast agents were used for imaging of cardiac perfusion. During the first pass of the contrast, there is a significant diffusion of the contrast agents into the interstitialmore » space, particularly for non-ionic and low-molecular-weight compounds.DiscussionThe original angiography data can be used to make a time–density curve, which represents the actual perfusion of the foot in time. Angiographic perfusion imaging is a post-processing modality for which no extra contrast or radiation is needed. With this technique, it is possible to get more information about the perfusion status and microcirculation of the foot. This is a step toward functional imaging in CLI patients.« less

Peripheral atherectomy practice patterns in the United States from the Vascular Quality Initiative.

PubMed

Mohan, Sathish; Flahive, Julie M; Arous, Edward J; Judelson, Dejah R; Aiello, Francesco A; Schanzer, Andres; Simons, Jessica P

2018-06-21

Peripheral atherectomy has been shown to have technical success in single-arm studies, but clinical advantages over angioplasty and stenting have not been demonstrated, leaving its role unclear. We sought to describe patterns of atherectomy use in a real-world U.S. cohort to understand how it is currently being applied. The Vascular Quality Initiative was queried to identify all patients who underwent peripheral vascular intervention from January 2010 to September 2016. Descriptive statistics were performed to analyze demographics of the patients, comorbidities, indication, treatment modalities, and lesion characteristics. The intermittent claudication (IC) and critical limb ischemia (CLI) cohorts were analyzed separately. Of 85,605 limbs treated, treatment indication was IC in 51% (n = 43,506) and CLI in 49% (n = 42,099). Atherectomy was used in 15% (n = 13,092) of cases, equivalently for IC (15%; n = 6674) and CLI (15%; n = 6418). There was regional variation in use of atherectomy, ranging from a low of 0% in one region to a high of 32% in another region. During the study period, there was a significant increase in the proportion of cases that used atherectomy (11% in 2010 vs 18% in 2016; P < .0001). Compared with nonatherectomy cases, those with atherectomy use had higher incidence of prior peripheral vascular intervention (IC, 55% vs 43% [P < .0001]; CLI, 47% vs 41% [P < .0001]), greater mean number of arteries treated (IC, 1.8 vs 1.6 [P < .0001]; CLI, 2.1 vs 1.7 [P < .0001]), and lower proportion of prior leg bypass (IC, 10% vs 14% [P < .0001]; CLI, 11% vs 17% [P < .0001]). There was lower incidence of failure to cross the lesion (IC, 1% vs 4% [P < .0001]; CLI, 4% vs 7% [P < .0001]) but higher incidence of distal embolization (IC, 1.9% vs 0.8% [P < .0001]; CLI, 3.0% vs 1.4% [P < .0001]) and, in the CLI cohort, arterial perforation (1.4% vs 1.0%; P = .01). Despite a lack of evidence for atherectomy over angioplasty and stenting, its use has increased across the United States from 2010 to 2016. It is applied equally to IC and CLI populations, with no identifiable pattern of comorbidities or lesion characteristics, suggesting that indications are not clearly delineated or agreed on. This study places impetus on further understanding of the optimal role for atherectomy and its long-term clinical benefit in the management of peripheral arterial disease. Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Arteriographic Patterns of Atherosclerosis and the Association between Diabetes Mellitus and Ethnicity in Chronic Critical Limb Ischemia.

PubMed

Chung, Jayer; Modrall, J Gregory; Knowles, Martyn; Xiang, Qun; Lavery, Lawrence A; Timaran, Carlos H; Valentine, R James

2017-04-01

Disparate outcomes in critical limb ischemia (CLI) persist between ethnicities. The contribution of modifiable factors versus intrinsic biologic differences remains unclear. Hence, we aimed to quantify the associations between ethnicity and anatomic patterns of arterial occlusive disease in CLI, adjusting for known atherosclerotic risk factors. We performed a retrospective, single-center review of consecutive patients presenting to the vascular surgery service with CLI. Arterial lesions were defined by location (aortoiliac = aorta and iliac arteries; femoral = common, profunda, and superficial femoral arteries; and popliteal-tibial = infrapopliteal and tibial arteries). Stenoses ≥50% were deemed hemodynamically significant. Associations between the patients' baseline arteriographic patterns, demographics, and medical comorbidities were defined using Kruskal-Wallis, χ 2 , and Mantel-Haenszel χ 2 tests. Between August 2010 and January 2014, 286 CLI patients (n = 172 male, n = 176 tissue loss) were evaluated by the Vascular Surgery service. Two hundred seventy subjects had baseline arteriograms for analysis (black n = 134, 50%; Hispanic n = 78, 29%; Caucasian n = 58, 21%.) All ethnicities presented most frequently with simultaneous disease in all infrainguinal segments (n = 124, 46%). Of Hispanics, 30% (n = 23) presented with isolated infrapopliteal disease, which was higher than any other ethnic group (P = 0.02, χ 2 ). Caucasians (n = 8, 14%) presented more frequently with isolated aortoiliac occlusive disease than either Hispanics (n = 0, 0%) or blacks (n = 2, 1%; P = 0.06). Diabetes mellitus was most prevalent among Hispanics (n = 72, 85%) relative to blacks (n = 77, 55%) and Caucasians (n = 32, 52%; P < 0.001, χ 2 ). Median hemoglobin A 1c (HbA 1c ) was also highest among Hispanics (7.3%, interquartile range [IQR] 6.2-9.9) versus blacks and Caucasians (6.6%, IQR 5.8-8.2 and 6.0%, IQR 5.6-7.6; P = 0.002, Kruskal-Wallis). Tobacco abuse was most frequent among Caucasians (n = 53, 87%) and blacks (n = 113, 81%). Forty-eight (57%) of Hispanics abused tobacco (P = 0.001, χ 2 .) Subgroup analysis of subjects stratified by baseline HbA 1c revealed that there was no relationship between ethnicity and isolated infrapopliteal disease among subjects with HbA 1c ≤8.8% (P = 0.58, Mantel-Haenszel χ 2 ). Conversely, patients with poorer glycemic control (HbA 1c  ≥ 8.9%) were more frequently Hispanic and had a higher probability of having isolated infrapopliteal disease (P = 0.005, Mantel-Haenszel χ 2 ). Hispanic patients present more frequently with isolated infrapopliteal arterial disease relative to other ethnicities, which may contribute to disparate CLI outcomes. Isolated infrapopliteal disease appears to be driven mostly be poorer glycemic control rather than inherent biologic differences between ethnicities. Future studies aimed at understanding disparate outcomes due to race after lower extremity revascularization may benefit from stratification by the severity of diabetes mellitus. Understanding the distribution of atherosclerotic disease may improve the ability to predict outcomes in limb-threatening ischemia. Published by Elsevier Inc.

Infrapopliteal stenting with silicon carbide-coated stents in critical limb ischemia: a 12 month follow-up study.

PubMed

Atar, Eli; Avrahami, Ram; Koganovich, Yuri; Litvin, Sergey; Knizhnik, Michael; Belenky, Alexander

2009-10-01

Critical limb ischemia is an increasingly common condition that has high surgical morbidity and limited non-surgical options. To evaluate the use of silicon carbide-coated Motion stents, as compared to reported data for bare metal stents, in elderly patients with infrapopliteal artery stenoses causing critical limb ischemia after failed or complicated percutaneous transluminal angioplasty. Between January 2003 and March 2004, 41 stents were inserted into 17 consecutive patients (11 males, 6 females, mean age 82 years, range 75-93) following unsuccessful or complicated PTA. Seven patients had one-vessel run-off, six had two-vessel and four had three vessel run-off. All patients suffered from CLI, had up to three lesions and more than one co-morbid condition, and were considered at high surgical risk. Silicon carbide-coated Motion coronary stents, 2.5-4 mm diameterand 25 and 30 mm length, were used. Pre-intervention assessment included clinical condition, ankle brachial index, Doppler ultrasound and digital subtracted angiography. Postintervention evaluation included clinical condition, ABI and Doppler ultrasound at 3, 6 and 12 months. The technical success rate per lesion was 100% (41/41). Two patients died of unrelated causes after 2 and 8 months respectively. Primary patency rates with duplex ultrasound were 68.7% (11/16) at 3 months, 43.7% (7/16) at 6 months and 40% (6/15) after 12 months. Nine patients developed complete occlusion in 13 stents; three of these patients underwent a below-knee amputation and two patients a partial foot amputation. Re-intervention (PTA only) was performed in 7 patients (43.7%). Secondary patency rate was 81.2% (13/16) at 6 months and 60% (9/15) at one year. Mean ABI index had improved at 6 months from 0.32 to 0.67, and to 0.53 at one year. Clinical improvement was evident in 87.5% (14/16) at 6 months and in 66.6% (10/15) at one year. Silicon carbide-coated stents are comparable to bare metal stents after 6 and 12 months in infrapopliteal interventions in CLI when stenting is indicated.

Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial.

PubMed

Norgren, Lars; Patel, Manesh R; Hiatt, William R; Wojdyla, Daniel M; Fowkes, F Gerry R; Baumgartner, Iris; Mahaffey, Kenneth W; Berger, Jeffrey S; Jones, W Schuyler; Katona, Brian G; Held, Peter; Blomster, Juuso I; Rockhold, Frank W; Björck, Martin

2018-01-01

Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established. The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss. In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI. Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822. Copyright © 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

How to Treat a Patient with Thromboangiitis Obliterans: A Systematic Review.

PubMed

Fazeli, Bahare; Dadgar Moghadam, Maliheh; Niroumand, Shabnam

2018-05-01

To date, there is still no treatment protocol for patients with thromboangiitis obliterans (TAO) who are also afflicted with critical limb ischemia (CLI). Smoking cessation on its own cannot be considered a treatment for the purposes of salvaging a limb of a TAO patient with CLI. The aim of this review was to evaluate different studies of various treatment protocols for avoiding amputation in TAO patients. A systematic search for relevant studies dating from 1990 to the end of 2016 was performed on the PubMed, SCOPUS, and Science Direct databases. Only 24 studies fulfilled the inclusion criteria, of which only one was a randomized controlled trial (RCT). The remaining studies were quasi-experimental with various treatments and follow-up durations. Therefore, meta-analysis was not performed. Judging from the major amputation rates after the suggested treatments were performed, no treatment was particularly effective. This review demonstrated that more standard RCTs are needed to resolve this treatment issue involved in TAO. In addition, because health insurance coverage for TAO patients differs by country, regional cost-benefit and cost-efficacy studies of the suggested treatments for TAO are highly recommended. Copyright © 2018 Elsevier Inc. All rights reserved.

Primary Self-EXPANDing Nitinol Stenting vs Balloon Angioplasty With Optional Bailout Stenting for the Treatment of Infrapopliteal Artery Disease in Patients With Severe Intermittent Claudication or Critical Limb Ischemia (EXPAND Study).

PubMed

Schulte, Karl-Ludwig; Pilger, Ernst; Schellong, Sebastian; Tan, Kong Ten; Baumann, Frederic; Langhoff, Ralf; Torsello, Giovanni; Zeller, Thomas; Amendt, Klaus; Brodmann, Marianne

2015-10-01

To compare primary placement of a self-expanding nitinol stent to percutaneous transluminal angioplasty (PTA) with bailout stenting in infrapopliteal arteries of patients with severe intermittent claudication or critical limb ischemia (CLI). In the EXPAND trial (ClinicalTrials.gov; identifier NCT00906022), 92 patients (mean age 72.9±9.5 years; 62 men) undergoing treatment for infrapopliteal stenosis in 11 European centers were randomized 1:1 to either self-expanding nitinol stenting with the Astron Pulsar/Pulsar-18 nitinol stent or PTA with bailout stenting. The primary endpoint was sustainable clinical improvement after 12 months, defined as a ≥1-category increase for Rutherford category 3 patients or a ≥2-category increase for CLI patients (Rutherford categories 4/5) compared with baseline. Furthermore, target lesion revascularization (TLR), mortality, and amputation were assessed after 12 months. Sustained clinical improvement at 1 year was observed in 74.3% of the patients treated with primary stenting and in 68.6% of the patients treated with PTA and bailout stenting (p>0.05). Kaplan-Meier estimates of freedom from TLR (76.6% and 77.6%), mortality (7.4% vs 2.1%), and amputation [8.9% (major 6.7%) vs 13.2% (major 8.7%)] at 1 year were not significantly different. Primary self-expanding nitinol stenting did not show statistically different clinical outcomes compared to angioplasty with bailout stenting for infrapopliteal lesions. © The Author(s) 2015.

Validation of the Society for Vascular Surgery's objective performance goals for critical limb ischemia in everyday vascular surgery practice.

PubMed

Goodney, Philip P; Schanzer, Andres; Demartino, Randall R; Nolan, Brian W; Hevelone, Nathanael D; Conte, Michael S; Powell, Richard J; Cronenwett, Jack L

2011-07-01

To develop standardized metrics for expected outcomes in lower extremity revascularization for critical limb ischemia (CLI), the Society for Vascular Surgery (SVS) has developed objective performance goals (OPGs) based on aggregate data from randomized trials of lower extremity bypass (LEB). It remains unknown, however, if these targets can be achieved in everyday vascular surgery practice. We applied SVS OPG criteria to 1039 patients undergoing 1039 LEB operations for CLI with autogenous vein (excluding patients on dialysis) within the Vascular Study Group of New England (VSGNE). Each of the individual OPGs was calculated within the VSGNE dataset, along with its surrounding 95% confidence intervals (CIs) and compared to published SVS OPGs using χ(2) comparisons and survival analysis. Across most risk strata, patients in the VSGNE and SVS OPG cohorts were similar (clinical high-risk [age >80 years and tissue loss]: 15.3% VSGNE; 16.2% SVS OPG; P = .58; anatomic high risk [infrapopliteal target artery]: 57.8% VSGNE; 60.2% SVS OPG; P = .32). However, the proportion of VSGNE patients designated as conduit high-risk (lack of single-segment great saphenous vein) was lower (10.2% VSGNE; 26.9% SVS OPG;P < .001). The primary safety endpoint, major adverse limb events (MALE) at 30 days, was lower in the VSGNE cohort (3.2%; 95% CI, 2.3-4.6) than the SVS OPG cohort (6.2%; 95% CI, 4.2-8.1; P = .05). The primary efficacy OPG endpoint, freedom from any MALE or postoperative death within the first year (MALE + postoperative death [POD]), was similar between VSGNE and SVS OPG cohorts (77%; 95% CI, 74%-80%) SVS OPG, 74% (95% CI, 71%-77%) VSGNE, P = .58). In the remaining safety and efficacy OPGs, the VSGNE cohort met or exceeded the benchmarks established by the SVS OPG cohort. Community and academic centers in everyday vascular surgery practice can meet OPGs derived from centers of excellence in LEB. Quality improvement initiatives, as well as clinical trials, should incorporate OPGs in their outcome measures to facilitate communication and comparison of risk-adjusted outcomes in the treatment of CLI. Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Prior failed ipsilateral percutaneous endovascular intervention in patients with critical limb ischemia predicts poor outcome after lower extremity bypass

PubMed Central

Nolan, Brian W.; De Martino, Randall R.; Stone, David H.; Schanzer, Andres; Goodney, Philip P.; Walsh, Daniel W.; Cronenwett, Jack L.

2017-01-01

Background Although open surgical bypass remains the standard revascularization strategy for patients with critical limb ischemia (CLI), many centers now perform peripheral endovascular intervention (PVI) as the first-line treatment for these patients. We sought to determine the effect of a prior ipsilateral PVI (iPVI) on the outcome of subsequent lower extremity bypass (LEB) in patients with CLI. Methods A retrospective cohort analysis of all patients undergoing infrainguinal LEB between 2003 and 2009 within hospitals comprising the Vascular Study Group of New England (VSGNE) was performed. Primary study endpoints were major amputation and graft occlusion at 1 year postoperatively. Secondary outcomes included in-hospital major adverse events (MAE), 1-year mortality, and composite 1-year major adverse limb events (MALE). Event rates were determined using life table analyses and comparisons were performed using the log-rank test. Multivariate predictors were determined using a Cox proportional hazards model with multilevel hierarchical adjustment. Results Of 1880 LEBs performed, 32% (n = 603) had a prior infrainguinal revascularization procedure (iPVI, 7%; ipsilateral bypass, 15%; contralateral PVI, 3%; contralateral bypass, 17%). Patients with prior iPVI, compared with those without a prior iPVI, were more likely to be women (32 vs 41%; P = .04), less likely to have tissue loss (52% vs 63%; P = .02), more likely to require arm vein conduit (16% vs 5%; P = .001), and more likely to be on statin (71% vs 54%; P = .01) and beta blocker therapy (92% vs 81%; P = .01) at the time of their bypass procedure. Other demographic factors were similar between these groups. Prior PVI or bypass did not alter 30-day MAE and 1-year mortality after the index bypass. In contrast, 1-year major amputation and 1-year graft occlusion rates were significantly higher in patients who had prior iPVI than those without (31% vs 20%; P = .046 and 28% vs 18%; P = .009), similar to patients who had a prior ipsilateral bypass (1 year major amputation, 29% vs 20%; P = .022; 1 year graft occlusion, 33% vs 18%; P = .001). Independent multivariate predictors of higher 1-year amputation and graft occlusion rates were prior iPVI, prior ipsilateral bypass, dialysis dependence, prosthetic conduit and distal (tibial and pedal) bypass target. Conclusions Prior iPVI is highly predictive for poor outcome in patients undergoing LEB for CLI with higher 1-year amputation and graft occlusion rates than those without prior revascularization, similar to prior ipsilateral bypass These findings provide information, which may help with the complex decisions surrounding revascularization options in patients with CLI. PMID:21802888

Risk factors for adverse outcomes after endovascular therapy for critical limb ischemia with tissue loss due to infrainguinal artery disease.

PubMed

Tnishibe, Toshiya; Yamamoto, Kiyohito; Toguchi, Kayo; Seike, Yoshimasa; Ito, Naoki; Nishibe, Masayasu; Koizumi, Jun; Dardik, Alan; Ogino, Hitoshi

2016-10-01

The purpose of this study was to analyze the risk factors for an adverse outcome after endovascular therapy (EVT) for critical limb ischemia (CLI) with tissue loss due to infrainguinal artery disease. We retrospectively reviewed the charts of patients with tissue loss (Rutherford class 5 and 6) due to infrainguinal artery disease who were managed with endovascular therapy (EVT) between January 2006 and December 2013. The primary endpoint was amputation-free survival (AFS), while the secondary endpoints were freedom from a major adverse limb event (MALE) plus perioperative (30 days) death (POD), limb salvage, and survival rates at one year. Multivariable perioperative predictors of AFS were identified using the stepwise Cox proportional hazards regression model. A total of 65 patients underwent EVT for infrainguinal artery disease on 72 limbs. The technical success rate was 94% (68/72), while the clinical success was attained in 54 of 72 limbs (72%). The AFS, MALE + POD, limb salvage, and survival rates at one year were 76%, 86%, 91%, and 81%, respectively. The multivariate analysis demonstrated that major tissue loss classified as Rutherford class 6 (HR, 5.68; 95% CI, 2.29-14.13; P<0.05) was negatively associated with decreased AFS, while clinical success (HR, 0.25; 95% CI, 0.11-0.60; P<0.05) was positively associated with increased AFS. EVT resulted in an acceptable rate of AFS, MALE+POD, limb salvage, and survival. However, we must keep in mind that there are significant limitations to be considered for EVT in patients with major tissue loss, and that, even if revascularization could be successfully performed, a significant number of the treated limbs are still in a critical situation, such as major amputation or death.

Endovascular treatment of popliteal artery segments P1 and P2 in patients with critical limb ischemia: initial experience using a helical nitinol stent with increased radial force.

PubMed

Goltz, Jan P; Ritter, Christian O; Kellersmann, Richard; Klein, Detlef; Hahn, Dietbert; Kickuth, Ralph

2012-06-01

To evaluate efficacy, safety, and midterm patency of a helical, self-expanding nitinol stent after failed percutaneous transluminal angioplasty (PTA) of popliteal artery segments P1 and P2 in patients with chronic critical limb ischemia (CLI) or lifestyle-limiting claudication. Between February 2009 and March 2011, 40 patients (23 men; mean age 77±10 years) classified as Rutherford category 3 (n = 10) or 4/5 (n = 30) underwent PTA of the proximal and mid popliteal artery followed by implantation of a SUPERA stent for elastic recoil, residual stenosis, or flow-limiting dissection. All patients had an elevated operative risk. Before and after the procedure and during the 12-month follow-up, a clinical investigation, ankle-brachial-index (ABI) measurement, and color-coded duplex sonography and/or digital subtraction angiography were performed. Primary endpoints were limb salvage and anatomical patency at 12 months. Stent implantation was successful in all patients. The major complication rate was 7.5% (an access-site pseudoaneurysm, 2 retroperitoneal hematomas, and 1 death from retroperitoneal bleeding). Mean follow-up was 15.9 months (range 0.5-27.9). The mean baseline ABI of 0.37 significantly increased to 0.91 at 12 months (p<0.01). Three (7.5%) patients underwent bypass surgery owing to lack of clinical improvement (<0.10 improvement in ABI). Primary and secondary patency rates at 12 months in the 34 patients eligible for follow-up were 68.4% and 79.8%, respectively. The major amputation rate was 5% at 1 year. Five (12.5%) in-stent stenoses and 1 of 2 (5.0%) in-stent occlusions were successfully recanalized (the second occlusion was asymptomatic). Implantation of this helical stent into segments of the popliteal artery at the knee joint in CLI patients is a safe and clinically effective bailout method with acceptable intermediate patency.

Pilot Assessment of the Repeatability of Indocyanine Green Fluorescence Imaging and Correlation with Traditional Foot Perfusion Assessments.

PubMed

Venermo, M; Settembre, N; Albäck, A; Vikatmaa, P; Aho, P-S; Lepäntalo, M; Inoue, Y; Terasaki, H

2016-10-01

Ankle brachial index (ABI), toe pressures (TP), and transcutaneous oxygen pressure (TcPO 2 ) are traditionally used in the assessment of critical limb ischemia (CLI). Indocyanine green (ICG) fluorescence imaging can be used to evaluate local circulation in the foot and to evaluate the severity of ischemia. This prospective study analyzed the suitability of a fluorescence imaging system (photodynamic eye [PDE]) in CLI. Forty-one patients with CLI were included. Of the patients, 66% had diabetes and there was an ischemic tissue lesion in 70% of the limbs. ABI, toe pressures, TcPO 2 and ICG-fluorescence imaging (ICG-FI) were measured in each leg. To study the repeatability of the ICG-FI, each patient underwent the study twice. After the procedure, foot circulation was measured using a time-intensity curve, where T1/2 (the time needed to achieve half of the maximum fluorescence intensity) and PDE10 (increase of the intensity during the first 10 s) were determined. A time-intensity curve was plotted using the same areas as for the TcPO 2 probes (n=123). The mean ABI was 0.43, TP 21 mmHg, TcPO 2 23 mmHg, T1/2 38 s, and PDE10 19 AU. Time-intensity curves were repeatable. In a Bland-Altman scatter plot, the 95% limits of agreement of PDE10 was 9.9 AU and the corresponding value of T1/2 was 14 s. Correlation between ABI and TP was significant (R=.73, p<.001), and it was weaker in diabetic patients (R=.47, p=.048) compared with non-diabetic patients (R=.89, p=.002). Correlations between ABI and TcPO 2 and TP and TcPO 2 were weak (R=.37, p=.05 and R=.43, p=.037, respectively). Correlation between TcPO 2 and PDE10 was strong in diabetic patients (R=.70, p=.003). According to this pilot study, ICG-FI with PDE can be used in the assessment of blood supply in the ischemic foot. Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Superficial femoral artery TASC D Registry: twelve-month effectiveness analysis of the Pulsar-18 SE nitinol stent in patients with critical limb ischemia.

PubMed

Lichtenberg, M; Stahlhoff, W; Boese, D

2013-08-01

Single center observational study analyzing the primary patency rate and freedom from target lesions revascularization rate of the Pulsar-18 nitinol stent after recanalization of long superficial femoral artery (SFA) occlusions (TASC D) in 22 patients with critical limb ischemia (CLI). Between 1/2011 and 7/2011, 22 consecutive patients (9 male, 13 female) with chronic total occlusions (CTO) of the femoro-popliteal arteries presenting with CLI (17 patients with Rutherford 4 score, and 5 patients with Rutherford 5 score) were enrolled and successfully recanalized using the Pulsar-18 self-expanding (SE) nitinol stent (BIOTRONIK AG, Buelach, Switzerland). Primary patency at 12 months was defined as no binary restenosis (>50%) on Duplex ultrasound (PSVR<2.5) and respectively no target lesion revascularization performed within 12 months. The average lesion length of the treated femoro-popliteal segment was 315 mm. Performing spot stenting average stent length in all patients was 245 mm (minimal 215 mm, maximal 315 mm). Technical success, with establishing an antegrade straight line flow to the foot through a reopened SFA, was achieved in all 22 patients. Subintimal and intraluminal recanalization techniques were used. Two patients with Rutherford 5 score had a minor amputation shortly after the recanalization procedure. All other patients had a complete wound healing of their lesions during a 6 month follow-up. After 12 month follow-up the primary patency rate of the Pulsar-18 SE nitinol stent was 77% with a per protocol restenosis in 5 of 22 patients. Seventeen patients showed a walking capacity on treadmill test >300 meters (Rutherford II). Two patients with a documented restenosis were Rutherford, these patients were treated conservatively. Three patients with restenosis and a Rutherford III score were scheduled for an endovascular target lesion revascularization leading to a freedom from target lesion revascularization rate of 86%. Endovascular intervention of long SFA occlusions using subintimal or intraluminal recanalization technique with implantation of the Pulsar-18 SE nitinol stent in CLI patients is safe and clinically effective with a primary patency rate after 12 months of 77% and a freedom from target lesion revascularization rate of 86%.

Study of the stability of packaging and storage conditions of human mesenchymal stem cell for intra-arterial clinical application in patient with critical limb ischemia.

PubMed

Gálvez-Martín, Patricia; Hmadcha, Abdelkrim; Soria, Bernat; Calpena-Campmany, Ana C; Clares-Naveros, Beatriz

2014-04-01

Critical limb ischemia (CLI) is associated with significant morbidity and mortality. In this study, we developed and characterized an intra-arterial cell suspension containing human mesenchymal stem cells (hMSCs) for the treatment of CLI. Equally, the stability of cells was studied in order to evaluate the optimal conditions of storage that guarantee the viability from cell processing to the administration phase. Effects of various factors, including excipients, storage temperature and time were evaluated to analyze the survival of hMSCs in the finished medicinal product. The viability of hMSCs in different packaging media was studied for 60 h at 4 °C. The best medium to maintain hMSCs viability was then selected to test storage conditions (4, 8, 25 and 37 °C; 60 h). The results showed that at 4 °C the viability was maintained above 80% for 48 h, at 8 °C decreased slightly, whereas at room temperature and 37 °C decreased drastically. Its biocompatibility was assessed by cell morphology and cell viability assays. During stability study, the stored cells did not show any change in their phenotypic or genotypic characteristics and physicochemical properties remained constant, the ability to differentiate into adipocytes and osteocytes and sterility requirements were also unaltered. Finally, our paper proposes a packing media composed of albumin 20%, glucose 5% and Ringer's lactate at a concentration of 1×10(6) cells/mL, which must be stored at 4 °C as the most suitable to maintain cell viability (>80%) and without altering their characteristics for more than 48 h. Copyright © 2013 Elsevier B.V. All rights reserved.

Therapeutic Efficacy of Autologous Non-Mobilized Enriched Circulating Endothelial Progenitors in Patients With Critical Limb Ischemia　- The SCELTA Trial.

PubMed

Liotta, Francesco; Annunziato, Francesco; Castellani, Sergio; Boddi, Maria; Alterini, Brunetto; Castellini, Giovanni; Mazzanti, Benedetta; Cosmi, Lorenzo; Acquafresca, Manlio; Bartalesi, Filippo; Dilaghi, Beatrice; Dorigo, Walter; Graziani, Gabriele; Bartolozzi, Benedetta; Bellandi, Guido; Carli, Giulia; Bartoloni, Alessandro; Fargion, Aaron; Fassio, Filippo; Fontanari, Paolo; Landini, Giancarlo; Lucente, Eleonora A M; Michelagnoli, Stefano; Orsi Battaglini, Carolina; Panigada, Grazia; Pigozzi, Clara; Querci, Valentina; Santarlasci, Veronica; Parronchi, Paola; Troisi, Nicola; Baggiore, Cristiana; Romagnani, Paola; Mannucci, Edoardo; Saccardi, Riccardo; Pratesi, Carlo; Gensini, Gianfranco; Romagnani, Sergio; Maggi, Enrico

2018-05-25

The therapeutic efficacy of bone marrow mononuclear cells (BM-MNC) autotransplantation in critical limb ischemia (CLI) has been reported. Variable proportions of circulating monocytes express low levels of CD34 (CD14 + CD34 low cells) and behave in vitro as endothelial progenitor cells (EPCs). The aim of the present randomized clinical trial was to compare the safety and therapeutic effects of enriched circulating EPCs (ECEPCs) with BM-MNC administration.Methods and Results:ECEPCs (obtained from non-mobilized peripheral blood by immunomagnetic selection of CD14 + and CD34 + cells) or BM-MNC were injected into the gastrocnemius of the affected limb in 23 and 17 patients, respectively. After a mean of 25.2±18.6-month follow-up, both groups showed significant and progressive improvement in muscle perfusion (primary endpoint), rest pain, consumption of analgesics, pain-free walking distance, wound healing, quality of life, ankle-brachial index, toe-brachial index, and transcutaneous PO 2 . In ECEPC-treated patients, there was a positive correlation between injected CD14 + CD34 low cell counts and the increase in muscle perfusion. The safety profile was comparable between the ECEPC and BM-MNC treatment arms. In both groups, the number of deaths and major amputations was lower compared with eligible untreated patients and historical reference patients. This study supports previous trials showing the efficacy of BM-MNC autotransplantation in CLI patients and demonstrates comparable therapeutic efficacy between BM-MNC and EPEPCs.

Subintimal Recanalization of Occluded Stents: The Substent Technique

DOE Office of Scientific and Technical Information (OSTI.GOV)

Diamantopoulos, Athanasios, E-mail: adiamant@upatras.gr; Katsanos, Konstantinos; Spiliopoulos, Stavros

2013-08-01

PurposeApplication of metal stents is complicated by neointimal hyperplasia leading to vessel restenosis and reocclusion. Treatment options in cases presenting with complete occlusion of the stented segment and recurrent critical limb ischemia (CLI) are limited. We present the option of the subintimal/substent technique in dealing with occluded stents.MethodsThe study included patients presenting with recurrent CLI due to impaired blood flow as a result of complete occlusion of previously inserted metal stents and unsuccessful intraluminal crossing of the lesion via either the antegrade or retrograde approach. In these cases, crossing the occlusion through the subintimal/substent plane was attempted. Primary end pointsmore » included technical success, safety of the procedure, clinical improvement, and limb salvage, while secondary end points were patient survival, primary patency, and vessel restenosis rates at 1-year follow-up. Study end points were calculated by Kaplan-Meier survival analysis.ResultsBetween July 2006 and October 2011, a total of 14 patients (mean age 69.14 {+-} 12.59 years, 12 men) were treated with the substent technique and included in the analysis. Technical success rate was 85.71 % (12 of 14), with a total lesion length of 193.57 {+-} 90.78 mm. The mean occluded stented segment length was 90.21 {+-} 44.34 mm. In 10 (83.33 %) of 12 cases, a new stent had to be placed by the side of the old occluded one, while the remaining two cases (16.67 %) were treated only with balloon angioplasty. No serious adverse events were noted during the immediate postprocedural period. All successfully treated patients improved clinically. Estimated limb salvage was 90.9 %, and patient survival rate was 90.0 % at 1 year's follow-up. Primary patency was 45.50 % and vessel restenosis 77.30 %.ConclusionSubintimal recanalization of occluded metal stents through the substent plane is a valuable alternative treatment option, especially in patients with recurrent CLI with few alternatives.« less

The Comprehensive Risk Assessment for Bypass (CRAB) facilitates efficient perioperative risk assessment for patients with critical limb ischemia.

PubMed

Meltzer, Andrew J; Graham, Ashley; Connolly, Peter H; Meltzer, Ellen C; Karwowski, John K; Bush, Harry L; Schneider, Darren B

2013-05-01

Specific perioperative risk assessment models have been developed for bariatric, pancreatic, and colorectal surgery. A similar instrument, specific for patients with critical limb ischemia (CLI), could improve patient-centered clinical decision making. We describe a novel tool to predict 30-day major morbidity and mortality (M&M) after bypass surgery for CLI. Data for 4985 individuals from the 2007 to 2009 National Surgical Quality Improvement Program were used to develop and internally validate the model. Outcome measures included mortality, major morbidity, and a composite end point (M&M). M&M included mortality and the most severe postoperative morbidities that were highly associated with death (eg, sepsis and major cardiopulmonary complications). More than 30 preoperative factors were tested for association with 30-day mortality, major morbidity, and M&M. Significant predictors in multivariate models were assigned integer values (points), which were added to calculate a patient's Comprehensive Risk Assessment For Bypass (CRAB) score. Performance was assessed (C-index) across all outcome measures and compared with other general tools (American Society of Anesthesiologists class, Surgical Risk Scale) and existing CLI-specific survival prediction models (Finnvasc score, Edifoligide for the Prevention of Infrainguinal Vein Graft Failure [PREVENT III] score) on a distinct validation sample (n = 1620). In the derivation data set (n = 3275), the 30-day mortality rate was 2.9%. The rate of any major morbidity was 19.1%. The composite end point M&M occurred in 10.1%. Significant predictors of M&M by multivariate analysis included age >75 years, prior amputation or revascularization, tissue loss, dialysis dependence, severe cardiac disease, emergency operation, and functional dependence. Applied to a distinct validation sample of 1620 patients, higher CRAB scores were significantly associated with higher rates of mortality, all major morbidities, and M&M (P < .0001). Comparison with other models by assessment of area under the receiver-operating characteristic curve revealed the CRAB was a more accurate predictor of mortality, all major morbidity, and M&M. The CRAB is a CLI-specific, risk assessment instrument derived from multi-institutional American College of Surgeons-National Surgical Quality Improvement Program surgical outcomes data that out-performs existing prognostic risk indices in the prediction of clinically significant adverse events after bypass surgery. Use of the CRAB as a risk assessment tool provides an evidence basis for patient-centered clinical decision making and may have a role in identifying patients at higher risk for surgical revascularization in whom an endovascular approach is preferable. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Atherectomy offers no benefits over balloon angioplasty in tibial interventions for critical limb ischemia.

PubMed

Todd, Kevin E; Ahanchi, Sadaf S; Maurer, Christian A; Kim, Jung H; Chipman, Candice R; Panneton, Jean M

2013-10-01

Endovascular adjuncts, like atherectomy, were developed to improve outcomes of endovascular arterial interventions. The true impact of atherectomy on endovascular outcomes remains to be determined, and little data exist on the influence of atherectomy on tibial interventions. Our study compares early and late outcomes of tibial intervention with angioplasty vs atherectomy-assisted interventions. We completed a retrospective review of all tibial interventions between 2008 and 2010. Outcomes were analyzed using single and multivariate analysis, Cox regression, and Kaplan-Meier curves. Primary outcomes were primary, primary assisted, and secondary patency rates, as well as limb salvage and survival rates. Over a 2-year period, 480 tibial interventions were completed for 421 patients. Eighty-seven percent (n = 418) of interventions were performed for critical limb ischemia (CLI) and 13% (n = 62) for claudication. The CLI cohort of 418 interventions was analyzed. These patients had a mean age of 71 years with a mean follow-up time of 16 ± 15 months (range, 0-59 months). Of the 418 interventions, 339 underwent percutaneous transluminal angioplasty (PTA): 333 PTA alone, six PTA + stent. The remaining 79 interventions received atherectomy: 33 laser, 13 directional, and 33 orbital either alone or in conjunction with PTA (11 atherectomy only, 68 atherectomy + PTA). The groups did not differ significantly in terms of demographics, risk factors, or technical success. The atherectomy group had more TASC B lesions (54% vs 38%; P = .013), while the PTA-alone group had more TASC D lesions (25% vs 13%; P = .004). TASC A and C lesions did not differ significantly between the groups. No significant differences existed with respect to the early (30-day) outcomes of loss of patency (11% vs 13%; P = .699), complications (8% vs 13%; P = .292), or major amputation (17% vs 13%; P = .344) in the PTA-alone group vs the atherectomy-assisted group. Kaplan-Meier analysis revealed no difference for all primary outcomes of PTA alone vs the atherectomy-assisted group at 12 and 36 months: primary patency (69%, 55% vs 61%, 46%; P = .158), primary assisted patency (83%, 71% vs 85%, 67%; P = .801), secondary patency (94%, 89% vs 95%, 89%; P = .892), limb salvage (79%, 70% vs 81%, 77%; P = .485), or survival (77%, 56% vs 80%, 50%; P = .944). The adjunctive use of atherectomy offered no improvement in primary outcomes over PTA alone in either early or late outcomes in CLI patients who underwent endovascular tibial interventions. Considering the additional cost and increased procedural time, these findings put into question the routine use of adjunctive atherectomy. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gandini, Roberto; Pipitone, Vincenzo; Stefanini, Matteo

The purpose of this study was to describe the efficacy of planned combined subintimal arterial flossing with antegrade-retrograde intervention (SAFARI) to obtain the precise recanalization of the patent portion of a distal runoff vessel in critical limb ischemia (CLI) patients presenting long occlusions involving the popliteal trifurcation. Four patients at risk of limb loss due to long occlusions involving the leg vessel tree and not suitable for a surgical bypass were treated by the subintimal antegrade and retrograde (posterior tibial or anterior tibial artery) approach. The patent portion of the runoff vessel was previously assessed by magnetic resonance angiography (MRA)more » and directly punctured under Doppler ultrasound (US) guidance. A subintimal channel rendezvous was performed to allow snaring of the guidewires. Subsequently, a balloon dilatation was performed without stent deployment. All patients were successfully recanalized and had complete healing of the limb lesions. At the 12-month follow-up all patients showed clinical improvement with no major complications related to the procedure. This combined antegrade and retrograde subintimal approach is currently an excellent endovascular option in patients with long occlusions extending onto the leg vessels trifurcation and at risk of limb loss.« less

A safety and feasibility report of combined direct thrombin and GP IIb/IIIa inhibition with bivalirudin and tirofiban in peripheral vascular disease intervention: treating critical limb ischemia like acute coronary syndrome.

PubMed

Allie, David E; Hebert, Chris J; Lirtzman, Mitchell D; Wyatt, Charles H; Keller, V Antoine; Khan, Mohamed H; Khan, Muhammad A; Fail, Peter S; Vivekananthan, Krishnamoorthy; Allie, Sonja E; Mitran, Elena V; Chaisson, Gary; Stagg, Samuel J; Allie, Adam A; McElderry, Michael W; Barker, Esmond A; Walker, Craig M

2005-08-01

The combination of glycoprotein (GP) IIb-IIIa inhibition and direct thrombin inhibition (DTI) with bivalirudin (Angiomax, The Medicines Company, Cambridge, Massachusetts) have shown ischemic and hemorrhagic outcomes benefit in coronary interventions and may have similar benefits in percutaneous peripheral interventions (PPI). The high incidence of diabetes, chronic renal disease, platelet dysfunction, hypercoagulability, inflammation and a thrombus-rich environment make a GP IIb-IIIa and DTI combination with tirofiban (Aggrastat Merck and Company, Inc., Whitehouse Station, New Jersey) an attractive anticoagulation strategy in the PPI treatment of critical limb ischemia (CLI). Between May 1, 2001 and January 31, 2003, a CLI treatment group of 149 patients received PPI with bivalirudin (0.75 mg per kg bolus with 1.75 mg per kg per hour periprocedural infusion) and tirofiban (10 mcg per kg per minute bolus with 12-hour 0.1 mcg per kg per minute infusion) as an anticoagulation and antiplatelet strategy, and were compared to a matched unfractionated heparin (UFH) control group without GP IIb-IIIa inhibitors. Clinical and hemostasis outcomes were analyzed, including distal embolization (DE). Procedural success was 95.9% and 97.3% in the UFH control group and DTI-GP IIb-IIIa group, respectively. Significant differences were observed in the sheath removal time < 2 hours (60.5% UFH group versus 19.4% DTI-GP IIb-IIIa group; p = < 0.0001). Vascular closure devices were used equally in both groups. No statistical significance was observed in major and minor complications, femoral access complications, acute (< 48 hours) or subacute (30 days) vessel thrombosis, and 6-month duplex ultrasound restenosis rate between the DTI-GP IIb-IIIa versus the UFH group. A trend towards statistical significance was observed in the 6-month secondary re-intervention and limb salvage rates (10.7% versus 18.8%; p = 0.0501 and 93.9% versus 88.5%; p = 0.053) in the DTI-GP IIb-IIIa versus the UFH group, respectively. Angiographically relevant DE occurred in 4 of 149 (1.3%) and 8 of 149 (5.4%) of the bivalirudin-tirofiban and UFH groups, respectively. The combination of DTI with bivalirudin and GP IIb-IIIa inhibition with tirofiban is a safe and feasible alternative anticoagulation and antiplatelet strategy in PPI, and may offer improved clinical and hemostasis outcomes in treating CLI. A larger, prospective randomized trial is warranted.

Validation of the Wound, Ischemia, foot Infection (WIfI) classification system in nondiabetic patients treated by endovascular means for critical limb ischemia.

PubMed

Beropoulis, Efthymios; Stavroulakis, Konstantinos; Schwindt, Arne; Stachmann, Arne; Torsello, Giovanni; Bisdas, Theodosios

2016-07-01

The Society for Vascular Surgery Lower Extremity Guidelines Committee developed the Wound, Ischemia, foot Infection (WIfI) a classification system to predict the amputation risk in patients with critical limb ischemia (CLI). A number of published studies have already evaluated its prognostic value. However, most of the included patients were diabetic, and the validation was done independent of the revascularization procedure. This single-center study evaluated the prognostic value of WIfI stages in nondiabetic patients treated by endovascular means. A retrospective analysis was performed of prospectively collected data of nondiabetic patients treated by endovascular means between January 2013 and September 2014. All patients were classified according to their wound status, ischemia index, and extent of foot infection to four classes: very low risk, low risk, moderate risk, and high risk. Comorbidities and vascular lesions for each group were analyzed. The prognostic value of WIfI was analyzed based on the amputation-free survival, overall survival rate, and freedom from amputation at 12 months. Data from 302 CLI patients treated in the study period were reviewed. A total of 219 patients (73%) underwent an endovascular intervention, and among them, 126 nondiabetic patients (58%) were enrolled in this study. Most patients were classified as low risk (33%), and the prevalence of very low-risk, moderate-risk, and very high-risk patients was 23%, 23%, and 21%, respectively. The modified Edifoligide for the Prevention of Infrainguinal Vein Graft Failure (PREVENT III) score was statistically significantly higher in the high-risk group (5.2 ± 2.4) than in the very low-risk, low-risk, and moderate-risk groups (4.3 ± 2.5, 3.5 ± 2.3, 4.5 ± 2.2, respectively; P = .048). One major amputation (1%) was performed during the hospital stay in a high-risk patient. Mean follow-up was 14 ± 8 months. The amputation-free survival at 12 months was 87%, 81%, 81%, and 62%, in the very low-risk, low-risk, moderate risk, and very high-risk groups, respectively (P = .106). The difference was statistically significant between the very low-risk and high-risk groups (hazard ratio, 3.4; 95% confidence interval, 1.1-10.3; P = .029). A similar trend was also observed for 1-year survival between the very low-risk and the high-risk groups (87%, 84%, 81%, 65%; P = .166). The amputation rate during the follow-up time was 0%, 2% (n = 6), 3% (n = 5), and 12% (n = 9) for the very low-risk, low-risk, moderate-risk, and very high-risk groups, respectively (P = .033). The WIfI classification system predicted the amputation risk and survival in this highly selected group of nondiabetic CLI patients treated by endovascular means, with a statistically significant difference between very low-risk and high-risk patients already at 1 year. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Transluminal Angioplasty of Peroneal Artery Branches in Diabetics: Initial Technical Experience

DOE Office of Scientific and Technical Information (OSTI.GOV)

Graziani, Lanfroi, E-mail: langrazi@tin.it; Silvestro, Antonio; Monge, Luca

2008-01-15

The present study aimed to report the technical feasibility of percutaneous transluminal angioplasty (PTA) of obstructed or insufficient collateral branches (anterior and posterior perforating branches) from distal peroneal to foot arteries in diabetic patients with chronic critical limb ischemia (CLI) and chronic noncrossable occlusion of the anterior and posterior tibial arteries. Twenty-four diabetic CLI patients (age, 67 {+-} 8 years; 87% males) undergoing collateral PTA were included. Baseline clinical angiographic and follow-up data were retrospectively reviewed. Collateral PTA was associated with a concomitant PTA of other sites in 21 (83%) cases. In 15 cases the treated collateral linked the peronealmore » with the plantaris communis; in 9 cases, the peroneal with the dorsalis pedis. Angiographic results of collateral PTA were good in 13 cases (<30% residual stenosis), whereas the result was considered moderate (30%-49% residual stenosis) in the remaining cases. Neither perforation nor acute occlusion of the treated collaterals or other relevant complications were observed. Mean follow-up was 32 {+-} 17 months. Major amputation was necessary for two (8.3%) patients. Cumulative limb salvage rates at 2 and 4 years were 96% and 87%, respectively. In conclusion, this initial experience shows that PTA of the collateral branches from distal peroneal to foot arteries is a feasible technique. Future studies are required to define the clinical role of this novel approach.« less

AMS INSIGHT--absorbable metal stent implantation for treatment of below-the-knee critical limb ischemia: 6-month analysis.

PubMed

Bosiers, Marc; Peeters, Patrick; D'Archambeau, Olivier; Hendriks, Jeroen; Pilger, Ernst; Düber, Christoph; Zeller, Thomas; Gussmann, Andreas; Lohle, Paul N M; Minar, Erich; Scheinert, Dierk; Hausegger, Klaus; Schulte, Karl-Ludwig; Verbist, Jürgen; Deloose, Koen; Lammer, J

2009-05-01

Endoluminal treatment of infrapopliteal artery lesions is a matter of controversy. Bioabsorbable stents are discussed as a means to combine mechanical prevention of vessel recoil with the advantages of long-term perspectives. The possibility of not having a permanent metallic implant could permit the occurrence of positive remodeling with lumen enlargement to compensate for the development of new lesions. The present study was designed to investigate the safety of absorbable metal stents (AMSs) in the infrapopliteal arteries based on 1- and 6-month clinical follow-up and efficacy based on 6-month angiographic patency. One hundred seventeen patients with 149 lesions with chronic limb ischemia (CLI) were randomized to implantation of an AMS (60 patients, 74 lesions) or stand-alone percutaneous transluminal angioplasty (PTA; 57 patients, 75 lesions). Seven PTA-group patients "crossed over" to AMS stenting. The study population consisted of patients with symptomatic CLI (Rutherford categories 4 and 5) and de novo stenotic (>50%) or occlusive atherosclerotic disease of the infrapopliteal arteries who presented with a reference diameter of between 3.0 and 3.5 mm and a lesion length of <15 mm. The primary safety endpoint was defined as absence of major amputation and/or death within 30 days after index intervention and the primary efficacy endpoint was the 6-month angiographic patency rate as confirmed by core-lab quantitative vessel analysis. The 30-day complication rate was 5.3% (3/57) and 5.0% (3/60) in patients randomized for PTA alone and PTA followed by AMS implantation, respectively. On an intention-to-treat basis, the 6-month angiographic patency rate for lesions treated with AMS (31.8%) was significantly lower (p = 0.013) than the rate for those treated with PTA (58.0%). Although the present study indicates that the AMS technology can be safely applied, it did not demonstrate efficacy in long-term patency over standard PTA in the infrapopliteal vessels.

Transpedal access after failed anterograde recanalization of complex below-the-knee and femoropoliteal occlusions in critical limb ischemia.

PubMed

Ruzsa, Zoltán; Nemes, Balázs; Bánsághi, Zoltán; Tóth, Károly; Kuti, Ferenc; Kudrnova, Slavka; Berta, Balázs; Hüttl, Kálmán; Merkely, Béla

2014-05-01

Successful angioplasty is one of the main factor of limb salvage during critical limb ischemia. In complex femoropopliteal to infrapopliteal occlusions, an anterograde recanalization attempt can fail in up to 20% of the cases. The purpose of this dual center pilot study was to evaluate the acute success and clinical impact of retrograde transpedal access for retrograde below-the-knee and femoropopliteal chronic total occlusions after failed anterograde attempt and to access the late complications at the puncture site. The clinical and angiographic data of 51 consecutive patients with CLI treated by retrograde transpedal recanalization between 2010 and 2011 were evaluated in a pilot study. We have examined the 2-month and 1 year major adverse events (MAEs) and clinical success. In all cases after failure of the anterograde recanalization of occluded below-the-knee segments due to unsuccessful penetration or failed re-entry, the anterior tibial or posterior tibial artery was punctured under fluoroscopic guidance and retrograde recanalization was performed. Direct revascularization was tried firstly following the angiographic zones, but in failed cases indirect revascularization was carried out with increasing the collateral flow to the wound. Successful direct retrograde revascularization was achieved successfully in 40 patients (78.4%) and indirect revascularization was done in 10 patients (19.6%). Revascularization was failed in one patient (2%). MAE at 2 and 12 months follow-up was 6 (11.7%) and 11 (24%). Limb salvage at 2 and 12 months was 93% and 82.3%, respectively. Balloon angioplasty was performed in all interventions and provisional stenting was done in 34 patients (66.7%). One major and three minor vascular complications occurred after the procedure. The mean basal and control creatinine level was 120.9 ± 133.4 and 123.8 ± 131.3 μmol/L (P = 0.83) after the procedure. Failed antegrade attempts to recanalize CTO-s of femoropopliteal and infrapopliteal vessels can be salvaged using a retrograde transpedal access, with a low acute and late complication rate. This technique could be valuable for patients with critical limb ischemia due to femoropopliteal and infrapopliteal occlusions. Copyright © 2013 Wiley Periodicals, Inc.

Traditional and nontraditional glycemic markers and risk of peripheral artery disease: The Atherosclerosis Risk in Communities (ARIC) study.

PubMed

Ding, Ning; Kwak, Lucia; Ballew, Shoshana H; Jaar, Bernard; Hoogeveen, Ron C; Ballantyne, Christie M; Sharrett, A Richey; Folsom, Aaron R; Heiss, Gerardo; Salameh, Maya; Coresh, Josef; Hirsch, Alan T; Selvin, Elizabeth; Matsushita, Kunihiro

2018-04-30

Traditional glycemic markers, fasting glucose and hemoglobin A1c (HbA1c), predict incident peripheral artery disease (PAD). However, it is unknown whether nontraditional glycemic markers, fructosamine, glycated albumin, and 1,5-anhydroglucitol, are associated with PAD and whether these glycemic markers demonstrate particularly strong associations with severe PAD, critical limb ischemia (CLI). We quantified the associations of these five glycemic markers with incident PAD (hospitalizations with PAD diagnosis or leg revascularization) in 11,634 ARIC participants using Cox regression models. Participants were categorized according to diabetes diagnosis and clinical cut-points of glycemic markers (nontraditional glycemic markers were categorized according to percentiles corresponding to the HbA1c cut-points). Over a median follow-up of 20.7 years, there were 392 cases of PAD (133 were CLI with tissue loss). HbA1c was more strongly associated with incident PAD than fasting glucose, with adjusted hazard ratios (HR) 6.00 (95% CI, 3.73-9.66) for diagnosed diabetes with HbA1c ≥ 7% and 3.53 (2.39-5.22) for no diagnosed diabetes with HbA1c ≥ 6.5% compared to no diagnosed diabetes with HbA1c <5.7%. Three nontraditional glycemic markers demonstrated risk gradients intermediate between HbA1c and fasting glucose and their risk gradients were substantially attenuated after adjusting for HbA1c. All glycemic markers consistently demonstrated stronger associations with CLI than PAD without CLI (p for difference <0.02 for all glycemic markers). Nontraditional glycemic markers were associated with incident PAD independent of fasting glucose but not necessarily HbA1c. Our results also support the importance of glucose metabolism in the progression to CLI. Copyright © 2018 Elsevier B.V. All rights reserved.

Decline in Antarctic Ozone Depletion and Lower Stratospheric Chlorine Determined From Aura Microwave Limb Sounder Observations

NASA Astrophysics Data System (ADS)

Strahan, Susan E.; Douglass, Anne R.

2018-01-01

Attribution of Antarctic ozone recovery to the Montreal protocol requires evidence that (1) Antarctic chlorine levels are declining and (2) there is a reduction in ozone depletion in response to a chlorine decline. We use Aura Microwave Limb Sounder measurements of O3, HCl, and N2O to demonstrate that inorganic chlorine (Cly) from 2013 to 2016 was 223 ± 93 parts per trillion lower in the Antarctic lower stratosphere than from 2004 to 2007 and that column ozone depletion declined in response. The mean Cly decline rate, 0.8%/yr, agrees with the expected rate based on chlorofluorocarbon lifetimes. N2O measurements are crucial for identifying changes in stratospheric Cly loading independent of dynamical variability. From 2005 to 2016, the ozone depletion and Cly time series show matching periods of decline, stability, and increase. The observed sensitivity of O3 depletion to changing Cly agrees with the sensitivity simulated by the Global Modeling Initiative chemistry transport model integrated with Modern Era Retrospective Analysis for Research and Applications 2 meteorology.

The Society for Vascular Surgery's objective performance goals for lower extremity revascularization are not generalizable to many open surgical bypass patients encountered in contemporary surgical practice.

PubMed

Saraidaridis, Julia T; Ergul, Emel; Patel, Virendra I; Stone, David H; Cambria, Richard P; Conrad, Mark F

2015-08-01

In 2009, the Society for Vascular Surgery (SVS) established objective performance goals (OPG) for lower extremity bypass (LEB) in patients with critical limb ischemia (CLI) based on pooled data from previously performed prospective studies in an effort to provide a benchmark and historical control for future trials. However, patients with a prosthetic conduit and end-stage renal disease were excluded from this cohort. In contemporary practice, many patients do not meet the criteria for SVS OPG inclusion, making generalization of the SVS OPG difficult. The goal of this study was to establish safety and efficacy measures for patients who were excluded from the original SVS OPG analysis. All patients who underwent LEB for CLI in the Vascular Study Group of New England (VSGNE) from 2003 to 2013 were identified. Patients were stratified into OPG-eligible and non-OPG-eligible cohorts. Outcomes included 30-day major adverse limb events, 30-day major adverse cardiovascular events, 1-year survival, and 1-year freedom from amputation. The SVS OPG methodology was used to create new performance goals for the non-OPG-eligible patients. We identified 3609 patients: 2360 OPG (65%) vs 1249 non-OPG (35%), and overall results were stratified as a function of OPG status. The 30-day major adverse limb event rate was 5.0% (5.5% non-OPG vs 4.4% OPG; P = .34), and the 30-day major adverse cardiovascular event rate was 7.3% (9.2% non-OPG vs 6.2% OPG; P = .001). At 1 year, survival was 84% (75.9% non-OPG vs 88.3% OPG; P < .001), and freedom from amputation was 86.9% (80.9% non-OPG vs 90.1% OPG; P < .001). The SVS OPG were attainable in New England for the population of patients who would have met SVS OPG study cohort inclusion criteria. However, 35% of the patients who underwent LEB for CLI in the last 10 years fell outside of these criteria by having end-stage renal disease or requiring a prosthetic conduit. We therefore suggest new benchmarks for these high-risk populations. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Diagnostic performance and radiation dose of lower extremity CT angiography using a 128-slice dual source CT at 80 kVp and high pitch.

PubMed

Kim, Jin Woo; Choo, Ki Seok; Jeon, Ung Bae; Kim, Tae Un; Hwang, Jae Yeon; Yeom, Jeong A; Jeong, Hee Seok; Choi, Yoon Young; Nam, Kyung Jin; Kim, Chang Won; Jeong, Dong Wook; Lim, Soo Jin

2016-07-01

Multi-detector computed tomography (MDCT) angiography is now used for the diagnosing patients with peripheral arterial disease. The dose of radiation is related to variable factors, such as tube current, tube voltage, and helical pitch. To assess the diagnostic performance and radiation dose of lower extremity CT angiography (CTA) using a 128-slice dual source CT at 80 kVp and high pitch in patients with critical limb ischemia (CLI). Twenty-eight patients (mean, 64.1 years; range, 39-80 years) with CLI were enrolled in this retrospective study and underwent CTA using a 128-slice dual source CT at 80 kVp and high pitch and subsequent intra-arterial digital subtraction angiography (DSA), which was used as a reference standard for assessing diagnostic performance. For arterial segments with significant disease (>50% stenosis), overall sensitivity, specificity, and accuracy of lower extremity CTA were 94.8% (95% CI, 91.7-98.0%), 91.5% (95% CI, 87.7-95.2%), and 93.1% (95% CI, 90.6-95.6%), respectively, and its positive and negative predictive values were 91.0% (95% CI, 87.1-95.0%), and 95.1% (95% CI, 92.1-98.1%), respectively. Mean radiation dose delivered to lower extremities was 266.6 mGy.cm. Lower extremity CTA using a 128-slice dual source CT at 80 kVp and high pitch was found to have good diagnostic performance for the assessment of patients with CLI using an extremely low radiation dose. © The Foundation Acta Radiologica 2015.

The Aortic Bifurcation Angle as a Factor in Application of the Outback for Femoropopliteal Lesions in Ipsilateral Versus Contralateral Approaches.

PubMed

Raskin, Daniel; Khaitovich, Boris; Balan, Shmuel; Silverberg, Daniel; Halak, Moshe; Rimon, Uri

2018-01-01

To assess the technical success of the Outback reentry device in contralateral versus ipsilateral approaches for femoropopliteal arterial occlusion. A retrospective review of patients treated for critical limb ischemia (CLI) using the Outback between January 2013 and July 2016 was performed. Age, gender, length and site of the occlusion, approach site, aortic bifurcation angle, and reentry site were recorded. Calcification score was assigned at both aortic bifurcation and reentry site. Technical success was assessed. During the study period, a total of 1300 endovascular procedures were performed on 489 patients for CLI. The Outback was applied on 50 femoropopliteal chronic total occlusions. Thirty-nine contralateral and 11 ipsilateral antegrade femoral were accessed. The device was used successfully in 41 patients (82%). There were nine failures, all in the contralateral approach group. Six due to inability to deliver the device due to acute aortic bifurcation angle and three due to failure to achieve luminal reentry. Procedural success was significantly affected by the aortic bifurcation angle (p = 0.013). The Outback has high technical success rates in treatment of femoropopliteal occlusion, when applied from either an ipsi- or contralateral approach. When applied in contralateral access, acute aortic bifurcation angle predicts procedural failure.

The chaos of hospitalisation for patients with Critical Limb Ischaemia approaching major amputation.

PubMed

Monaro, Susan; West, Sandra; Pinkova, Jana; Gullick, Janice

2018-05-18

To illuminate the hospital experience for patients and families when major amputation has been advised for critical limb ischaemia (CLI). CLI creates significant burden to the health system and the family, particularly as the person with CLI approaches amputation. Major amputation is often offered as a late intervention for CLI in response to the marked deterioration of an ischaemic limb, and functional decline from reduced mobility, intractable pain, infection and/or toxaemia. While a wealth of clinical outcome data on CLI and amputation exists internationally, little is known about the patient/ family-centred experience of hospitalisation to inform preservation of personhood and patient-centred care-planning. Longitudinal qualitative study using Heideggerian Phenomenology. 14 patients and 13 family carers provided a semi-structured interview after advice for major amputation. Where amputation followed, a second interview (6-months post-procedure) was provided by eight patients and seven family carers. Forty-two semi-structured interviews were audio-recorded and transcribed verbatim. Hermeneutic phenomenological analysis followed. Hospitalisation for CLI, with or without amputation, created a sense of chaos, characterised by being fragile and needing more time for care (fragile body and fragile mind, nurse busyness, and carer hyper-vigilance), being adrift within uncontrollable spaces (noise, unreliable space, precarious accommodation and unpredictable scheduling), and being confused by missed and mixed messages (multiple stakeholders, information overload, and cultural/linguistic diversity). Patients and families need a range of strategies to assist mindful decision-making in preparation for amputation in what for them is a chaotic process occurring within a chaotic environment. Cognitive deficits increase the care complexity and burden of family advocacy. A co-ordinated, interprofessional response should improve systems for communication, family engagement, operation scheduling and discharge-planning to support preparation, adjustment and allow a sense of safety to develop. Formal peer-support for patients and caregivers should be actively facilitated. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The LIBERTY study: Design of a prospective, observational, multicenter trial to evaluate the acute and long-term clinical and economic outcomes of real-world endovascular device interventions in treating peripheral artery disease.

PubMed

Adams, George L; Mustapha, Jihad; Gray, William; Hargus, Nick J; Martinsen, Brad J; Ansel, Gary; Jaff, Michael R

2016-04-01

Most peripheral artery disease (PAD) clinical device trials are supported by commercial manufacturers and designed for regulatory device approval, with extensive inclusion/exclusion criteria to support homogeneous patient populations. High-risk patients with advanced disease, including critical limb ischemia (CLI), are often excluded leading to difficulty in translating trial results into real-world clinical practice. As a result, physicians have no direct guidance regarding the use of endovascular devices. There is a need for objectively assessed studies to evaluate clinical, functional, and economic outcomes in PAD patient populations. LIBERTY is a prospective, observational, multicenter study sponsored by Cardiovascular Systems Inc (St Paul, MN) to evaluate procedural and long-term clinical and economic outcomes of endovascular device interventions in patients with symptomatic lower extremity PAD. Approximately 1,200 patients will be enrolled and followed up to 5 years: 500 patients in the "Claudicant Rutherford 2-3" arm, 600 in the "CLI Rutherford 4-5" arm, and 100 in the "CLI Rutherford 6" arm. The study will use 4 core laboratories for independent analysis and will evaluate the following: procedural and lesion success, rates of major adverse events, duplex ultrasound interpretations, wound status, quality of life, 6-minute walk test, and economic analysis. The LIBERTY Patient Risk Score(s) will be developed as a clinical predictor of outcomes to provide guidance for interventions in this patient population. LIBERTY will investigate real-world PAD patients treated with endovascular revascularization with rigorous study guidelines and independent oversight of outcomes. This study will provide observational, all-comer patient clinical data to guide future endovascular therapy. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Prior contralateral amputation predicts worse outcomes for lower extremity bypasses performed in the intact limb.

PubMed

Baril, Donald T; Goodney, Philip P; Robinson, William P; Nolan, Brian W; Stone, David H; Li, YouFu; Cronenwett, Jack L; Schanzer, Andres

2012-08-01

To date, history of a contralateral amputation as a potential predictor of outcomes after lower extremity bypass (LEB) for critical limb ischemia (CLI) has not been studied. We sought to determine if a prior contralateral lower extremity amputation predicts worse outcomes in patients undergoing LEB in the remaining intact limb. A retrospective analysis of all patients undergoing infrainguinal LEB for CLI between 2003 and 2010 within hospitals comprising the Vascular Study Group of New England was performed. Patients were stratified according to whether or not they had previously undergone a contralateral major or minor amputation before LEB. Primary end points included major amputation and graft occlusion at 1 year postoperatively. Secondary end points included in-hospital major adverse events, discharge status, and mortality at 1 year. Of 2636 LEB procedures, 228 (8.6%) were performed in the setting of a prior contralateral amputation. Patients with a prior amputation compared to those without were younger (66.5 vs 68.7; P = .034), more like to have congestive heart failure (CHF; 25% vs 16%; P = .002), hypertension (94% vs 85%; P = .015), renal insufficiency (26% vs 14%; P = .0002), and hemodialysis-dependent renal failure (14% vs 6%; P = .0002). They were also more likely to be nursing home residents (8.0% vs 3.6%; P = .036), less likely to ambulate without assistance (41% vs 80%; P < .0002), and more likely to have had a prior ipsilateral bypass (20% vs 12%; P = .0005). These patients experience increased in-hospital major adverse events, including myocardial infarction (MI; 8.9% vs 4.2%; P = .002), CHF (6.1% vs 3.4%; P = .044), deterioration in renal function (9.0% vs 4.7%; P = .006), and respiratory complications (4.2% vs 2.3%; P = .034). They were less likely to be discharged home (52% vs 72%; P < .0001) and less likely to be ambulatory on discharge (25% vs 55%; P < .0001). Although patients with a prior contralateral amputation experienced increased rates of graft occlusion (38% vs 17%; P < .0001) and major amputation (16% vs 7%; P < .0001) at 1 year, there was not a significant difference in mortality (16% vs 10%; P = .160). On multivariable analysis, prior contralateral amputation was an independent predictor of both major amputation (odds ratio, 1.73; confidence interval, 1.06-2.83; P = .027) and graft occlusion (odds ratio, 1.93; confidence interval, 1.39-2.68; P < .0001) at 1 year. Patients with prior contralateral amputations who present with CLI in the intact limb represent a high-risk population, even among patients with advanced peripheral arterial disease. When considering LEB in this setting, both physicians and patients should expect increased rates of perioperative adverse events, increased rates of 1-year graft occlusion, and decreased rates of limb salvage, when compared with patients who have not undergone a contralateral amputation. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Prior contralateral amputation predicts worse outcomes for lower extremity bypasses performed in the intact limb

PubMed Central

Baril, Donald T.; Goodney, Philip P.; Robinson, William P.; Nolan, Brian W.; Stone, David H.; Li, YouFu; Cronenwett, Jack L.; Schanzer, Andres

2013-01-01

Introduction To date, history of a contralateral amputation as a potential predictor of outcomes after lower extremity bypass (LEB) for critical limb ischemia (CLI) has not been studied. We sought to determine if a prior contralateral lower extremity amputation predicts worse outcomes in patients undergoing LEB in the remaining intact limb. Methods A retrospective analysis of all patients undergoing infrainguinal LEB for CLI between 2003 and 2010 within hospitals comprising the Vascular Study Group of New England was performed. Patients were stratified according to whether or not they had previously undergone a contralateral major or minor amputation before LEB. Primary end points included major amputation and graft occlusion at 1 year postoperatively. Secondary end points included in-hospital major adverse events, discharge status, and mortality at 1 year. Results Of 2636 LEB procedures, 228 (8.6%) were performed in the setting of a prior contralateral amputation. Patients with a prior amputation compared to those without were younger (66.5 vs 68.7; P = .034), more like to have congestive heart failure (CHF; 25% vs 16%; P = .002), hypertension (94% vs 85%; P = .015), renal insufficiency (26% vs 14%; P = .0002), and hemodialysis-dependent renal failure (14% vs 6%; P = .0002). They were also more likely to be nursing home residents (8.0% vs 3.6%; P = .036), less likely to ambulate without assistance (41% vs 80%; P < .0002), and more likely to have had a prior ipsilateral bypass (20% vs 12%; P = .0005). These patients experience increased in-hospital major adverse events, including myocardial infarction (MI; 8.9% vs 4.2%; P = .002), CHF (6.1% vs 3.4%; P = .044), deterioration in renal function (9.0% vs 4.7%; P = .006), and respiratory complications (4.2% vs 2.3%; P = .034). They were less likely to be discharged home (52% vs 72%; P < .0001) and less likely to be ambulatory on discharge (25% vs 55%; P < .0001). Although patients with a prior contralateral amputation experienced increased rates of graft occlusion (38% vs 17%; P < .0001) and major amputation (16% vs 7%; P < .0001) at 1 year, there was not a significant difference in mortality (16% vs 10%; P = .160). On multivariable analysis, prior contralateral amputation was an independent predictor of both major amputation (odds ratio, 1.73; confidence interval, 1.06–2.83; P = .027) and graft occlusion (odds ratio, 1.93; confidence interval, 1.39–2.68; P < .0001) at 1 year. Conclusions Patients with prior contralateral amputations who present with CLI in the intact limb represent a high-risk population, even among patients with advanced peripheral arterial disease. When considering LEB in this setting, both physicians and patients should expect increased rates of perioperative adverse events, increased rates of 1-year graft occlusion, and decreased rates of limb salvage, when compared with patients who have not undergone a contralateral amputation. PMID:22480762

A nationwide analysis of 30-day readmissions related to critical limb ischemia.

PubMed

Masoomi, Reza; Shah, Zubair; Quint, Clay; Hance, Kirk; Vamanan, Karthik; Prasad, Anand; Hoel, Andrew; Dawn, Buddhadeb; Gupta, Kamal

2018-06-01

Objectives There is paucity of information regarding critical limb ischemia-related readmission rates in patients admitted with critical limb ischemia. We studied 30-day critical limb ischemia-related readmission rate, its predictors, and clinical outcomes using a nationwide real-world dataset. Methods We did a secondary analysis of the 2013 Nationwide Readmissions Database. We included all patients with a primary diagnosis of extremity rest pain, ulceration, and gangrene secondary to peripheral arterial disease. From this group, all patients readmitted with similar diagnosis within 30 days were recorded. Results Of the total 25,111 index hospitalization for critical limb ischemia, 1270 (5%) were readmitted with a primary diagnosis of critical limb ischemia within 30 days. The readmission rate was highest (9.5%) for the group that did not have any intervention (revascularization or major amputation) and was lowest for surgical revascularization and major amputation groups (2.6% and 1.3%, P value <0.001 for all groups). Severity of critical limb ischemia at index admission was associated with a significantly higher rate of 30-day readmission. Critical limb ischemia-related readmission was associated with a higher rate of major amputation (29.6% vs. 16.2%, P<0.001), a lower rate of any revascularization procedure (46% vs. 62.6%, P<0.001), and a higher likelihood of discharge to a skilled nursing facility (43.2% vs. 32.2%, P<0.001) compared to index hospitalization. Conclusions In patients with primary diagnosis of critical limb ischemia, 30-day critical limb ischemia-related readmission rate was affected by initial management strategy and the severity of critical limb ischemia. Readmission was associated with a significantly higher rate of amputation, increased length of stay, and a more frequent discharge to an alternate care facility than index admission and thus may serve as a useful quality of care metric in critical limb ischemia patients.

Distributed vasculogenesis from modular agarose-hydroxyapatite-fibrinogen microbeads.

PubMed

Rioja, Ana Y; Daley, Ethan L H; Habif, Julia C; Putnam, Andrew J; Stegemann, Jan P

2017-06-01

Critical limb ischemia impairs circulation to the extremities, causing pain, disrupted wound healing, and potential tissue necrosis. Therapeutic angiogenesis seeks to repair the damaged microvasculature directly to restore blood flow. In this study, we developed modular, micro-scale constructs designed to possess robust handling qualities, allow in vitro pre-culture, and promote microvasculature formation. The microbead matrix consisted of an agarose (AG) base to prevent aggregation, combined with cell-adhesive components of fibrinogen (FGN) and/or hydroxyapatite (HA). Microbeads encapsulating a co-culture of human umbilical vein endothelial cells (HUVEC) and fibroblasts were prepared and characterized. Microbeads were generally 80-100µm in diameter, and the size increased with the addition of FGN and HA. Addition of HA increased the yield of microbeads, as well as the homogeneity of distribution of FGN within the matrix. Cell viability was high in all microbead types. When cell-seeded microbeads were embedded in fibrin hydrogels, HUVEC sprouting and inosculation between neighboring microbeads were observed over seven days. Pre-culture of microbeads for an additional seven days prior to embedding in fibrin resulted in significantly greater HUVEC network length in AG+HA+FGN microbeads, as compared to AG, AG+HA or AG+FGN microbeads. Importantly, composite microbeads resulted in more even and widespread endothelial network formation, relative to control microbeads consisting of pure fibrin. These results demonstrate that AG+HA+FGN microbeads support HUVEC sprouting both within and between adjacent microbeads, and can promote distributed vascularization of an external matrix. Such modular microtissues may have utility in treating ischemic tissue by rapidly re-establishing a microvascular network. Critical limb ischemia (CLI) is a chronic disease that can lead to tissue necrosis, amputation, and death. Cell-based therapies are being explored to restore blood flow and prevent the complications of CLI. In this study, we developed small, non-aggregating agarose-hydroxyapatite-fibrinogen microbeads that contained endothelial cells and fibroblasts. Microbeads were easy to handle and culture, and endothelial sprouts formed within and between microbeads. Our data demonstrates that the composition of the microbead matrix altered the degree of endothelial sprouting, and that the addition of hydroxyapatite and fibrinogen resulted in more distributed sprouting compared to pure fibrin microbeads. The microbead format and control of the matrix formulation may therefore be useful in developing revascularization strategies for the treatment of ischemic disease. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Outcomes of lower extremity bypass performed for acute limb ischemia

PubMed Central

Baril, Donald T.; Patel, Virendra I.; Judelson, Dejah R.; Goodney, Philip P.; McPhee, James T.; Hevelone, Nathanael D.; Cronenwett, Jack L.; Schanzer, Andres

2013-01-01

Objective Acute limb ischemia remains one of the most challenging emergencies in vascular surgery. Historically, outcomes following interventions for acute limb ischemia have been associated with high rates of morbidity and mortality. The purpose of this study was to determine contemporary outcomes following lower extremity bypass performed for acute limb ischemia. Methods All patients undergoing infrainguinal lower extremity bypass between 2003 and 2011 within hospitals comprising the Vascular Study Group of New England were identified. Patients were stratified according to whether or not the indication for lower extremity bypass was acute limb ischemia. Primary end points included bypass graft occlusion, major amputation, and mortality at 1 year postoperatively as determined by Kaplan-Meier life table analysis. Multivariable Cox proportional hazards models were constructed to evaluate independent predictors of mortality and major amputation at 1 year. Results Of 5712 lower extremity bypass procedures, 323 (5.7%) were performed for acute limb ischemia. Patients undergoing lower extremity bypass for acute limb ischemia were similar in age (66 vs 67; P = .084) and sex (68% male vs 69% male; P = .617) compared with chronic ischemia patients, but were less likely to be on aspirin (63% vs 75%; P < .0001) or a statin (55% vs 68%; P < .0001). Patients with acute limb ischemia were more likely to be current smokers (49% vs 39%; P < .0001), to have had a prior ipsilateral bypass (33% vs 24%; P = .004) or a prior ipsilateral percutaneous intervention (41% vs 29%; P = .001). Bypasses performed for acute limb ischemia were longer in duration (270 vs 244 minutes; P = .007), had greater blood loss (363 vs 272 mL; P < .0001), and more commonly utilized prosthetic conduits (41% vs 33%; P = .003). Acute limb ischemia patients experienced increased in-hospital major adverse events (20% vs 12%; P < .0001) including myocardial infarction, congestive heart failure exacerbation, deterioration in renal function, and respiratory complications. Patients who underwent lower extremity bypass for acute limb ischemia had no difference in rates of graft occlusion (18.1% vs 18.5%; P = .77), but did have significantly higher rates of limb loss (22.4% vs 9.7%; P < .0001) and mortality (20.9% vs 13.1%; P < .0001) at 1 year. On multivariable analysis, acute limb ischemia was an independent predictor of both major amputation (hazard ratio, 2.16; confidence interval, 1.38–3.40; P = .001) and mortality (hazard ratio, 1.41; confidence interval, 1.09–1.83; P = .009) at 1 year. Conclusions Patients who present with acute limb ischemia represent a less medically optimized subgroup within the population of patients undergoing lower extremity bypass. These patients may be expected to have more complex operations followed by increased rates of perioperative adverse events. Additionally, despite equivalent graft patency rates, patients undergoing lower extremity bypass for acute ischemia have significantly higher rates of major amputation and mortality at 1 year. PMID:23714364

Outcomes of lower extremity bypass performed for acute limb ischemia.

PubMed

Baril, Donald T; Patel, Virendra I; Judelson, Dejah R; Goodney, Philip P; McPhee, James T; Hevelone, Nathanael D; Cronenwett, Jack L; Schanzer, Andres

2013-10-01

Acute limb ischemia remains one of the most challenging emergencies in vascular surgery. Historically, outcomes following interventions for acute limb ischemia have been associated with high rates of morbidity and mortality. The purpose of this study was to determine contemporary outcomes following lower extremity bypass performed for acute limb ischemia. All patients undergoing infrainguinal lower extremity bypass between 2003 and 2011 within hospitals comprising the Vascular Study Group of New England were identified. Patients were stratified according to whether or not the indication for lower extremity bypass was acute limb ischemia. Primary end points included bypass graft occlusion, major amputation, and mortality at 1 year postoperatively as determined by Kaplan-Meier life table analysis. Multivariable Cox proportional hazards models were constructed to evaluate independent predictors of mortality and major amputation at 1 year. Of 5712 lower extremity bypass procedures, 323 (5.7%) were performed for acute limb ischemia. Patients undergoing lower extremity bypass for acute limb ischemia were similar in age (66 vs 67; P = .084) and sex (68% male vs 69% male; P = .617) compared with chronic ischemia patients, but were less likely to be on aspirin (63% vs 75%; P < .0001) or a statin (55% vs 68%; P < .0001). Patients with acute limb ischemia were more likely to be current smokers (49% vs 39%; P < .0001), to have had a prior ipsilateral bypass (33% vs 24%; P = .004) or a prior ipsilateral percutaneous intervention (41% vs 29%; P = .001). Bypasses performed for acute limb ischemia were longer in duration (270 vs 244 minutes; P = .007), had greater blood loss (363 vs 272 mL; P < .0001), and more commonly utilized prosthetic conduits (41% vs 33%; P = .003). Acute limb ischemia patients experienced increased in-hospital major adverse events (20% vs 12%; P < .0001) including myocardial infarction, congestive heart failure exacerbation, deterioration in renal function, and respiratory complications. Patients who underwent lower extremity bypass for acute limb ischemia had no difference in rates of graft occlusion (18.1% vs 18.5%; P = .77), but did have significantly higher rates of limb loss (22.4% vs 9.7%; P < .0001) and mortality (20.9% vs 13.1%; P < .0001) at 1 year. On multivariable analysis, acute limb ischemia was an independent predictor of both major amputation (hazard ratio, 2.16; confidence interval, 1.38-3.40; P = .001) and mortality (hazard ratio, 1.41; confidence interval, 1.09-1.83; P = .009) at 1 year. Patients who present with acute limb ischemia represent a less medically optimized subgroup within the population of patients undergoing lower extremity bypass. These patients may be expected to have more complex operations followed by increased rates of perioperative adverse events. Additionally, despite equivalent graft patency rates, patients undergoing lower extremity bypass for acute ischemia have significantly higher rates of major amputation and mortality at 1 year. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Is Atherectomy the Best First-Line Therapy for Limb Salvage in Patients With Critical Limb Ischemia?

PubMed Central

Loor, Gabriel; Skelly, Christopher L.; Wahlgren, Carl-Magnus; Bassiouny, Hisham S.; Piano, Giancarlo; Shaalan, Wael

2010-01-01

Objective To determine the efficacy of atherectomy for limb salvage compared with open bypass in patients with critical limb ischemia. Methods Ninety-nine consecutive bypass and atherectomy procedures performed for critical limb ischemia between January 2003 and October 2006 were reviewed. Results A total of 99 cases involving TASC C (n = 43, 44%) and D (n = 56, 56%) lesions were treated with surgical bypass in 59 patients and atherectomy in 33 patients. Bypass and atherectomy achieved similar 1-year primary patency (64% vs 63%; P = .2). However, the 1-year limb salvage rate was greater in the bypass group (87% vs 69%; P = .004). In the tissue loss subgroup, there was a greater limb salvage rate for bypass patients versus atherectomy (79% vs 60%; P = .04). Conclusions Patients with critical limb ischemia may do better with open bypass compared with atherectomy as first-line therapy for limb salvage. PMID:19640919

Cost-Effectiveness Analysis of Infrapopliteal Drug-Eluting Stents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katsanos, Konstantinos, E-mail: katsanos@med.upatras.gr; Karnabatidis, Dimitris; Diamantopoulos, Athanasios

2013-02-15

IntroductionThere are no cost-utility data about below-the-knee placement of drug-eluting stents. The authors determined the cost-effectiveness of infrapopliteal drug-eluting stents for critical limb ischemia (CLI) treatment. The event-free individual survival outcomes defined by the absence of any major events, including death, major amputation, and target limb repeat procedures, were reconstructed on the basis of two published infrapopliteal series. The first included spot Bail-out use of Sirolimus-eluting stents versus bare metal stents after suboptimal balloon angioplasty (Bail-out SES).The second was full-lesion Primary Everolimus-eluting stenting versus plain balloon angioplasty and bail-out bare metal stenting as necessary (primary EES). The number-needed-to-treat (NNT) tomore » avoid one major event and incremental cost-effectiveness ratios (ICERs) were calculated for a 3-year postprocedural period for both strategies. Overall event-free survival was significantly improved in both strategies (hazard ratio (HR) [confidence interval (CI)]: 0.68 [0.41-1.12] in Bail-out SES and HR [CI]: 0.53 [0.29-0.99] in Primary EES). Event-free survival gain per patient was 0.89 (range, 0.11-3.0) years in Bail-out SES with an NNT of 4.6 (CI: 2.5-25.6) and a corresponding ICER of 6,518 Euro-Sign (range 1,685-10,112 Euro-Sign ). Survival gain was 0.91 (range 0.25-3.0) years in Primary EES with an NNT of 2.7 (CI: 1.7-5.8) and an ICER of 11,581 Euro-Sign (range, 4,945-21,428 Euro-Sign ) per event-free life-year gained. Two-way sensitivity analysis showed that stented lesion length >10 cm and/or DES list price >1000 Euro-Sign were associated with the least economically favorable scenario in both strategies. Both strategies of bail-out SES and primary EES placement in the infrapopliteal arteries for CLI treatment exhibit single-digit NNT and relatively low corresponding ICERs.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Airoldi, Flavio, E-mail: flavio.airoldi@multimedica.it; Faglia, Ezio, E-mail: ezio.faglia@multimedica.it; Losa, Sergio, E-mail: sergio.losa@multimedica.it

Subintimal angioplasty (SAP) is frequently performed for the treatment of critical limb ischemia (CLI) and has been recognized as an effective technique for these patients. Nevertheless, this approach is limited by the lack of controlled re-entry into the true lumen of the target vessel. We describe a novel device for true lumen re-entry after subintimal recanalization of superficial femoral arteries (SFA). We report our experience with six patients treated between April 2009 and January 2010 with a novel system designed to facilitate true lumen re-entry. The device was advanced by ipsilateral antegrade approach through a 6-French sheath. Successful reaccess intomore » the true lumen was obtained in five of six patients without complications. The patient in whom the reaccess to the true lumen was not possible underwent successful bypass surgery. At 30 days follow-up, the SFA was patent in all patients according to echo-Doppler examination. Our preliminary experience indicates that this novel re-entry device increases the success rate of percutaneous revascularization of chronically occluded SFA.« less

Automated carbon dioxide digital angiography for lower-limb arterial disease evaluation: safety assessment and comparison with standard iodinated contrast media angiography.

PubMed

Scalise, Filippo; Novelli, Eugenio; Auguadro, Carla; Casali, Valentina; Manfredi, Mariella; Zannoli, Romano

2015-01-01

Carbon dioxide (CO2) has been validated as a contrast agent in a large series of studies. A particular advantages of CO2 over iodinated contrast medium (ICM) is the absence of nephrotoxicity and allergic reactions. One of the limitations of CO2 angiography is the difficulty of CO2 manual injection due to its compressibility. The manual gas injection does not permit optimal control of the gas output. Development of an automated CO2 injector has overcome these problems. This study compares the feasibility, safety, and diagnostic accuracy of automated CO2 digital subtraction angiography (DSA) in comparison with ICM-DSA in the evaluation of critical limb ischemic (CLI) patients. We performed DSA with both CO2 and ICM on 40 consecutive CLI patients and directly compared the two techniques. Sixteen females and 24 males participated in the study (mean age, 71.7 years). We assessed the diagnostic accuracy of CO2 in identifying arterial stenosis in the lower limb, with ICM-DSA used as the gold standard. The overall diagnostic accuracy of CO2-DSA was 96.9% (sensitivity, 99.0%; specificity, 96.1%; positive predictive value, 91.1%; negative predictive value, 99.6%). Tolerable minor symptoms occurred in 3 patients. No allergic reactions or significant decline in renal function were observed in patients receiving the CO2 injection. Carbon dioxide DSA is a valuable and safe alternative to traditional ICM-DSA for evaluating CLI patients. This modality should be considered as the standard choice for CLI patients undergoing angiographic evaluation who are known to have renal insufficiency or contrast allergy.

Consumed Ischemia of Lower Limbs in the Newborn: A Case Report

PubMed Central

Hamid, Jiber; Rita, Hajji; Youssef, Zrihni; Abdellatif, Bouarhroum

2013-01-01

The limb ischemia is a rare phenomenon in the newborn. It is most often a postnatal ischemia secondary to arterial or venous catheterization, to neonatal infection. Maternal diabetes is most often implicated. The diagnosis implies an urgent situation which may result in extremity gangrene and ultimate loss of limb. PMID:24251263

Endovascular Treatment of Severely Calcified Femoropopliteal Lesions Using the "Pave-and-Crack" Technique: Technical Description and 12-Month Results.

PubMed

Dias-Neto, Marina; Matschuck, Manuela; Bausback, Yvonne; Banning-Eichenseher, Ursula; Steiner, Sabine; Branzan, Daniela; Staab, Holger; Varcoe, Ramon L; Scheinert, Dierk; Schmidt, Andrej

2018-06-01

To report midterm results of the "pave-and-crack" technique to facilitate safe and effective scaffolding of heavily calcified femoropopliteal lesions in preparation for delivery of a Supera interwoven stent. Data were collected retrospectively on 67 consecutive patients (mean age 71±8 years; 54 men) treated with this technique between November 2011 and February 2017 at a single center. A third (22/64, 34%) of the patients had critical limb ischemia (CLI). Most lesions were TASC D (52/67, 78%), and the majority were occlusions (61/66, 92%). The mean lesion length was 26.9±11.2 cm. Nearly two-thirds (40/64, 62%) had grade 4 calcification (Peripheral Arterial Calcium Scoring System). To prepare for Supera stenting, the most heavily calcified segments of the lesion were predilated aggressively to obliterate recoil. A Viabahn stent-graft was then implanted to "pave" the lesion and protect from vessel rupture as aggressive predilation continued until the calcified plaque was "cracked" before lining the entire lesion with a Supera stent. Patency and target lesion revascularization (TLR) rates were estimated using the Kaplan-Meier method. Procedural success was achieved in 100% and technical success (residual stenosis <30%) in 98% (66/67). The mean cumulative stent lengths were 16±9 cm for the Viabahn and 23±12 cm for the Supera. Only 2 complications occurred (distal embolization and access-site pseudoaneurysm). Two CLI patients died within 30 days, and 3 patients (all claudicants) underwent a TLR. Patients were followed for a mean 19±18 months, during which another 2 CLI patients died and 1 patient had a major amputation. One-year primary and secondary patency estimates were 79% and 91%, respectively; freedom from TLR was 85%. Despite severe lesion calcification, patients experienced high technical success and a safe and durable therapy at midterm follow-up with the femoropopliteal "pave-and-crack" technique.

Day-Case Treatment of Peripheral Arterial Disease: Results from a Multi-Center European Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spiliopoulos, Stavros, E-mail: stavspiliop@med.uoa.gr, E-mail: stavspiliop@upatras.gr; Karnabatidis, Dimitrios, E-mail: karnaby@med.upatras.gr; Katsanos, Konstantinos, E-mail: katsanos@med.upatras.gr

PurposeThe purpose of the study was to investigate safety and feasibility of day-case endovascular procedures for the management of peripheral arterial disease.Materials and MethodsThis was a multi-center, retrospective study including all patients treated over a 30-month period with endovascular angioplasty or stenting for intermittent claudication (IC) or critical limb ischemia (CLI) on a day-case basis, in Interventional Radiology (IR) departments of three European tertiary hospitals. Exclusion criteria were not related to the type of lesion and included unavailability of an adult able to take care of patient overnight; high bleeding risk and ASA score ≥4. Primary efficacy outcome was themore » rate of procedures performed on an outpatient basis requiring no further hospitalization and primary safety outcome was freedom from 30-day major complications’ rate.ResultsThe study included 652 patients (male 75 %; mean age 68 ± 10 years; range: 27–93), 24.6 % treated for CLI. In 53.3 % of the cases a 6Fr sheath was used. Technical success was 97.1 %. Haemostasis was obtained by manual compression in 52.4 % of the accesses. The primary efficacy outcome occurred in 95.4 % (622/652 patients) and primary safety outcome in 98.6 % (643/652 patients). Major complications included five (0.7 %) retroperitoneal hematomas requiring transfusion; one (0.1 %) common femoral artery pseudoaneurysm successfully treated with US-guided thrombin injection, two cases of intra-procedural distal embolization treated with catheter-directed local thrombolysis and one on-table cardiac arrest necessitating >24 h recovery. No major complication was noted after same-day discharge.ConclusionsDay-case endovascular procedures for the treatment of IC or CLI can be safely and efficiently performed in experienced IR departments of large tertiary hospitals.« less

Update and validation of the Society for Vascular Surgery wound, ischemia, and foot infection threatened limb classification system.

PubMed

Mills, Joseph L

2014-03-01

The diagnosis of critical limb ischemia, first defined in 1982, was intended to delineate a patient cohort with a threatened limb and at risk for amputation due to severe peripheral arterial disease. The influence of diabetes and its associated neuropathy on the pathogenesis-threatened limb was an excluded comorbidity, despite its known contribution to amputation risk. The Fontaine and Rutherford classifications of limb ischemia severity have also been used to predict amputation risk and the likelihood of tissue healing. The dramatic increase in the prevalence of diabetes mellitus and the expanding techniques of arterial revascularization has prompted modification of peripheral arterial disease classification schemes to improve outcomes analysis for patients with threatened limbs. The diabetic patient with foot ulceration and infection is at risk for limb loss, with abnormal arterial perfusion as only one determinant of outcome. The wound extent and severity of infection also impact the likelihood of limb loss. To better predict amputation risk, the Society for Vascular Surgery Lower Extremity Guidelines Committee developed a classification of the threatened lower extremity that reflects these important clinical considerations. Risk stratification is based on three major factors that impact amputation risk and clinical management: wound, ischemia, and foot infection. This classification scheme is relevant to the patient with critical limb ischemia because many are also diabetic. Implementation of the wound, ischemia, and foot infection classification system in critical limb ischemia patients is recommended and should assist the clinician in more meaningful analysis of outcomes for various forms of wound and arterial revascularizations procedures required in this challenging, patient population. Copyright © 2014 Elsevier Inc. All rights reserved.

Biochemical markers of acute limb ischemia, rhabdomyolysis, and impact on limb salvage.

PubMed

Watson, J Devin B; Gifford, Shaun M; Clouse, W Darrin

2014-12-01

Biochemical markers of ischemia reperfusion injury have been of interest to vascular surgeons and researchers for many years. Acute limb ischemia is the quintessential clinical scenario where these markers would seem relevant. The use of biomarkers to preoperatively or perioperatively predict which patients will not tolerate limb-salvage efforts or who will have poor functional outcomes after salvage is of immense interest. Creatinine phosphokinase, myoglobin, lactate, lactate dehydrogenase, potassium, bicarbonate, and neutrophil/leukocyte ratios are a few of the studied biomarkers available. Currently, the most well-studied aspect of ischemia reperfusion injury is rhabdomyolysis leading to acute kidney injury. The last 10 years have seen significant progression and improvement in the treatment of rhabdomyolysis, from minor supportive care to use of continuous renal replacement therapy. Identification of specific biomarkers with predictive outcome characteristics in the setting of ischemia reperfusion injury will help guide therapeutic development and potentially mitigate pathophysiologic changes in acute limb ischemia, including rhabdomyolysis. These may further lead to improvements in short- and long-term surgical outcomes and limb salvage, as well as a better understanding of the timing and selection of intervention. Copyright © 2015 Elsevier Inc. All rights reserved.

Benefit of revascularisation to critical limb ischaemia patients evaluated by a patient-oriented scoring system.

PubMed

Chisci, E; Perulli, A; Iacoponi, F; Setacci, F; de Donato, G; Palasciano, G; Cappelli, A; Setacci, C

2012-05-01

The concept of patency and limb salvage are physician-oriented endpoints in critical limb ischaemia (CLI). These endpoints have failed to enhance function after revascularisation. The aim of this study was to create a scoring system to predict 1-year functional status and to assess the benefit to patients possible by revascularisation. During the period 2007-2009, 480 consecutive patients (mean age ± SD, 83.2 ± 8.7 years) underwent repair for CLI. Preoperative, operative and functional status characteristics and post-operative outcomes were recorded. The following patient-oriented outcomes were investigated pre- and postoperatively: basic and instrumental activities of daily living (BADL and IADL) and ambulatory and living status. Statistical analysis was performed to assess predictors of functional benefit from revascularisation. The variables significant on multivariable analysis were used to generate a scoring system to pre and postoperatively grade individual patient risk of losing baseline functional status at 1 year (CLI functional score). Ninety-three of 480 patients (19.3%) were in Rutherford class IV, 208 (43.3%) in class V and 179 (37.4%) in class VI. Surgical, endovascular and hybrid operations were performed in 108 (22.5%), 319 (66.5%) and 53 (11%) patients, respectively; mean follow-up was 408 ± 363 days. Improved or unchanged functional status was observed in 276 patients (57.5%). Preoperative mean ± SD BADL and IADL (4.26 ± 1.98 and 3.92 ± 2.69, respectively) were modified from mean values at 1-year follow-up (4.19 ± 2.06 and 4.12 ± 3, respectively) (p = 0.401 and p < 0.05, respectively). In the same time interval, mortality was 50%, limb salvage 50.4%, CLI-related new hospitalisations 50.8%, relief of symptoms 18.5% and tissue healing 14.5%. A CLI functional score of >80% indicates that patients are likely to lose functional abilities and require assistance for ambulation or ADL, as well as risking outcomes such as major amputation, new CLI-related hospitalisation or re-operation (p < 0.001). Preoperative poor living status, dependence in daily activities, advanced local disease (lesion >2 cm, infection and poor tibial runoff), American Society of Anesthesiologists (ASA) score > II, previous cerebrovascular event and heart disease were the strongest pre-operative negative predictors of losing baseline functional status. Major amputation was the only negative post-operative predictor. Considering patient-oriented outcomes, our study showed that revascularisation could be worthwhile in nearly 60% of CLI patients. A non-revascularisation strategy such as primary amputation or palliation could be indicated in patients with a poor pre-operative living status, dependence for daily activities, advanced local disease, extensive comorbid conditions and a score >80%. To make our findings generalisable, the score needs to be validated in independent cohorts at different centres before it can be recommended for application. Copyright © 2012 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

The impact of coronary artery disease and left ventricular ejection fraction on the prognosis of patients with peripheral artery disease.

PubMed

Tsujimura, Takuya; Iida, Osamu; Ishihara, Takayuki; Fujita, Masashi; Masuda, Masaharu; Okamoto, Shin; Nanto, Kiyonori; Kanda, Takashi; Sunaga, Akihiro; Takahara, Mitsuyoshi; Uematsu, Masaaki

2017-11-01

The impact of the severity of coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) on the prognosis of patients with peripheral artery disease (PAD) has not been systematically studied. We retrospectively analysed 622 patients with PAD (intermittent claudication (IC): n = 446; critical limb ischaemia (CLI): n = 176). The association of SYNTAX score and LVEF with mortality was analysed using the Cox proportional hazard model. In patients with IC, a high SYNTAX score was significantly associated with mortality, whereas reduced LVEF was significantly associated with mortality in patients with CLI. The prognostic impact of CAD and LVEF appears different between patients with IC and CLI. © 2017 Royal Australasian College of Physicians.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Madaric, Juraj, E-mail: jurmad@hotmail.com; Klepanec, Andrej; Mistrik, Martin

Induction of therapeutic angiogenesis by autologous bone marrow mononuclear cell transplantation has been identified as a potential new option in patients with advanced lower-limb ischemia. There is little evidence of the benefit of intra-arterial cell application in upper-limb critical ischemia. We describe a patient with upper-extremity critical limb ischemia with digital gangrene resulting from hypothenar hammer syndrome successfully treated by intra-arterial autologous bone marrow mononuclear cell transplantation.

Predictors of improved quality of life and claudication in patients undergoing spinal cord stimulation for critical lower limb ischemia.

PubMed

Tshomba, Yamume; Psacharopulo, Daniele; Frezza, Serena; Marone, Enrico Maria; Astore, Domenico; Chiesa, Roberto

2014-04-01

The aim of this study was to determine predictors of improved quality of life and claudication in patients undergoing spinal cord stimulation (SCS) for critical lower limb ischemia. We retrospectively analyzed 101 consecutive patients with few meter claudication and nonhealing ulcer who underwent definitive SCS. These patients were selected among 274 SCS patients treated at our center from 1995 to 2012. All presented with non-reconstructable critical leg ischemia (NR-CLI) and underwent supervised exercise therapy, best medical care and regular ulcers standard or advanced medications for at least 1 month before SCS implantation. We measured self-perceived quality of life using the SF-36 questionnaire. Patients with an improved walking distance of at least 30 meters after SCS had significant improvement on SF-36 questionnaire scores. We considered 30 meters as the cut-off for clinically significant improvement in pain-free walking distance, and we defined this value as functional success. Logistic regression was applied to assess baseline and other patient variables as possible predictors of functional success. Neither perioperative mortality nor significant complications were found. At a median follow-up of 69 months (range 1-202 months), mortality, major amputation, and minor amputation were 8.9%, 5.9%, and 6.9%, respectively. Functional clinical success was reported in 25.7% of cases. Independent predictors of functional success at univariate analysis included delay between the onset of the ulcer and SCS (P < 0.001) and the pain-free walking distance before SCS (P < 0.002). The only predictive factor of functional success at multivariate analysis was the delay between the onset of ulcer and SCS (median delay in patients with and without functional success was 3 and 15 months, respectively). In particular, comparable to pain-free walking distance before SCS, the success rate decreased by 40% for each month elapsed from onset of ulcer to SCS. In our series of patients who underwent SCS, reduced delay between the onset of ulcer and SCS was associated with improved quality of life and walking distance. Larger series are required to confirm these data and to assess clinical implications. Copyright © 2014 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jens, Sjoerd, E-mail: s.jens@amc.uva.nl; Lucatelli, Pierleone, E-mail: pierleone.lucatelli@gmail.com; Koelemay, Mark J. W., E-mail: m.j.koelemaij@amc.uva.nl

Purpose. To evaluate the additional value of three-dimensional rotational angiography (3DRA) of the foot compared with digital subtraction angiography (DSA) in patients with critical limb ischemia (CLI). Technique. For 3DRA, the C-arm was placed in the propeller position with the foot in an isocentric position. The patient's unaffected foot was positioned in a footrest outside the field of view. For correct timing of 3DRA, the delay from contrast injection in the popliteal artery at the level of knee joint to complete pedal arterial enhancement was assessed using DSA. With this delay, 3DRA was started after injection of 15 ml contrast.more » Imaging of the 3DRA could directly be reconstructed and visualized.Materials and MethodsPatients undergoing 3DRA of the foot were prospectively registered. DSA and 3DRA images were scored separately for arterial patency and presence of collaterals. Treatment strategies were proposed based on DSA with and without the availability of 3DRA. Results. Eleven patients underwent 3DRA of the foot. One 3DRA was not included because the acquisition was focused on the heel instead of the entire foot. Diagnostic quality of 3DRA was good in all ten patients. 3DRA compared with DSA showed additional patent arteries in six patients, patent plantar arch in three patients, and collaterals between the pedal arteries in five patients. Additional information from 3DRA resulted in a change of treatment strategy in six patients. Conclusion, 3DRA of the foot contains valuable additional real-time information to better guide peripheral vascular interventions in patients with CLI and nonhealing tissue lesions.« less

Revascularization and Muscle Adaptation to Limb Demand Ischemia in Diet Induced Obese Mice

PubMed Central

Albadawi, Hassan; Tzika, Aria; Rask-Madsen, Christian; Crowley, Lindsey M.; Koulopoulos, Michael W.; Yoo, Hyung-Jin; Watkins, Michael T.

2016-01-01

Background Obesity and type 2 diabetes are major risk factors for peripheral arterial disease (PAD) in humans which can result in lower limb demand ischemia and exercise intolerance. Exercise triggers skeletal muscle adaptation including increased vasculogenesis. The goal of this study was to determine whether demand ischemia modulates revascularization, fiber size, and signaling pathways in the ischemic hind limb muscles of mice with diet-induced obesity (DIO). Materials and Methods DIO mice (n=7) underwent unilateral femoral artery ligation (FAL) and recovered for 2-weeks followed by 4-weeks with daily treadmill exercise to induce demand ischemia. A parallel sedentary ischemia group (n=7) had FAL without exercise. The contralateral limb muscles of sedentary ischemia served as control. Muscles were examined for capillary density, myofiber cross-sectional area (CSA), cytokine levels, and phosphorylation of STAT3 and ERK1/2. Results Exercise significantly enhanced capillary density (p<0.01) and markedly lowered CSA (p<0.001) in demand ischemia compared to sedentary ischemia. These findings coincided with a significant increase in G-CSF (p<0.001) and IL-7 (p<0.01) levels. In addition, phosphorylation of STAT3 and ERK1/2 (p<0.01) were increased while UCP-1 and MCP-1 protein levels were lower (p<0.05) without altering VEGF and TNFα protein levels. Demand ischemia increased the PGC1α mRNA (p<0.001) without augmenting PGC1α protein levels. Conclusions Exercise induced limb demands ischemia in the setting of DIO causes myofiber atrophy despite an increase in muscle capillary density. The combination of persistent increase in TNFα, lower VEGF and failure to increase PGC1α protein may reflect a deficient adaption to demand ischemia in DIO. PMID:27620999

Divergent Systemic and Local Inflammatory Response to Hind Limb Demand Ischemia in Wild Type And ApoE−/− Mice

PubMed Central

Crawford, Robert S.; Albadawi, Hassan; Robaldo, Alessandro; Peck, Michael A.; Abularrage, Christopher J.; Yoo, Hyung-Jin; LaMuraglia, Glenn M.; Watkins, Michael T.

2013-01-01

Introduction Studies were designed to determine whether the ApoE−/− phenotype modulates the local skeletal muscle and systemic inflammatory (plasma) responses to lower extremity demand ischemia. The ApoE−/− phenotype is an experimental model for atherosclerosis in humans. Methods Aged female ApoE −/− and C57BL6 mice underwent femoral artery ligation, then divided into sedentary and demand ischemia (exercise) groups on day 14. Baseline and post exercise limb perfusion and hind limb function were assessed. On day 14, animals in the demand ischemia group underwent daily treadmill exercise through day 28. Sedentary mice were not exercised. On day 28, plasma and skeletal muscle from ischemic limbs were harvested from sedentary and exercised mice. Muscle was assayed for angiogenic and pro-inflammatory proteins, markers of skeletal muscle regeneration, and evidence of skeletal muscle fiber maturation. Results Hind limb ischemia was similar in ApoE −/− and C57 mice prior to the onset of exercise. Under sedentary conditions, plasma VEGF, IL-6, but not KC or MIP-2 were higher in ApoE (P<0.0001). Following exercise, plasma levels of VEGF, KC and MIP-2, but not IL-6 were lower in ApoE (P<0.004). The cytokines KC and MIP-2 in muscle was greater in exercised ApoE−/− mice as compared to C57BL6 mice (p=0.01). Increased PAR activity, and mature muscle regeneration was associated with demand ischemia in the C57BL6 mice as compared to the ApoE −/− mice (p=0.01). Conclusion Demand limb ischemia in the ApoE−/− phenotype exacerbated the expression of select systemic cytokines in plasma and blunted indices of muscle regeneration. PMID:23528286

Chronic diseases are not being managed effectively in either high-risk or low-risk populations in South Africa.

PubMed

Brand, Martin; Woodiwiss, Angela J; Michel, Frederic; Booysens, Hendrik L; Majane, Olebogeng H I; Maseko, Muzi J; Veller, Martin G; Norton, Gavin R

2013-07-29

Primary healthcare is the foundation of a country's healthcare system. Without an efficient and cost-effective programme, the level of healthcare offered across all levels of health management is adversely affected. To analyse the effectiveness of the management of hypertension and diabetes mellitus (DM) among two distinct patient populations, one with significant cardiovascular risk factors and the other without. We performed a case control study of a high-risk group of patients presenting with chronic critical limb ischaemia (CLI) to the Divisions of Vascular Surgery at Charlotte Maxeke Johannesburg Academic Hospital and Chris Hani Baragwanath Academic Hospital, and a randomly selected group of 'healthy' community participants from Johannesburg's South Western Townships (Soweto). We assessed 217 patients with CLI and 1 030 participants from the community. We assessed the number of patients who were not achieving their therapeuatic targets, among those known to be hypertensive (CLI: 44.7%; community: 59.9%) and diabetic (CLI: 83.5%; community: 66%). Undiagnosed diabetes affected 10.8% of patients with CLI and 11% of the community sample. Traditional vascular risk factors are managed poorly at both primary healthcare and at tertiary care levels. There is a need to identify factors that will address this issue.

Practical importance and modern methods of the evaluation of skin microcirculation during chronic lower limb ischemia in patients with peripheral arterial occlusive disease and/or diabetes.

PubMed

Kluz, J; Małecki, R; Adamiec, R

2013-02-01

Skin ischemia is one of the crucial phenomena during chronic lower limb ischemia in patients with peripheral arterial occlusive disease and/or diabetes. However, risk stratification for development of ischemic ulceration and/or skin necrosis in those patients is not easy, mostly due to the complex structure of the dermal vascular bed and limited possibilities for studying the skin capillaries in everyday practice. All definitions of critical limb ischemia thus far have considered mostly the clinical symptoms and the degree of macrocirculatory impairment. Despite the fact that the reduction of absolute dermal perfusion and improper distribution of perfusion in ischemic feet, primarily diminished perfusion or even a complete loss of blood flow in nutritional capillaries, rather than arterial occlusion per se, is the eventual reason for critical limb ischemia symptoms, the vessels of the microcirculation are not routinely assessed in clinical practice. Monitoring of microcirculatory parameters, as a part of integrated diagnostic approach, may have a considerable value in the evaluation of risk, progression of the disease and the effectiveness of therapeutic intervention in individual patients. Relative simplicity and availability of different non-invasive methods, including video capillaroscopy and laser Doppler fluxmetry, should constitute a premise to their wider application in clinical management of chronic limb ischemia.

Sleep Is Critical for Remote Preconditioning-Induced Neuroprotection.

PubMed

Brager, Allison J; Yang, Tao; Ehlen, J Christopher; Simon, Roger P; Meller, Robert; Paul, Ketema N

2016-11-01

Episodes of brief limb ischemia (remote preconditioning) in mice induce tolerance to modeled ischemic stroke (focal brain ischemia). Since stroke outcomes are in part dependent on sleep-wake history, we sought to determine if sleep is critical for the neuroprotective effect of limb ischemia. EEG/EMG recording electrodes were implanted in mice. After a 24 h baseline recording, limb ischemia was induced by tightening an elastic band around the left quadriceps for 10 minutes followed by 10 minutes of release for two cycles. Two days following remote preconditioning, a second 24 h EEG/EMG recording was completed and was immediately followed by a 60-minute suture occlusion of the middle cerebral artery (modeled ischemic stroke). This experiment was then repeated in a model of circadian and sleep abnormalities ( Bmal1 knockout [KO] mice sleep 2 h more than wild-type littermates). Brain infarction was determined by vital dye staining, and sleep was assessed by trained identification of EEG/EMG recordings. Two days after limb ischemia, wild-type mice slept an additional 2.4 h. This additional sleep was primarily comprised of non-rapid eye movement (NREM) sleep during the middle of the light-phase (i.e., naps). Repeating the experiment but preventing increases in sleep after limb ischemia abolished tolerance to ischemic stroke. In Bmal1 knockout mice, remote preconditioning did not increase daily sleep nor provide tolerance to subsequent focal ischemia. These results suggest that sleep induced by remote preconditioning is both sufficient and necessary for its neuroprotective effects on stroke outcome. © 2016 Associated Professional Sleep Societies, LLC.

Collateral circulation of the rat lower limb and its significance in ischemia-reperfusion studies.

PubMed

Rosero, Olivér; Németh, Károly; Turóczi, Zsolt; Fülöp, András; Garbaisz, Dávid; Győrffy, András; Szuák, András; Dorogi, Bence; Kiss, Mátyás; Nemeskéri, Ágnes; Harsányi, László; Szijártó, Attila

2014-12-01

Rats are the most commonly used animal model for studies of acute lower limb ischemia-reperfusion. The ischemia induced by arterial clamping may cause milder damage than the application of a tourniquet if the presence of a possible collateral system is considered. Male Wistar rats were randomized into three groups: in group A, the muscle weight affected by ischemia was measured; in group B, the severity of muscle damage caused by the application of a tourniquet and by infrarenal aortic occlusion was examined. Blood and muscle samples were taken from group B to assess the serum necroenzyme, potassium and TNF-α levels, as well as the muscle fiber viability and for histological examinations. In group C, the identification of the lower limb collateral system was performed using corrosion casting. Tourniquet application affected the lower muscle mass and resulted in significantly more severe injury compared to infrarenal aortic occlusion. This difference was reflected in the serum necroenzyme, potassium and TNF-α levels. The histological examination and viability assay confirmed these findings. The corrosion casts showed several anastomoses capable of supplying the lower limb. Tourniquet application proved to be capable of inducing absolute lower limb ischemia, in contrast to infrarenal aortic ligation, where a rich collateral system is considered to help mitigate the injury.

Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice.

PubMed

Albadawi, Hassan; Tzika, A Aria; Rask-Madsen, Christian; Crowley, Lindsey M; Koulopoulos, Michael W; Yoo, Hyung-Jin; Watkins, Michael T

2016-09-01

Obesity and type 2 diabetes are major risk factors for peripheral arterial disease in humans, which can result in lower limb demand ischemia and exercise intolerance. Exercise triggers skeletal muscle adaptation including increased vasculogenesis. The goal of this study was to determine whether demand ischemia modulates revascularization, fiber size, and signaling pathways in the ischemic hind limb muscles of mice with diet-induced obesity (DIO). DIO mice (n = 7) underwent unilateral femoral artery ligation and recovered for 2 wks followed by 4 wks with daily treadmill exercise to induce demand ischemia. A parallel sedentary ischemia (SI) group (n = 7) had femoral artery ligation without exercise. The contralateral limb muscles of SI served as control. Muscles were examined for capillary density, myofiber cross-sectional area, cytokine levels, and phosphorylation of STAT3 and ERK1/2. Exercise significantly enhanced capillary density (P < 0.01) and markedly lowered cross-sectional area (P < 0.001) in demand ischemia compared with SI. These findings coincided with a significant increase in granulocyte colony-stimulating factor (P < 0.001) and interleukin-7 (P < 0.01) levels. In addition, phosphorylation levels of STAT3 and ERK1/2 (P < 0.01) were increased, whereas UCP1 and monocyte chemoattractant protein-1 protein levels were lower (P < 0.05) without altering vascular endothelial growth factor and tumor necrosis factor alpha protein levels. Demand ischemia increased the PGC1α messenger RNA (P < 0.001) without augmenting PGC1α protein levels. Exercise-induced limb demand ischemia in the setting of DIO causes myofiber atrophy despite an increase in muscle capillary density. The combination of persistent increase in tumor necrosis factor alpha, lower vascular endothelial growth factor, and failure to increase PGC1α protein may reflect a deficient adaption to demand ischemia in DIO. Copyright © 2016 Elsevier Inc. All rights reserved.

Peripheral arterial disease and critical limb ischaemia: still poor outcomes and lack of guideline adherence.

PubMed

Reinecke, Holger; Unrath, Michael; Freisinger, Eva; Bunzemeier, Holger; Meyborg, Matthias; Lüders, Florian; Gebauer, Katrin; Roeder, Norbert; Berger, Klaus; Malyar, Nasser M

2015-04-14

Only few and historic studies reported a bad prognosis of peripheral arterial disease (PAD) and critical limb ischaemia (CLI). The contemporary state of treatment and outcomes should be assessed. From the largest public health insurance in Germany, all in- and outpatient diagnosis and procedural data were retrospectively obtained from a cohort of 41 882 patients hospitalized due to PAD during 2009-2011, including a follow-up until 2013. Patients were classified in Rutherford categories 1-3 (n = 21 197), 4 (n = 5353), 5 (n = 6916), and 6 (n = 8416). The proportions of patients with classical risk factors such as hypertension, dyslipidaemia, and smoking declined with higher Rutherford categories (each P < 0.001) while diabetes, chronic kidney disease, and chronic heart failure increased (each P < 0.001). Angiographies and revascularizations were performed less often in advanced PAD (each P < 0.001). In-hospital amputations increased continuously from 0.5% in Rutherford 1-3 to 42% in Rutherford 6, as also myocardial infarctions, strokes, and deaths (each P < 0.001). Among 4298 amputated patients with CLI, 37% had not received any angiography or revascularization neither during index hospitalization nor the 24 months before. During follow-up (mean 1144 days), 7825 patients were amputated and 10 880 died. Kaplan-Meier models projected 4-year mortality risks of 18.9, 37.7, 52.2, and 63.5% in Rutherford 1-3, 4, 5, and 6, and for amputation of 4.6, 12.1, 35.3, and 67.3%, respectively. In multivariable Cox regression models, PAD categories were significant predictors of death, amputation, myocardial infarction, and stroke (each P < 0.001). Length of in-hospital stay (5.8 ± 6.7 days, 10.7 ± 11.1days, 15.2 ± 13.8 days and 22.1 ± 20.3 days; P < 0.001) and mean case costs (3662 ± 3186 €, 5316 ± 6139 €, 6021 ± 4892 €, and 8461 ± 8515 €; P < 0.001) increased continuously in Rutherford 1-3, 4, 5, and 6. While only 49% of the patients suffered from CLI, these produced 65% of in-hospital costs (141 million €), and 56% during follow-up (336 million €). Regardless of recent advances in PAD treatment, current outcomes remain poor especially in CLI. Despite overwhelming evidence for reduction of limb loss by revascularization, CLI patients still received significantly less angiographies and revascularizations. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Human primary CD34+ cells transplantation for critical limb ischemia.

PubMed

Lian, Weishuai; Hu, Xiaoxiao; Pan, Long; Han, Shilong; Cao, Chuanwu; Jia, Zhongzhi; Li, Maoquan

2018-06-11

The goal of this study was to characterize the properties of human CD34 + cells in culture and investigate the feasibility and efficacy of CD34 + transplantation in a mouse model of limb ischemia and in patients with no-option critical limb ischemia. Human CD34 + cells isolated from peripheral blood and grown in culture for up to four passages stained positively for the surface markers CD34 and CD133 and showed high viability after cryopreservation and recovery. Seven days after surgery to induce limb ischemia, ischemic muscles of nude mice were injected with CD34 + cells. Two weeks later, mice were scored for extent of ischemic injury, and muscle tissue was collected for immunohistochemical analysis of vascular endothelial cells and RT-PCR analysis of cytokine expression. Injury scores of CD34 + -treated, but not control, mice were significantly different before and after transplantation. Vascular density and expression of VEGF and bFGF mRNAs were also significantly increased in the treated mice. Patients with severe lower extremity arterial ischemia were injected with their own CD34 + cells in the affected calf, foot, or toe. Significant improvements were observed in peak pain-free walking time, ankle-brachial index, and transcutaneous partial oxygen pressure. These findings demonstrate that growth of human CD34 + cells in vitro and cryopreservations are feasible. Such cells may provide a renewable source of stem cells for transplantation, which appears to be a feasible, safe, and effective treatment for patients with critical limb ischemia. © 2018 Wiley Periodicals, Inc.

Outcomes of Peripheral Vascular Interventions in Select Patients With Lower Extremity Acute Limb Ischemia.

PubMed

Inagaki, Elica; Farber, Alik; Kalish, Jeffrey A; Eslami, Mohammad H; Siracuse, Jeffrey J; Eberhardt, Robert T; Rybin, Denis V; Doros, Gheorghe; Hamburg, Naomi M

2018-04-12

Contemporary data on patients presenting with acute limb ischemia (ALI), who are selected for treatment with endovascular peripheral vascular interventions (PVI), are limited. Our study examined outcomes following endovascular PVI in patients with ALI by comparing with patients treated for chronic critical limb ischemia using a regional quality improvement registry. Of the 11 035 patients in the Vascular Study Group of New England PVI database (2010-2014), we identified 365 patients treated for lower extremity ALI who were 5:1 frequency matched (by procedure year and arterial segments treated) to 1808 patients treated for critical limb ischemia. ALI patients treated with PVI had high burden of atherosclerotic risk factors and were more likely to have had prior ipsilateral revascularizations. ALI patients were less likely to be treated with self-expanding stents and more likely to undergo thrombolysis than patients with critical limb ischemia. In multivariable analysis, ALI was associated with higher technical failure (odds ratio 1.7, 95% confidence interval, 1.1%-2.5%), increased rate of distal embolization (odds ratio 2.7, 95% confidence interval, 1.5%-4.9%), longer length of stay (means ratio 1.6, 95% confidence interval, 1.4%-1.8%), and higher in-hospital mortality (odds ratio 2.8, 95% confidence interval, 1.3%-5.9%). ALI was not associated with risk of major amputation or mortality at 1 year. In a multicenter cohort of patients treated with PVI, we found that ALI patients selected for treatment with endovascular techniques experienced greater short-term adverse events but similar long-term outcomes as their critical limb ischemia counterparts. Further studies are needed to refine the selection of ALI patients who are best served by PVI. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Divergent systemic and local inflammatory response to hind limb demand ischemia in wild-type and ApoE-/- mice.

PubMed

Crawford, Robert S; Albadawi, Hassan; Robaldo, Alessandro; Peck, Michael A; Abularrage, Christopher J; Yoo, Hyung-Jin; Lamuraglia, Glenn M; Watkins, Michael T

2013-08-01

We designed studies to determine whether the ApoE-/- phenotype modulates the local skeletal muscle and systemic inflammatory (plasma) responses to lower extremity demand ischemia. The ApoE-/- phenotype is an experimental model for atherosclerosis in humans. Aged female ApoE-/- and C57BL6 mice underwent femoral artery ligation, then were divided into sedentary and demand ischemia (exercise) groups on day 14. We assessed baseline and postexercise limb perfusion and hind limb function. On day 14, animals in the demand ischemia group underwent daily treadmill exercise through day 28. Sedentary mice were not exercised. On day 28, we harvested plasma and skeletal muscle from ischemic limbs from sedentary and exercised mice. We assayed muscle for angiogenic and proinflammatory proteins, markers of skeletal muscle regeneration, and evidence of skeletal muscle fiber maturation. Hind limb ischemia was similar in ApoE-/- and C57 mice before the onset of exercise. Under sedentary conditions, plasma vascular endothelial cell growth factor and interleukin-6, but not keratinocyte chemoattractant factor (KC) or macrophage inflammatory protein-2 (MIP-2), were higher in ApoE (P < 0.0001). After exercise, plasma levels of vascular endothelial cell growth factor, KC, and MIP-2, but not IL-6, were lower in ApoE (P < 0.004). The cytokines KC and MIP-2 in muscle were greater in exercised ApoE-/- mice compared with C57BL6 mice (P = 0.01). Increased poly-ADP-ribose activity and mature muscle regeneration were associated with demand ischemia in the C57BL6 mice, compared with the ApoE-/- mice (P = 0.01). Demand limb ischemia in the ApoE-/- phenotype exacerbated the expression of select systemic cytokines in plasma and blunted indices of muscle regeneration. Copyright © 2013 Elsevier Inc. All rights reserved.

Dietary glutamine supplementation enhances endothelial progenitor cell mobilization in streptozotocin-induced diabetic mice subjected to limb ischemia.

PubMed

Su, Shiau-Tsz; Yeh, Chiu-Li; Hou, Yu-Chen; Pai, Man-Hui; Yeh, Sung-Ling

2017-02-01

Diabetes is a metabolic disorder with increased risk of vascular diseases. Tissue ischemia may occur with diabetic vascular complications. Bone marrow-derived endothelial progenitor cells (EPCs) constitute a reparative response to ischemic injury. This study investigated the effects of oral glutamine (GLN) supplementation on circulating EPC mobilization and expression of tissue EPC-releasing markers in diabetic mice subjected to limb ischemia. Diabetes was induced by a daily intraperitoneal injection of streptozotocin for 5 days. Diabetic mice were divided into 2 nonischemic groups and 6 ischemic groups. One of the nonischemic and 3 ischemic groups were fed the control diet, while the remaining 4 groups received diets with identical components except that part of the casein was replaced by GLN. The respective diets were fed to the mice for 3 weeks, and then the nonischemic mice were sacrificed. Unilateral hindlimb ischemia was created in the ischemic groups, and mice were sacrificed at 1, 7 or 21 days after ischemia. Their blood and ischemic muscle tissues were collected for further analyses. Results showed that plasma matrix metallopeptidase (MMP)-9 and the circulating EPC percentage increased after limb ischemia in a diabetic condition. Compared to groups without GLN, GLN supplementation up-regulated plasma stromal cell-derived factor (SDF)-1 and muscle MMP-9, SDF-1, hypoxia-inducible factor-1 and vascular endothelial growth factor gene expression. The CD31-immunoreactive intensities were also higher in the ischemic limb. These findings suggest that GLN supplementation enhanced circulating EPC mobilization that may promote endothelium repair at ischemic tissue in diabetic mice subjected to limb ischemia. Copyright © 2016 Elsevier Inc. All rights reserved.

EZH2 Modulates Angiogenesis In Vitro and in a Mouse Model of Limb Ischemia

PubMed Central

Mitić, Tijana; Caporali, Andrea; Floris, Ilaria; Meloni, Marco; Marchetti, Micol; Urrutia, Raul; Angelini, Gianni D; Emanueli, Costanza

2015-01-01

Epigenetic mechanisms may regulate the expression of pro-angiogenic genes, thus affecting reparative angiogenesis in ischemic limbs. The enhancer of zest homolog-2 (EZH2) induces thtrimethylation of lysine 27 on histone H3 (H3K27me3), which represses gene transcription. We explored (i) if EZH2 expression is regulated by hypoxia and ischemia; (ii) the impact of EZH2 on the expression of two pro-angiogenic genes: eNOS and BDNF; (iii) the functional effect of EZH2 inhibition on cultured endothelial cells (ECs); (iv) the therapeutic potential of EZH2 inhibition in a mouse model of limb ischemia (LI). EZH2 expression was increased in cultured ECs exposed to hypoxia (control: normoxia) and in ECs extracted from mouse ischemic limb muscles (control: absence of ischemia). EZH2 increased the H3K27me3 abundance onto regulatory regions of eNOS and BDNF promoters. In vitro RNA silencing or pharmacological inhibition by 3-deazaneplanocin (DZNep) of EZH2 increased eNOS and BDNF mRNA and protein levels and enhanced functional capacities (migration, angiogenesis) of ECs under either normoxia or hypoxia. In mice with experimentally induced LI, DZNep increased angiogenesis in ischaemic muscles, the circulating levels of pro-angiogenic hematopoietic cells and blood flow recovery. Targeting EZH2 for inhibition may open new therapeutic avenues for patients with limb ischemia. PMID:25189741

Using multimodal imaging techniques to monitor limb ischemia: a rapid noninvasive method for assessing extremity wounds

NASA Astrophysics Data System (ADS)

Luthra, Rajiv; Caruso, Joseph D.; Radowsky, Jason S.; Rodriguez, Maricela; Forsberg, Jonathan; Elster, Eric A.; Crane, Nicole J.

2013-03-01

Over 70% of military casualties resulting from the current conflicts sustain major extremity injuries. Of these the majority are caused by blasts from improvised explosive devices. The resulting injuries include traumatic amputations, open fractures, crush injuries, and acute vascular disruption. Critical tissue ischemia—the point at which ischemic tissues lose the capacity to recover—is therefore a major concern, as lack of blood flow to tissues rapidly leads to tissue deoxygenation and necrosis. If left undetected or unaddressed, a potentially salvageable limb may require more extensive debridement or, more commonly, amputation. Predicting wound outcome during the initial management of blast wounds remains a significant challenge, as wounds continue to "evolve" during the debridement process and our ability to assess wound viability remains subjectively based. Better means of identifying critical ischemia are needed. We developed a swine limb ischemia model in which two imaging modalities were combined to produce an objective and quantitative assessment of wound perfusion and tissue viability. By using 3 Charge-Coupled Device (3CCD) and Infrared (IR) cameras, both surface tissue oxygenation as well as overall limb perfusion could be depicted. We observed a change in mean 3CCD and IR values at peak ischemia and during reperfusion correlate well with clinically observed indicators for limb function and vitality. After correcting for baseline mean R-B values, the 3CCD values correlate with surface tissue oxygenation and the IR values with changes in perfusion. This study aims to not only increase fundamental understanding of the processes involved with limb ischemia and reperfusion, but also to develop tools to monitor overall limb perfusion and tissue oxygenation in a clinical setting. A rapid and objective diagnostic for extent of ischemic damage and overall limb viability could provide surgeons with a more accurate indication of tissue viability. This may help reducing the number of surgical interventions required, by aiding surgeons in identifying and demarcating areas of critical tissue ischemia, so that a more adequate debridement may be performed. This would have obvious benefits of reducing patient distress and decreasing both the overall recovery time and cost of rehabilitation.

Analysis of temporal dynamics in imagery during acute limb ischemia and reperfusion

NASA Astrophysics Data System (ADS)

Irvine, John M.; Regan, John; Spain, Tammy A.; Caruso, Joseph D.; Rodriquez, Maricela; Luthra, Rajiv; Forsberg, Jonathon; Crane, Nicole J.; Elster, Eric

2014-03-01

Ischemia and reperfusion injuries present major challenges for both military and civilian medicine. Improved methods for assessing the effects and predicting outcome could guide treatment decisions. Specific issues related to ischemia and reperfusion injury can include complications arising from tourniquet use, such as microvascular leakage in the limb, loss of muscle strength and systemic failures leading to hypotension and cardiac failure. Better methods for assessing the viability of limbs/tissues during ischemia and reducing complications arising from reperfusion are critical to improving clinical outcomes for at-risk patients. The purpose of this research is to develop and assess possible prediction models of outcome for acute limb ischemia using a pre-clinical model. Our model relies only on non-invasive imaging data acquired from an animal study. Outcome is measured by pathology and functional scores. We explore color, texture, and temporal features derived from both color and thermal motion imagery acquired during ischemia and reperfusion. The imagery features form the explanatory variables in a model for predicting outcome. Comparing model performance to outcome prediction based on direct observation of blood chemistry, blood gas, urinalysis, and physiological measurements provides a reference standard. Initial results show excellent performance for the imagery-base model, compared to predictions based direct measurements. This paper will present the models and supporting analysis, followed by recommendations for future investigations.

Predictors for adverse outcome after iliac angioplasty and stenting for limb-threatening ischemia.

PubMed

Timaran, Carlos H; Stevens, Scott L; Freeman, Michael B; Goldman, Mitchell H

2002-09-01

The role of iliac artery angioplasty and stenting (IAS) for the treatment of limb-threatening ischemia is not defined. IAS has been used primarily for patients with disabling claudication. Because poorer results have been shown in patients with critical ischemia after iliac artery angioplasty, the purpose of this study was to estimate the influence of risk factors on the outcome of iliac angioplasty and stent placement in patients with limb-threatening ischemia. During a 5-year period (from 1996 to 2001), 85 iliac angioplasty and stent placement procedures (107 stents) were performed in 31 women and 43 men with limb-threatening ischemia. Patients with claudication were specifically excluded. The criteria prepared by the Ad Hoc Committee on Reporting Standards (Society for Vascular Surgery/International Society for Cardiovascular Surgery) were followed to define the variables. The TransAtlantic InterSociety Consensus classification was used to characterize the type of iliac lesions. Both univariate (Kaplan-Meier [KM]) and multivariate analyses (Cox proportional hazards model) were used to determine the association between variables, cumulative patency, limb salvage, and survival. Indications for iliac angioplasty with stenting were ischemic rest pain (56%) and tissue loss (44%). Primary stenting was performed in 36 patients (42%). Stents were placed selectively after iliac angioplasty mainly for residual stenosis or pressure gradient (43%). Overall, primary stent patency rate was 90% at 1 year, 74% at 3 years, and 69% at 5 years. Primary stent patency rate was significantly reduced in women compared with men (KM, log-rank test, P <.001). Primary patency rates at 1, 3, and 5 years were 79%, 57%, and 38% for women and 92%, 88%, and 88% for men. Primary stent patency rate also was significantly reduced in patients with renal insufficiency (creatinine level, >1.6 mg/dL; KM, log-rank test, P <.001). Cox regression analysis identified female gender (relative risk, 5.1; 95% CI, 1.8 to 7.9; P =.002) and renal insufficiency (relative risk, 6.6; 95% CI, 1.6 to 14.2; P =.01) as independent predictors of decreased primary stent patency. No independent predictors for limb salvage and survival were identified. Women undergoing iliac angioplasty and stenting for limb-threatening ischemia have significantly reduced primary stent patency rates and may need additional procedures to obtain satisfactory clinical improvement and limb salvage. Patients with renal insufficiency and critical ischemia also have reduced primary stent patency rates after IAS. Limb salvage, as shown in this study, is not affected by previous iliac stent failure.

Management of Infrapopliteal Arterial Disease: Critical Limb Ischemia.

PubMed

Mustapha, Jihad A; Diaz-Sandoval, Larry J

2014-10-01

According to the TransAtlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease, "there is increasing evidence to support a recommendation for angioplasty in patients with critical limb ischemia and infrapopliteal artery occlusion." Management of infrapopliteal artery disease starts with diagnosis using modern preprocedural noninvasive and invasive imaging. Interventionalists need to learn the role of chronic total occlusion cap analysis and collateral zone recognition in angiosome-directed interventions for management of critical limb ischemia and be familiar with equipment and device selection and a stepwise approach for endovascular interventions. Interventionalists need to know which crossing tools to use to successfully cross-complex chronic total occlusion caps. Copyright © 2014 Elsevier Inc. All rights reserved.

Diagnosis and treatment of limb fractures associated with acute peripheral ischemia.

PubMed

Popescu, G I; Lupescu, O; Nagea, M; Patru, C

2013-01-01

Acute Peripheral Ischemia (API) is the most severe acute complication after both open and closed fractures, as ischemia compromises not only the vitality of the affected limb, but also the patient's life, because metabolic anaerobic changes following ischemia have serious local and general consequences. These explain why early diagnosis of API is very important for the prognosis of the traumatized limb.The authors analyse cases when API was not diagnosed immediately after trauma, but some time after the first examination, due to either low systolic BP or to late onset of API. The patients were analysed concerning the type of the fracture, the reason for delayed diagnosis of API, the moment of API diagnosis and the arterial injury. In all those cases, surgery was performed immediately after API diagnosis, in order to identify and treat the complex injuries(bone and vascular). Celsius.

Primary stenting for TASC C and D femoropopliteal lesions: one-year results from a multicentric trial on 203 patients.

PubMed

Brouillet, Julie; Deloose, Koen; Goueffic, Yann; Poirier, Mathieu; Midy, Dominique; Caradu, Caroline; Ducasse, Eric

2018-06-01

Recent advances in endovascular techniques have made it a seductive choice in the management of TASC C and D lesions. Currently, this tendency remains controversial, despite high success rates. The aim of the study was to regroup and harmonize the results of three surgical teams in 5 centers in order to obtain the largest series ever published on TASC C and D femoro-popliteal lesions primary stenting. Two hundred and three patients and 209 lower limbs were included from March 2008 to October 2013. Each patient underwent primary stenting for TASC C or D femoro-popliteal lesions. Mean age was 70±10; 71.4% were male with a 39.8% rate of coronary heart disease, 20.1% of renal insufficiency and 35.9% of diabetes; 57,4% suffered from claudication and 42.6% from critical limb ischemia (CLI); 61.8% of the 144 limbs analyzed for run-off presented with 3 patent infra-popliteal arteries. Four hundred and three stents were implanted in the 209 limbs included. Median stented length was 252 mm. Associated procedures were performed in 35 patients (17.0%) including 4.3% minor amputations. The 30-day mortality rate was 1.4% (3 patients). Major complications occurred in 19 patients (9.3%) including 7 patients (3.4%) presented with early in-stent thrombosis. Median follow-up duration was 12 months (range 9.5-17.2 months). The 12-month mortality rate was 11.8% (24 patients). The 3, 6 and 12 months primary patency rates according to Kaplan Meier estimates were 98.1±0.9, 85.2±2.5 and 67.0±3.3% respectively. Secondary patency rates were 96.1±1.9, 89.3±3.0 and 75.7±4.2% respectively. A subgroup analysis reported significantly higher patency rates for TASC C lesions compared to TASC D lesions (82.1% vs. 44% respectively, P=0.009). The 12-month in-stent thrombosis and restenosis rates were 19.6% and 13.9% respectively. A subgroup analysis showed higher rates of in-stent restenosis for TASC D lesions compared to TASC C lesions (35% vs. 10% respectively, P=0.005). The stent fracture rate was equal to 10.2% (30 stents). Occurrence of in-stent thrombosis and restenosis were associated with 3 and 5 cases of stent fracture (type II to IV) respectively. Freedom from TLR was 70.5%. Rutherford class decreased from 3.7 to 0.9 (3.52±1.06 to 0.75±1.24) (P<0.0001). At 12 months 61.3% were asymptomatic, 33.3% suffered from claudication (21.3% Rutherford 1) and 5.4% suffered from CLI. Healing rates were 63.9% with a limb salvage rate of 95.5% and a major amputation rate of 3.8%. This is the largest series of TASC C and D femoro-popliteal lesions primary stenting to our knowledge. The results are encouraging with acceptable primary patency and clinical improvement at 12 months. Results from mid- to long-term follow-up are awaited.

Vascular access in critical limb ischemia.

PubMed

Kang, Won Yu; Campia, Umberto; Ota, Hideaki; Didier, Romain J; Negi, Smita I; Kiramijyan, Sarkis; Koifman, Edward; Baker, Nevin C; Magalhaes, Marco A; Lipinski, Michael J; Escarcega, Ricardo O; Torguson, Rebecca; Waksman, Ron; Bernardo, Nelson L

2016-01-01

Currently, percutaneous endovascular intervention is considered a first line of therapy for treating patients with critical limb ischemia. As the result of remarkable development of techniques and technologies, percutaneous endovascular intervention has led to rates of limb salvage comparable to those achieved with bypass surgery, with fewer complications, even in the presence of lower rates of long-term patency. Currently, interventionalists have a multiplicity of access routes including smaller arteries, with both antegrade and retrograde approaches. Therefore, the choice of the optimal access site has become an integral part of the success of the percutaneous intervention. By understanding the technical aspects, as well as the advantages and limitations of each approach, the interventionalists can improve clinical outcomes in patients with severe peripheral arterial disease. This article reviews the access routes in critical limb ischemia, their advantages and disadvantages, and the clinical outcomes of each. Copyright © 2016 Elsevier Inc. All rights reserved.

Aging and Outcome in Patients With Peripheral Artery Disease and Critical Limb Ischemia.

PubMed

Skonetzki, Saskia; Lüders, Florian; Engelbertz, Christiane; Malyar, Nasser M; Freisinger, Eva; Meyborg, Matthias; Reinecke, Holger

2016-10-01

Aging of the population is one of the major challenges facing public health systems. The impact of aging on acute and long-term outcome of patients with peripheral artery disease (PAD) and critical limb ischemia (CLI) is currently not sufficiently clarified. This analysis consists of comprehensive, anonymized data obtained from the largest public health insurance in Germany. A total of 41,740 PAD patients with an index hospitalization between January 1, 2009, and December 31, 2011, and a follow-up time up to 4 years were included (40-49 years: n = 1179; 50-59 years: n = 5415; 60-69 years: n = 10,565; 70-79 years: n = 13,313; 80-89 years: n = 9714; and 90-100 years: n = 1554). Advanced age was associated with female gender (men-women ratio up to 1:3.3), less smoking, less frequent obesity, more often chronic heart failure (up to 9-fold), chronic kidney disease (up to 4-fold), fewer angiographies (up to 0.8-fold), fewer endovascular (up to 0.5-fold) and surgical revascularizations (up to 0.9-fold), higher rates of amputation (up to 2.5-fold), acute renal failure (up to 3.7-fold), in-hospital mortality (up to 12-fold), myocardial infarction (up to 2.8-fold), ischemic stroke (up to 1.5-fold), infection (up to 1.4-fold), and sepsis (up to 1.8-fold) (each P < .001). During follow-up, advanced age was a highly significant independent predictor of long-term mortality, myocardial infarction, and stroke (each P < .001). Lengths of hospital stay (up to 1.3-fold longer) and reimbursement costs (up to 1.1-fold higher) were clearly associated with advanced age (each P < .001). This study demonstrates the impact of aging on morbidity, in-hospital treatment, complications, and acute and long-term outcome of PAD patients. Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

Hybrid Revascularization for Critical Limb Ischemia Triggered by Multiple Organ Dysfunction Due to Acute Pneumonia; Urgent Catheter Intervention Followed by Low-Density-Lipoprotein Apheresis and Elective Peripheral Bypass Surgery

PubMed Central

2014-01-01

A 66-year-old man was referred for treatment of critical limb ischemia arising with multiple organ dysfunction due to acute pneumonia. Angiographic examinations demonstrated total obstruction of the bilateral external iliac arteries and the bilateral superficial femoral arteries with collateral circulation to the distal vessels. Urgent percutaneous transluminal angioplasty dissolved the obstruction of the left external iliac artery, and subsequent low-density-lipoprotein apheresis ameliorated his progressive ischemia in the lower extremities. Femoro-femoral and bilateral femoro-popliteal bypasses were performed 31 days after the endovascular intervention, which achieved successful limb salvage with the relief of ischemic symptoms related to arteriosclerotic obliterans. PMID:24995063

Importance of postprocedural Wound, Ischemia, and foot Infection (WIfI) restaging in predicting limb salvage.

PubMed

Leithead, Charles; Novak, Zdenek; Spangler, Emily; Passman, Marc A; Witcher, Adam; Patterson, Mark A; Beck, Adam W; Pearce, Benjamin J

2018-02-01

The Wound, Ischemia, and foot Infection (WIfI) classification system was created to encompass demographic changes and expanding techniques of revascularization to perform meaningful analyses of outcomes in the treatment of the threatened limb. The WIfI index is intended to be analogous to the TNM staging system for cancer, with restaging to be done after control of infection and after revascularization. Our goal was to evaluate the effectiveness of WIfI restaging after therapy in the prediction of limb outcomes. Preoperative WIfI scoring was performed prospectively for all critical limb ischemia patients who underwent revascularization from January 2014 to June 2015. WIfI restaging and assessment of outcomes were performed retrospectively through August 2016. WIfI classification was determined at the following intervals: preoperatively, immediately postoperatively, and 1 month and 6 months after intervention. Amputation-free survival (AFS) was the primary end point. Kaplan-Meier plot analysis and comparisons of preoperative grades with respective postoperative grades were performed using paired t-test, χ 2 test, and correlation analyses. A total of 180 limbs and 172 critical limb ischemia patients underwent revascularization, of which 29 limbs had major amputations (16%). Wound grades generally improved after surgery across the entire cohort. Major amputation was associated with preoperative wound grade and remained associated with wound grade at postoperative restaging at 1 month and beyond on the basis of amputation frequency analysis (preoperatively, 1 month, and 6 months, P = .03, < .001, and < .001, respectively). Wound grade was significantly associated with AFS at 1 month and 6 months after intervention (log-rank, P < .001 for restaging intervals). Ischemia grades improved initially with a slight decline across the cohort at 6 months. Ischemia grade at 1 month postoperatively was associated with AFS (log-rank, P = .03). Foot infection grades also improved at each time interval. Foot infection grade was associated with AFS at 1 month postoperatively (log-rank, P < .001) and at 6 months (log-rank, P = .017). WIfI restaging is an important tool for predicting limb loss and assessing adequacy of intervention, more so than baseline WIfI alone. The 1- and 6-month postoperative ischemia grade correlated with AFS, whereas preoperative grade did not. The 1- and 6-month postoperative wound and foot infection grades additionally correlated with AFS. WIfI restaging at 1 month and 6 months postoperatively may help identify a cohort that remains at higher risk for limb loss and may merit more expeditious reintervention. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Thromboxane A2 moderates permeability after limb ischemia.

PubMed Central

Lelcuk, S; Alexander, F; Valeri, C R; Shepro, D; Hechtman, H B

1985-01-01

Reperfusion after limb ischemia results in muscle edema as well as excess secretion of thromboxane A2 (TxA2), an agent associated with permeability increase in other settings. This study tests whether TxA2 moderates the permeability following limb ischemia. A tourniquet inflated to 300 mmHg was applied for 2 hours around the hind limb of four groups of dogs. In untreated animals (N = 25), 2 hours following tourniquet release, plasma TxB2 values rose from 320 pg/ml to 2416 pg/ml (p less than 0.001), and popliteal lymph values rose from 378 pg/ml to 1046 pg/ml (p less than 0.001). Platelet TxB2 was unaltered and plasma 6-keto-PGF1 alpha levels did not vary. Following ischemia, lymph flow (QL) increased from 0.07 to 0.37 ml/h (p less than 0.05), while the lymph/plasma (L/P) protein ratio was unchanged at 0.41. These measurements indicate increased permeability since increase in hydrostatic pressure in a second group by tourniquet inflation to 50 mmHg (N = 7) led to a rise in QL from 0.07 to 0.22 ml/h, but a fall in the L/P ratio to 0.32, a value lower than the ischemic group (p less than 0.05). Pretreatment with the imidazole derivative ketoconazole (N = 11) reduced platelet Tx synthesis from 42 ng to 2 ng/10(9) platelets, but lymph TxB2 levels rose to 1703 pg/ml after ischemia, indicating an extravascular or vessel wall site of synthesis not inhibited by ketoconazole. Pretreatment with a lower molecular weight imidazole derivative OKY 046 (N = 9) inhibited all Tx synthesis after ischemia. Prior to tourniquet inflation, both OKY 046 and ketoconazole lowered plasma TxB2 levels as well as the L/P ratio (p less than 0.05). After ischemia, OKY 046, but not ketoconazole, maintained the L/P ratio at 0.33, a value below that of untreated animals (p less than 0.05). These results indicate that nonplatelet-derived TxA2 modulates both baseline and ischemia-induced increases in microvascular permeability in the dog hind limb. PMID:3840349

Successful limb salvage through staged bypass combined with free gracilis muscle transfer for critical limb ischemia with osteomyelitis after failed endovascular therapy.

PubMed

Miyake, Keisuke; Kikuchi, Shinsuke; Okuda, Hiroko; Koya, Atsuhiro; Abe, Satomi; Sawa, Yoshiki; Ota, Tetsuo; Azuma, Nobuyoshi

2018-05-02

Critical limb ischemia with osteomyelitis is so difficult to treat that even appropriate revascularization and wound therapy cannot achieve limb salvage because of uncontrollable infection. It is still difficult to judge the possibility of limb salvage before revascularization. A 73-year-old male complained of a small ulcer on his left toe, which was treated with multiple endovascular therapy. After failed endovascular therapy, he suffered extensive tissue loss with tibial osteomyelitis. We carried out staged surgery that was composed of dual bypass to the sural artery and posterior tibial artery. After intensive debridement and wound care, insertion of a subsequent free gracilis muscle flap to cover the exposed tibial bone was performed, achieving functional limb salvage. Even in the threatened limb with extensive tissue loss and osteomyelitis, intensive and multidisciplinary treatment with staged revascularization, muscle transfer, and appropriate wound care achieved functional limb salvage.

The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection.

PubMed

Johnsen, Jacob; Pryds, Kasper; Salman, Rasha; Løfgren, Bo; Kristiansen, Steen Buus; Bøtker, Hans Erik

2016-03-01

Remote ischemic preconditioning (rIPC), induced by cycles of transient limb ischemia and reperfusion (IR), is cardioprotective. The optimal rIPC-algorithm is not established. We investigated the effect of cycle numbers and ischemia duration within each rIPC-cycle and the influence of effector organ mass on the efficacy of cardioprotection. Furthermore, the duration of the early phase of protection by rIPC was investigated. Using a tourniquet tightened at the inguinal level, we subjected C57Bl/6NTac mice to intermittent hind-limb ischemia and reperfusion. The rIPC-protocols consisted of (I) two, four, six or eight cycles, (II) 2, 5 or 10 min of ischemia in each cycle, (III) single or two hind-limb occlusions and (IV) 0.5, 1.5, 2.0 or 2.5 h intervals from rIPC to index cardiac ischemia. All rIPC algorithms were followed by 5 min of reperfusion. The hearts were subsequently exposed to 25 min of global ischemia and 60 min of reperfusion in an ex vivo Langendorff model. Cardioprotection was evaluated by infarct size and post-ischemic hemodynamic recovery. Four to six rIPC cycles yielded significant cardioprotection with no further protection by eight cycles. Ischemic cycles lasting 2 min offered the same protection as cycles of 5 min ischemia, whereas prolonged cycles lasting 10 min abrogated protection. One and two hind-limb preconditioning were equally protective. In our mouse model, the duration of protection by rIPC was 1.5 h. These findings indicate that the number and duration of cycles rather than the tissue mass exposed to rIPC determines the efficacy of rIPC.

Exploring the Role of TRPV and CGRP in Adenosine Preconditioning and Remote Hind Limb Preconditioning-Induced Cardioprotection in Rats.

PubMed

Singh, Amritpal; Randhawa, Puneet Kaur; Bali, Anjana; Singh, Nirmal; Jaggi, Amteshwar Singh

2017-04-01

The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff's isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dt max and -dp/dt min . Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.

Percutaneous ex-vivo femoral arterial bypass: a novel approach for treatment of acute limb ischemia as a complication of femoral arterial catheterization.

PubMed

Merhi, William M; Turi, Zoltan G; Dixon, Simon; Safian, Robert D

2006-09-01

This report describes the use of a percutaneous ex-vivo femoral arterial bypass in three patients with acute lower extremity ischemia that occurred as a complication of femoral artery catheterization. Utilizing standard equipment and techniques, a percutaneous ex-vivo femoral artery bypass can restore antegrade flow to the ischemic limb in patients with impaired aorto-iliac inflow circulation, which may arise from iatrogenic dissection or the need for large in-dwelling sheaths required for hemodynamic support. This technique is considered a temporizing measure when conventional therapies are not possible. Contrast angiography is recommended to localize and define the cause of limb ischemia, and to permit safe placement of vascular sheaths in the "donor and recipient" arteries.

Possible role of thromboxane A2 in remote hind limb preconditioning-induced cardioprotection.

PubMed

Sharma, Roohani; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

2016-01-01

Remote hind limb preconditioning (RIPC) is a protective strategy in which short episodes of ischemia and reperfusion in a remote organ (hind limb) protects the target organ (heart) against sustained ischemic reperfusion injury. The present study was designed to investigate the possible role of thromboxane A2 in RIPC-induced cardioprotection in rats. Remote hind limb preconditioning was performed by four episodes of 5 min of inflation and 5 min of deflation of pressure cuff. Occlusion of the hind limb with blood pressure cuff is most feasible, non-invasive, clinically relevant, and safe method for inducing RIPC. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120-min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. The extent of myocardial infarct size along with the functional parameters including left ventricular developed pressure (LVDP), dp/dtmax, and dp/dtmin were also measured. Ozagrel (thromboxane synthase inhibitor) and seratrodast (thromboxane A2 receptor antagonist) were employed as pharmacological modulators of thromboxane A2. Remote hind limb preconditioning significantly attenuated ischemia/reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of ozagrel and seratrodast completely abolished the cardioprotective effects of RIPC suggesting the key role of thromboxane A2 in RIPC-induced cardioprotection. It may be concluded that brief episodes of preconditioning ischemia and reperfusion activates the thromboxane synthase enzyme that produces thromboxane A2, which may elicit cardioprotection either involving humoral or neurogenic pathway.

An early validation of the Society for Vascular Surgery lower extremity threatened limb classification system.

PubMed

Cull, David L; Manos, Ginger; Hartley, Michael C; Taylor, Spence M; Langan, Eugene M; Eidt, John F; Johnson, Brent L

2014-12-01

The Society for Vascular Surgery (SVS) recently established the Lower Extremity Threatened Limb Classification System, a staging system using Wound characteristic, Ischemia, and foot Infection (WIfI) to stratify the risk for limb amputation at 1 year. Although intuitive in nature, this new system has not been validated. The purpose of the following study was to determine whether the WIfI system is predictive of limb amputation and wound healing. Between 2007 and 2010, we prospectively obtained data related to wound characteristics, extent of infection, and degree of postrevascularization ischemia in 139 patients with foot wounds who presented for lower extremity revascularization (158 revascularization procedures). After adapting those data to the WIfI classifications, we analyzed the influence of wound characteristics, extent of infection, and degree of ischemia on time to wound healing; empirical Kaplan-Meier survival curves were compared with theoretical outcomes predicted by WIfI expert consensus opinion. Of the 158 foot wounds, 125 (79%) healed. The median time to wound healing was 2.7 months (range, 1-18 months). Factors associated with wound healing included presence of diabetes mellitus (P = .013), wound location (P = .049), wound size (P = .007), wound depth (P = .004), and degree of ischemia (P < .001). The WIfI clinical stage was predictive of 1-year limb amputation (stage 1, 3%; stage 2, 10%; stage 3, 23%; stage 4, 40%) and wound nonhealing (stage 1, 8%; stage 2, 10%; stage 3, 23%; stage 4, 40%) and correlated with the theoretical outcome estimated by the SVS expert panel. The theoretical framework for risk stratification among patients with critical limb ischemia provided by the SVS expert panel appears valid. Further validation of the WIfI classification system with multicenter data is justified. Copyright © 2014 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Lipoate ameliorates ischemia-reperfusion in animal models.

PubMed

Freisleben, H J

2000-01-01

Ischemia and reperfusion were studied in isolated working rat hearts and in exarticulated rat hind limbs. Free radicals are known to be generated in ischemia/reperfusion and to propagate complications. To reduce reperfusion injury, conditions were ameliorated including the treatment with antioxidants, lipoate or dihydrolipoate. In isolated working rat hearts, cardiac and mitochondrial parameters are impaired during hypoxia and partially recover in reperfusion. Dihydrolipoate, if added into the perfusion buffer at 0.3 microM concentration, keeps the pH higher (7.15) during hypoxia, as compared to controls (6.98). This compound accelerates and stabilizes the recovery of the aortic flow. With dihydrolipoate, ATP synthesis is increased, ATPase activity (ATP hydrolysis) reduced, intracellular creatine kinase activity maintained and thus phosphocreatine contents are higher than in controls. For exarticulated rat hind limbs, the dihydrolipoate group contained 8.3 microM in the modified reperfusate. Recovery of the contractile function was 49% vs. 34% in controls and muscle flexibility was maintained whereas it decreased by 15% in the controls. Release of creatine kinase from cells was significantly lower with dihydrolipoate. Lipoate/dihydrolipoate effectively reduced reperfusion injury in isolated working rat hearts and in exarticulated rat hind limbs after extended ischemia. Finally, the compound was successfully applied in an in vivo pig hind limb model.

Rheolytic thrombectomy in the management of limb ischemia: 30-day results from a multicenter registry.

PubMed

Ansel, Gary M; George, Barry S; Botti, Charles F; McNamara, Thomas O; Jenkins, J Stephen; Ramee, Steven R; Rosenfield, Kenneth; Noethen, Alice A; Mehta, Tejas

2002-08-01

To evaluate the use of rheolytic thrombectomy (RT) with the AngioJet catheter for treatment of lower extremity ischemia due to arterial/graft thrombotic occlusion. A retrospective multicenter review was performed of 99 consecutive patients (52 men; mean age 67 +/- 13 years, range 30-90) who underwent RT for thrombotic occlusions in native arteries (n=80) or bypass grafts (n=19). Pre- and postprocedural limb ischemia and in-hospital events were evaluated. Amputation and mortality rates at 30 days were determined. The majority of patients (78.8%) presented within 14 days of symptom onset. RT resulted in substantial to complete thrombus removal in 70 (70.7%) patients and partial in 22 (22.2%); there was no angiographic change in 7 (7.1%). Adjunctive post RT thrombolysis was used in 37 patients. Underlying stenoses found in 81 limbs were treated with one or more of the following procedures: balloon angioplasty (n=62), stenting (n=35), or nonemergent surgical revision (n=5). In-hospital complications included 2 major amputations, 5 cases of minor tissue loss, 7 rethromboses, and 3 cases of transient renal insufficiency. Four (4.0% patients died in-hospital; the 95 surviving patients all had viable limbs at discharge. Mortality and amputation rates at 30 days were 7.1% and 4.0%, respectively. Percutaneous treatment of thrombotic occlusions with RT, followed by definitive treatment of the underlying stenosis, is a promising therapeutic option for patients with limb-threatening ischemia.

Application of autologous platelet-rich plasma to enhance wound healing after lower limb revascularization: A case series and literature review.

PubMed

Massara, Mafalda; Barillà, David; De Caridi, Giovanni; Serra, Raffaele; Volpe, Alberto; Surace, Rosangela; Foti, Giovanni; Marcuccio, Daniela; Pucci, Giulia; Volpe, Pietro

2015-01-01

Dermal tissue loss in patients affected by critical limb ischemia represents a serious wound-healing problem, with high morbidity, prolonged hospital stay, and high patient care costs. Treatment of ischemic foot lesions requires limb revascularization by endovascular or open surgical intervention and individualized patient-specific wound care, including antibiotic therapy; devitalized/infected wound debridement; and advanced wound dressing. In selected patients, spinal cord stimulation, vacuum-assisted closure therapy, and bioengineered tissue or skin substitutes and growth factors have been shown to improve wound healing. In this study, we present our preliminary results on topical application of autologous platelet-rich plasma to enhance the process of wound healing after revascularization of lower limbs in patients affected by critical limb ischemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Recent trends in morbidity and in-hospital outcomes of in-patients with peripheral arterial disease: a nationwide population-based analysis.

PubMed

Malyar, Nasser; Fürstenberg, Torsten; Wellmann, Jürgen; Meyborg, Matthias; Lüders, Florian; Gebauer, Katrin; Bunzemeier, Holger; Roeder, Norbert; Reinecke, Holger

2013-09-01

The prevalence of peripheral arterial disease (PAD) and especially of critical limb ischaemia (CLI) is announced to rise dramatically worldwide, with a considerable impact on the health care and socio-economic systems. We aimed to characterize the recent trends in morbidity and in-hospital outcome of PAD among all hospitalized patients in the entire German population between 2005 and 2009. Nationwide data of all hospitalizations in Germany in 2005, 2007, and 2009 were analysed regarding the prevalence of PAD, comorbidities, endovascular (EVR) and surgical revascularizations (SR), major and minor amputations, in-hospital mortality, and associated costs. From 2005 to 2009, total PAD cases increased by 20.7% (from 400 928 to 483 961), with an increase of CLI subset from 40.6 to 43.5%. Total EVR increased by 46%, while thromb-embolectomy, endarterectomy, and patch plastic increased by 67, 42, and 21%, respectively. Peripheral bypasses decreased by 2%. Major amputation decreased from 4.6 to 3.5%, while minor amputation slightly increased from 4.98 to 5.11%. The crude overall in-hospital mortality remained unchanged in claudicants (2.2%), while it decreased from 9.8 to 8.4% in CLI patients. However, mortality rate according to the Poisson model (n/1000 hospital residence days) increased significantly in claudicants (P < 0.001). Total reimbursement costs for PAD in-patient care increased by 21% with an average per case costs in 2009 of €4506 in a claudicant and €6791 in a CLI patient. This population-based analysis documents the significant rise of PAD, particularly of the CLI subset, and highlights the malign prognosis associated with PAD as indicated by high amputation and in-hospital mortality rates.

The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI).

PubMed

Mills, Joseph L; Conte, Michael S; Armstrong, David G; Pomposelli, Frank B; Schanzer, Andres; Sidawy, Anton N; Andros, George

2014-01-01

Critical limb ischemia, first defined in 1982, was intended to delineate a subgroup of patients with a threatened lower extremity primarily because of chronic ischemia. It was the intent of the original authors that patients with diabetes be excluded or analyzed separately. The Fontaine and Rutherford Systems have been used to classify risk of amputation and likelihood of benefit from revascularization by subcategorizing patients into two groups: ischemic rest pain and tissue loss. Due to demographic shifts over the last 40 years, especially a dramatic rise in the incidence of diabetes mellitus and rapidly expanding techniques of revascularization, it has become increasingly difficult to perform meaningful outcomes analysis for patients with threatened limbs using these existing classification systems. Particularly in patients with diabetes, limb threat is part of a broad disease spectrum. Perfusion is only one determinant of outcome; wound extent and the presence and severity of infection also greatly impact the threat to a limb. Therefore, the Society for Vascular Surgery Lower Extremity Guidelines Committee undertook the task of creating a new classification of the threatened lower extremity that reflects these important considerations. We term this new framework, the Society for Vascular Surgery Lower Extremity Threatened Limb Classification System. Risk stratification is based on three major factors that impact amputation risk and clinical management: Wound, Ischemia, and foot Infection (WIfI). The implementation of this classification system is intended to permit more meaningful analysis of outcomes for various forms of therapy in this challenging, but heterogeneous population. Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Low-molecular weight heparin protamine complex augmented the potential of adipose-derived stromal cells to ameliorate limb ischemia.

PubMed

Kishimoto, Satoko; Inoue, Ken-Ichi; Nakamura, Shingo; Hattori, Hidemi; Ishihara, Masayuki; Sakuma, Masashi; Toyoda, Shigeru; Iwaguro, Hideki; Taguchi, Isao; Inoue, Teruo; Yoshida, Ken-Ichiro

2016-06-01

Heparin/protamine micro/nanoparticles (LH/P-MPs) were recently developed as low-molecular weight, biodegradable carriers for adipose-derived stromal cells (ADSCs). These particles can be used for a locally delivered stem cell therapy that promotes angiogenesis. LH/P-MPs bind to the cell surface of ADSCs and promote cell-to-cell interaction and aggregation of ADSCs. Cultured ADSC/LH/P-MP aggregates remain viable. Here, we examined the ability of these aggregates to rescue limb loss in a mouse model of hindlimb ischemia. Unilateral hindlimb ischemia was induced in adult male BALB/c mice by ligation of the iliac artery and hindlimb vein. For allotransplantation of ADSCs from the same inbred strain, we injected ADSC alone or ADSC/LH/P-MP aggregates or control medium (sham-treated) directly into the ischemic muscles. Ischemic limb blood perfusion, vessel density, and vessel area were recorded. The extent of ischemic limb necrosis or limb loss was assessed on postoperative days 2, 7, and 14. Compared with the sham-treatment control, treatment with ADSCs alone showed modest effects on blood perfusion recovery and increased the number of α-SMA-positive vessels. Response to ADSC/LH/P-MP aggregates was significantly greater than ADSCs alone for every endpoint. ADSC/LH/P-MP aggregates more effectively prevented the loss of ischemic hindlimbs than ADSCs alone or the sham-treatment. The LH/P-MPs augmented the effects of ADSCs on angiogenesis and reversal of limb ischemia. Use of ADSC/LH/P-MP aggregates offers a novel and convenient treatment method and potentially represents a promising new therapeutic approach to inducing angiogenesis in ischemic diseases. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

[Acute limb ischemia from the general surgeon's point of view. How much knowledge of vascular surgery is necessary?].

PubMed

Kopp, R; Weidenhagen, R; Hornung, H; Jauch, K W; Lauterjung, L

2003-12-01

The diagnosis of acute peripheral ischemia can be obtained based on clinical presentation, inspection, and palpation of the affected extremity. Unfractionated heparin as a single shot is immediately given followed by continuous infusion when diagnosis is clinically evident and contraindications are excluded. Thromboembolectomy using a Fogarty catheter is immediately performed in patients with evidence of arterial embolization and signs of advanced ischemia (TASC IIb/III) followed by intraoperative angiography. Patients with evidence of arterial thrombosis require urgent angiography followed by thrombectomy and probably subsequent endovascular or surgical interventions and vascular reconstruction. For patients with moderate ischemia (TASC IIa), initial diagnostic angiography is recommended followed by primary thrombectomy with subsequent intraoperative angiography and immediate endovascular or operative treatment of remaining vascular problems. As an alternative therapeutic option initial catheter-guided local thrombolysis can be performed in selected patients with the intention of subsequent limb revascularization or unmasking relevant vessel alterations leading to specific endovascular or surgically performed vascular reconstruction. Possible development of muscle ischemia because of increased compartment pressure should be considered and fasciotomy performed when indicated. Primary amputation of the severely ischemic limb after initial thrombectomy might be recommended in patients with life-threatening organ failure related to muscle necrosis.

BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy.

PubMed

McClung, Joseph M; McCord, Timothy J; Ryan, Terence E; Schmidt, Cameron A; Green, Tom D; Southerland, Kevin W; Reinardy, Jessica L; Mueller, Sarah B; Venkatraman, Talaignair N; Lascola, Christopher D; Keum, Sehoon; Marchuk, Douglas A; Spangenburg, Espen E; Dokun, Ayotunde; Annex, Brian H; Kontos, Christopher D

2017-07-18

Critical limb ischemia is a manifestation of peripheral artery disease that carries significant mortality and morbidity risk in humans, although its genetic determinants remain largely unknown. We previously discovered 2 overlapping quantitative trait loci in mice, Lsq-1 and Civq-1 , that affected limb muscle survival and stroke volume after femoral artery or middle cerebral artery ligation, respectively. Here, we report that a Bag3 variant (Ile81Met) segregates with tissue protection from hind-limb ischemia. We treated mice with either adeno-associated viruses encoding a control (green fluorescent protein) or 2 BAG3 (Bcl-2-associated athanogene-3) variants, namely Met81 or Ile81, and subjected the mice to hind-limb ischemia. We found that the BAG3 Ile81Met variant in the C57BL/6 (BL6) mouse background segregates with protection from tissue necrosis in a shorter congenic fragment of Lsq-1 (C.B6- Lsq1-3 ). BALB/c mice treated with adeno-associated virus encoding the BL6 BAG3 variant (Ile81; n=25) displayed reduced limb-tissue necrosis and increased limb tissue perfusion compared with Met81- (n=25) or green fluorescent protein- (n=29) expressing animals. BAG3 Ile81 , but not BAG3 Met81 , improved ischemic muscle myopathy and muscle precursor cell differentiation and improved muscle regeneration in a separate, toxin-induced model of injury. Systemic injection of adeno-associated virus-BAG3 Ile81 (n=9), but not BAG3 Met81 (n=10) or green fluorescent protein (n=5), improved ischemic limb blood flow and limb muscle histology and restored muscle function (force production). Compared with BAG3 Met81 , BAG3 Ile81 displayed improved binding to the small heat shock protein (HspB8) in ischemic skeletal muscle cells and enhanced ischemic muscle autophagic flux. Taken together, our data demonstrate that genetic variation in BAG3 plays an important role in the prevention of ischemic tissue necrosis. These results highlight a pathway that preserves tissue survival and muscle function in the setting of ischemia. © 2017 American Heart Association, Inc.

[The long-term results and indications for use of Gore-Texgrafts in the femoropopliteal position in patients with atherosclerotic lesion of lower limb arteries].

PubMed

Pokrovskiĭ, A V; Dan, V N; Zotikov, A E; Chupin, A V; Shubin, A A; Chikharev, M V

2004-01-01

Presented herein are the long-term results of femoropopliteal reconstructions above the knee joint fisure in patients with atherosclerotic lesion of the femoropopliteal segment using Gore-Tex grafts. The retrospective study accrued 108 patients. Of these, IIB degree lower limb ischemia (according to the A.V. Pokrovsky classification) was initially present in 64 (60.2%) and critical ischemia in 52 (40.8%) patients. Patients suffering from lower limb ischemia of varying degree did not significantly differ in the age or coexistent diseases. The mean value of the ankle/brachial index (ABI) accounted for 0.46+/-0.23 in patients with IIB degree ischemia and for 0.40+/-0.27 in patients with critical lower limb ischemia. All the patients were evaluated for the condition of the distal bed according to the scheme proposed by Rutherford et al. in 1997. The patients were distributed into three groups: patients with "good" runoff (from 1 to 4 points, n=65), patients with "satisfactory" runoff (from 5 to 7 points, n=36), and those with an "unsatisfactory" condition of the distal bed (runoff point over 7, n=7). The long-term results were assessed in 81 (75%) patients over the period as long as 105 months. The mean follow up accounted for 58,4 months. One year later the graft patency in the total patient group constituted 73.1%, after 3 years it was equal to 54.8%, and after 5 years to 49.9%. It is demonstrated that the initial runoff point exerted a significant effect on the graft patency. It is noteworthy that in patients with an initially "good" runoff point, 57.5% of the grafts were patent 5 years after operation whereas in patients with a "satisfactory" point only 35.3% turned out patent (p<0.05). Patients with an initially "unsatisfactory" runoff point developed thrombosis of all grafts over the period as long as 6 months following operation. The five-year limb salvage was observed in 77.6% of patients. It has been revealed over the 5-year period that the degree of initial limb ischemia did not produce any significant effect on the graft patency or limb salvage. The scheme for runoff assessment allows to define in a differentiated way the indications for use of Gore-Tex grafts in the femoropopliteal position. The runoff point had a significant effect on the long-term 5-year patency of the grafts.

Society for Vascular Surgery Wound, Ischemia, foot Infection (WIfI) score correlates with the intensity of multimodal limb treatment and patient-centered outcomes in patients with threatened limbs managed in a limb preservation center.

PubMed

Robinson, William P; Loretz, Lorraine; Hanesian, Colleen; Flahive, Julie; Bostrom, John; Lunig, Nicholas; Schanzer, Andres; Messina, Louis

2017-08-01

The Society for Vascular Surgery Wound, Ischemia, foot Infection (WIfI) system aims to stratify threatened limbs according to their anticipated natural history and estimate the likelihood of benefit from revascularization, but whether it accurately stratifies outcomes in limbs undergoing aggressive treatment for limb salvage is unknown. We investigated whether the WIfI stage correlated with the intensity of limb treatment required and patient-centered outcomes. We stratified limbs from a prospectively maintained database of consecutive patients referred to a limb preservation center according to WIfI stage (October 2013-May 2015). Comorbidities, multimodal limb treatment, including foot operations and revascularization, and patient-centered outcomes (wound healing, limb salvage, amputation-free survival, maintenance of ambulatory and independent living status, and mortality) were compared among WIfI stages. Multivariate analysis was performed to identify predictors of wound healing and limb salvage. We identified 280 threatened limbs encompassing all WIfI stages in 257 consecutive patients: stage 1, 48 (17%); stage 2, 67 (24%); stage 3, 64 (23%); stage 4, 83 (30%); and stage 5 (unsalvageable), 18 (6%). Operative foot débridement, minor amputation, and use of revascularization increased with increasing WIfI stage (P ≤ .04). Revascularization was performed in 106 limbs (39%), with equal use of open and endovascular procedures. Over a median follow-up of 209 days (interquartile range, 95, 340) days, 1-year Kaplan-Meier wound healing cumulative incidence was 71%, and the proportion with complete wound healing decreased with increasing WIfI stage. Major amputation was required in 26 stage 1 to 4 limbs (10%). Increasing WIfI stage was associated with decreased 1-year Kaplan-Meier limb salvage (stage 1: 96%, stage 2: 84%, stage 3: 90%, and stage 4: 78%; P = .003) and amputation-free survival (P = .006). Stage 4 WIfI independently predicted amputation (hazard ratio, 12; 95% confidence interval, 1.6-94). Amputation rates in patients with severe Ischemia grade 3 were lower in those who underwent revascularization than in those who did not (14% vs 41%; P = .01) Ambulatory and independent living status at follow-up deteriorated significantly from baseline in stage 4 but not stage 1 to 3 patients. Mortality was not different between WIfI stages. In patients treated aggressively for limb salvage, WIfI stage correlated with intensity of multimodal limb treatment and with limb salvage and patient-centered outcomes at 1 year. Revascularization improved limb salvage in severe ischemia. These data support the Society for Vascular Surgery WIfI system as a powerful tool to risk-stratify patients with threatened limbs and guide treatment. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Low energy shock wave therapy induces angiogenesis in acute hind-limb ischemia via VEGF receptor 2 phosphorylation.

PubMed

Holfeld, Johannes; Tepeköylü, Can; Blunder, Stefan; Lobenwein, Daniela; Kirchmair, Elke; Dietl, Marion; Kozaryn, Radoslaw; Lener, Daniela; Theurl, Markus; Paulus, Patrick; Kirchmair, Rudolf; Grimm, Michael

2014-01-01

Low energy shock waves have been shown to induce angiogenesis, improve left ventricular ejection fraction and decrease angina symptoms in patients suffering from chronic ischemic heart disease. Whether there is as well an effect in acute ischemia was not yet investigated. Hind-limb ischemia was induced in 10-12 weeks old male C57/Bl6 wild-type mice by excision of the left femoral artery. Animals were randomly divided in a treatment group (SWT, 300 shock waves at 0.1 mJ/mm2, 5 Hz) and untreated controls (CTR), n = 10 per group. The treatment group received shock wave therapy immediately after surgery. Higher gene expression and protein levels of angiogenic factors VEGF-A and PlGF, as well as their receptors Flt-1 and KDR have been found. This resulted in significantly more vessels per high-power field in SWT compared to controls. Improvement of blood perfusion in treatment animals was confirmed by laser Doppler perfusion imaging. Receptor tyrosine kinase profiler revealed significant phosphorylation of VEGF receptor 2 as an underlying mechanism of action. The effect of VEGF signaling was abolished upon incubation with a VEGFR2 inhibitor indicating that the effect is indeed VEGFR 2 dependent. Low energy shock wave treatment induces angiogenesis in acute ischemia via VEGF receptor 2 stimulation and shows the same promising effects as known from chronic myocardial ischemia. It may therefore develop as an adjunct to the treatment armentarium of acute muscle ischemia in limbs and myocardium.

Investigations on the role of leukotrienes in remote hind limb preconditioning-induced cardioprotection in rats.

PubMed

Singh, Baljeet; Randhawa, Puneet Kaur; Singh, Nirmal; Jaggi, Amteshwar Singh

2016-05-01

The cardioprotective effects of remote hind limb preconditioning (RIPC) are well established, but its mechanisms still remain to be explored. Therefore, the present study was aimed to explore the possible involvement of 5-lipoxygenase-derived leukotrienes in RIPC. The hind limb was tied by a pressure cuff and was subjected to four episodes of inflation and deflation (5min each) to induce remote hind-limb preconditioning. Thereafter, the hearts were isolated and were subjected to global ischemia (30min) followed by reperfusion (120min) on the Langendorff apparatus. The extent of myocardial injury was assessed by measuring lactate dehydrogenase (LDH) and creatine kinase (CK) levels in the coronary effluent; the infarct size using TTC staining, and the hemodynamic parameters including LVDP, dp/dtmax and dp/dtmin. RIPC significantly decreased ischemia and reperfusion-induced increase in LDH, CK release, infarct size and improved LVDP, dp/dtmax and dp/dtmin. Administration of montelukast, leukotriene receptor antagonist (10 and 20mg/kg) and zileuton, 5-lipoxygenase inhibitor, (2.5 and 5mg/kg) abolished RIPC-induced cardioprotection. It may be concluded that hind limb ischemia stimulates 5-lipoxygenase to release leukotrienes which may elicit cardioprotection by humoral or neurogenic pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Inhalation of Carbon Monoxide Reduces Skeletal Muscle Injury Following Hind Limb Ischemia Reperfusion Injury in Mice

PubMed Central

Patel, Rajendra; Albadawi, Hassan; Steudel, Wolfgang; Hashmi, Faraz F.; Kang, Jeanwan; Yoo, Hyung-Jin; Watkins, Michael T.

2011-01-01

Introduction The purpose of this study was to determine if inhaled carbon monoxide (CO) can ameliorate skeletal muscle injury, modulate endogenous heme oxygenase-1 (HO) expression, improve indices of tissue integrity and inflammation following hind limb ischemia reperfusion(IR). Methods C57BL6 mice inhaling CO (250ppm) or room air were subjected to 1.5 hrs of ischemia followed by limb reperfusion for either 3 or 6 hours (total treatment time of 4.5 or 7.5 hrs). After the initial period of reperfusion, all mice breathed only room air until 24 hours after the onset of ischemia. Mice were sacrificed at either the end of CO treatment or at 24 hours reperfusion. Skeletal muscle was subjected to histologic and biochemical analysis. Results CO treatment for 7.5 hours protected skeletal muscle from histologic and structural evidence of skeletal muscle injury. Serum and tissue cytokines were significantly reduced (p<0.05) in mice treated with CO for 7.5 hours. Tubulin, Heme Oxygenase, and ATP levels were higher in CO treated mice. Conclusions Inhaled CO protected muscle from structural injury and energy depletion following IR. PMID:22450026

Poloxamer 188 protects against ischemia-reperfusion injury in a murine hind-limb model.

PubMed

Murphy, Adrian D; McCormack, Michael C; Bichara, David A; Nguyen, John T; Randolph, Mark A; Watkins, Michael T; Lee, Raphael C; Austen, William G

2010-06-01

Ischemia-reperfusion injury can activate pathways generating reactive oxygen species, which can injure cells by creating holes in the cell membranes. Copolymer surfactants such as poloxamer 188 are capable of sealing defects in cell membranes. The authors postulated that a single-dose administration of poloxamer 188 would decrease skeletal myocyte injury and mortality following ischemia-reperfusion injury. Mice underwent normothermic hind-limb ischemia for 2 hours. Animals were treated with 150 microl of poloxamer 188 or dextran at three time points: (1) 10 minutes before ischemia; (2) 10 minutes before reperfusion; and (3) 2 or 4 hours after reperfusion. After 24 hours of reperfusion, tissues were analyzed for myocyte injury (histology) and metabolic dysfunction (muscle adenosine 5'-triphosphate). Additional groups of mice were followed for 7 days to assess mortality. When poloxamer 188 treatment was administered 10 minutes before ischemia, injury was reduced by 84 percent, from 50 percent injury in the dextran group to 8 percent injury in the poloxamer 188 group (p < 0.001). When administered 10 minutes before reperfusion, poloxamer 188 animals demonstrated a 60 percent reduction in injury compared with dextran controls (12 percent versus 29 percent). Treatment at 2 hours, but not at 4 hours, postinjury prevented substantial myocyte injury. Preservation of muscle adenosine 5'-triphosphate paralleled the decrease in myocyte injury in poloxamer 188-treated animals. Poloxamer 188 treatment significantly reduced mortality following injury (10 minutes before, 75 percent versus 25 percent survival, p = 0.0077; 2 hours after, 50 percent versus 8 percent survival, p = 0.032). Poloxamer 188 administered to animals decreased myocyte injury, preserved tissue adenosine 5'-triphosphate levels, and improved survival following hind-limb ischemia-reperfusion injury.

Use of Tourniquets and their Effects on Limb Function in the Modern Combat Environment

DTIC Science & Technology

2010-03-01

pressure by tightening a tourniquet, the pressure can soon damage nerves (>500 mm Hg) while remaining ineffective. Many tourniquet manufacturers are unaware...testing, and clinical use.2,57 TOURNIQUET USE, TISSUE ISCHEMIA, AND LIMB FUNCTION Skin , bone, tendon, fat, fascia, joints, and vessels tolerate ischemia...injury in a combat support hospital: results of a case control study. J Trauma 2008;64(Suppl 2):S99–106 [discussion: S106–7]. 21. Bellamy RF . The

Curcumin and dexmedetomidine prevents oxidative stress and renal injury in hind limb ischemia/reperfusion injury in a rat model.

PubMed

Karahan, M A; Yalcin, S; Aydogan, H; Büyükfirat, E; Kücük, A; Kocarslan, S; Yüce, H H; Taskın, A; Aksoy, N

2016-06-01

Curcumin and dexmedetomidine have been shown to have protective effects in ischemia-reperfusion injury on various organs. However, their protective effects on kidney tissue against ischemia-reperfusion injury remain unclear. We aimed to determine whether curcumin or dexmedetomidine prevents renal tissue from injury that was induced by hind limb ischemia-reperfusion in rats. Fifty rats were divided into five groups: sham, control, curcumin (CUR) group (200 mg/kg curcumin, n = 10), dexmedetomidine (DEX) group (25 μg/kg dexmedetomidine, n = 10), and curcumin-dexmedetomidine (CUR-DEX) group (200 mg/kg curcumin and 25 μg/kg dexmedetomidine). Curcumin and dexmedetomidine were administered intraperitoneally immediately after the end of 4 h ischemia, just 5 min before reperfusion. The extremity re-perfused for 2 h and then blood samples were taken and total antioxidant capacity (TAC), total oxidative status (TOS) levels, and oxidative stress index (OSI) were measured, and renal tissue samples were histopathologically examined. The TAC activity levels in blood samples were significantly lower in the control than the other groups (p < 0.01 for all comparisons). The TOS activity levels in blood samples were significantly higher in Control group and than the other groups (p <  0.01 for all comparison). The OSI were found to be significantly increased in the control group compared to others groups (p < 0.001 for all comparisons). Histopathological examination revealed less severe lesions in the sham, CUR, DEX, and CUR-DEX groups, compared with the control group (p < 0.01). Rat hind limb ischemia-reperfusion causes histopathological changes in the kidneys. Curcumin and dexmedetomidine administered intraperitoneally was effective in reducing oxidative stress and renal histopathologic injury in an acute hind limb I/R rat model.

Therapeutic Benefits and Adverse Effects of Combined Proangiogenic Gene Therapy in Mouse Critical Leg Ischemia.

PubMed

Lebas, Benoît; Galley, Julien; Renaud-Gabardos, Edith; Pujol, Françoise; Lenfant, Françoise; Garmy-Susini, Barbara; Chaufour, Xavier; Prats, Anne-Catherine

2017-04-01

Critical leg ischemia (CLI) represents the ultimate stage of peripheral arterial disease. Despite current surgery advances, patients with CLI have limited therapeutic options. Therapeutic angiogenesis thus appears as a powerful approach, aiming to stimulate vessel formation by angiogenic molecules administration. In this context, combined gene therapy has been proved to be the most efficient. The present study aims to compare, in a preclinical mouse model, the therapeutic benefit of a combination of 2 angiogenic factors fibroblast growth factor 2 (FGF2) and Cyr61 using plasmid and viral vectors, able to generate short- or long-term transgene expression in the leg, respectively. Two therapeutic genes, FGF2 and Cyr61, were introduced into internal ribosome entry site-based expression vectors (FGFiCyr) allowing co-expression of the 2 transgenes. The proangiogenic plasmid pC-FGFiCyr was assessed by intramuscular administration followed by electrotransfer into ischemic legs. To generate long-term transgene expression, the FGFiCyr bicistronic cassette was introduced into an adenoassociated virus-derived vector (rAAV). The rAAV treatment was performed either before or immediately after surgery. Therapeutic effects were analyzed by laser Doppler imaging, clinical score, and angiography. The plasmid pC-FGFiCyr improved revascularization, reperfusion, and clinical score. Surprisingly, when AAV-FGFiCyr was injected 21 or 28 days before surgery, the proangiogenic rAAV was drastically deleterious on all measured parameters. In contrast, when administrated shortly after surgery, AAV-FGFiCyr generated therapeutic benefits, with a significantly better clinical score than after treatment with the plasmid. Therapeutic effects of the angiogenic combination FGF2-Cyr61 is observed with short-term transgene expression, but the treatment is significantly more efficient when a long-term expression viral vector is used. However, the rAAV-FGFiCyr generated therapeutic benefit only when injected in an ischemic leg, whereas the same dose of rAAV exhibited deleterious effects when administrated to healthy animals. These data may contribute to the understanding of the moderate success of proangiogenic treatments in CLI gene therapy clinical assays. Copyright © 2016 Elsevier Inc. All rights reserved.

Surrogate and clinical endpoints for studies in peripheral artery occlusive disease: Are statistics the brakes?

PubMed

Waliszewski, Matthias W; Redlich, Ulf; Breul, Victor; Tautenhahn, Jörg

2017-04-30

The aim of this review is to present the available clinical and surrogate endpoints that may be used in future studies performed in patients with peripheral artery occlusive disease (PAOD). Importantly, we describe statistical limitations of the most commonly used endpoints and offer some guidance with respect to study design for a given sample size. The proposed endpoints may be used in studies using surgical or interventional revascularization and/or drug treatments. Considering recently published study endpoints and designs, the usefulness of these endpoints for reimbursement is evaluated. Based on these potential study endpoints and patient sample size estimates with different non-inferiority or tests for difference hypotheses, a rating relative to their corresponding reimbursement values is attempted. As regards the benefit for the patients and for the payers, walking distance and the ankle brachial index (ABI) are the most feasible endpoints in a relatively small study samples given that other non-vascular impact factors can be controlled. Angiographic endpoints such as minimal lumen diameter (MLD) do not seem useful from a reimbursement standpoint despite their intuitiveness. Other surrogate endpoints, such as transcutaneous oxygen tension measurements, have yet to be established as useful endpoints in reasonably sized studies with patients with critical limb ischemia (CLI). From a reimbursement standpoint, WD and ABI are effective endpoints for a moderate study sample size given that non-vascular confounding factors can be controlled.

Alimentary Limb Ischemia During Roux-en-Y Gastric Bypass and its Management.

PubMed

Mittal, Tarun; Dey, Ashish; Nali, Abhilash; Taha Mustafa, Sheikh Mohammad; Malik, Vinod K

2018-05-01

Ischemia of the tip of the alimentary limb involving the gastrojejunostomy (GJ) is an unusual complication during Roux-en-Y gastric bypass (RYGB). Revision of the GJ may be needed to manage this complication. We present a case of inadvertent perforation of the jejunum by a gastric calibration tube, which was recognized on the table and appropriate measures are then taken. Repair of this enterotomy however then led to ischemia of the tip of alimentary limb extending to a portion of the GJ anastomosis. We present its subsequent management. Our patient is a morbidly obese female patient with a BMI value of 44.6 kg/msq undergoing RYGB. We performed an antecolic, antegastric linear-stapled gastrojejunostomy of 2.5 cm. After hand-sewn closure of the common enterotomy, we tried passing a 38-F Bougie through the anastomosis into the Roux limb. During this maneuver, the Bougie inadvertently perforated the Roux limb at the mesenteric border. Following the repair of this jejunal rent, the distal part of the Roux limb became dusky and involved a portion of the gastrojejunal anastomosis. The gastrojejunostomy was therefore completely revised. Intraoperatively, methylene blue dye test was done which showed no leak. Post-operative gastrografin study revealed no leak and liquids were started on POD1. Inadvertent injury by a Bougie is a rare but known complication in laparoscopic RYGB. Intraoperative recognition of the complication is essential to prompt the necessary repair. Revision of the gastrojejunostomy is necessary if the Roux limb or the anastomosis itself is ischemic and can be accomplished with good results.

Molecular imaging of the paracrine proangiogenic effects of progenitor cell therapy in limb ischemia.

PubMed

Ryu, Jae Choon; Davidson, Brian P; Xie, Aris; Qi, Yue; Zha, Daogang; Belcik, J Todd; Caplan, Evan S; Woda, Juliana M; Hedrick, Catherine C; Hanna, Richard N; Lehman, Nicholas; Zhao, Yan; Ting, Anthony; Lindner, Jonathan R

2013-02-12

Stem cells are thought to enhance vascular remodeling in ischemic tissue in part through paracrine effects. Using molecular imaging, we tested the hypothesis that treatment of limb ischemia with multipotential adult progenitor cells (MAPCs) promotes recovery of blood flow through the recruitment of proangiogenic monocytes. Hind-limb ischemia was produced in mice by iliac artery ligation, and MAPCs were administered intramuscularly on day 1. Optical imaging of luciferase-transfected MAPCs indicated that cells survived for 1 week. Contrast-enhanced ultrasound on days 3, 7, and 21 showed a more complete recovery of blood flow and greater expansion of microvascular blood volume in MAPC-treated mice than in controls. Fluorescent microangiography demonstrated more complete distribution of flow to microvascular units in MAPC-treated mice. On ultrasound molecular imaging, expression of endothelial P-selectin and intravascular recruitment of CX(3)CR-1-positive monocytes were significantly higher in MAPC-treated mice than in the control groups at days 3 and 7 after arterial ligation. Muscle immunohistology showed a >10-fold-greater infiltration of monocytes in MAPC-treated than control-treated ischemic limbs at all time points. Intravital microscopy of ischemic or tumor necrosis factor-α-treated cremaster muscle demonstrated that MAPCs migrate to perimicrovascular locations and potentiate selectin-dependent leukocyte rolling. In vitro migration of human CD14(+) monocytes was 10-fold greater in response to MAPC-conditioned than basal media. In limb ischemia, MAPCs stimulate the recruitment of proangiogenic monocytes through endothelial activation and enhanced chemotaxis. These responses are sustained beyond the MAPC lifespan, suggesting that paracrine effects promote flow recovery by rebalancing the immune response toward a more regenerative phenotype.

Drug-eluting balloon angioplasty versus uncoated balloon angioplasty for peripheral arterial disease of the lower limbs.

PubMed

Kayssi, Ahmed; Al-Atassi, Talal; Oreopoulos, George; Roche-Nagle, Graham; Tan, Kong Teng; Rajan, Dheeraj K

2016-08-04

Atherosclerotic peripheral arterial disease (PAD) can lead to disabling ischemia and limb loss. Treatment modalities have included risk factor optimization through life-style modifications and medications, or operative approaches using both open and minimally invasive techniques, such as balloon angioplasty. Drug-eluting balloon (DEB) angioplasty has emerged as a promising alternative to uncoated balloon angioplasty for the treatment of this difficult disease process. By ballooning and coating the inside of atherosclerotic vessels with cytotoxic agents, such as paclitaxel, cellular mechanisms responsible for atherosclerosis and neointimal hyperplasia are inhibited and its devastating complications are prevented or postponed. DEBs are considerably more expensive than uncoated balloons, and their efficacy in improving patient outcomes is unclear. To assess the efficacy of drug-eluting balloons (DEBs) compared with uncoated, nonstenting balloon angioplasty in people with symptomatic lower-limb peripheral arterial disease (PAD). The Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched December 2015) and Cochrane Register of Studies (CRS) (2015, Issue 11). The TSC searched trial databases for details of ongoing and unpublished studies. We included all randomized controlled trials that compared DEBs with uncoated, nonstenting balloon angioplasty for intermittent claudication (IC) or critical limb ischemia (CLI). Two review authors (AK, TA) independently selected the appropriate trials and performed data extraction, assessment of trial quality, and data analysis. The senior review author (DKR) adjudicated any disagreements. Eleven trials that randomized 1838 participants met the study inclusion criteria. Seven of the trials included femoropopliteal arterial lesions, three included tibial arterial lesions, and one included both. The trials were carried out in Europe and in the USA and all used the taxane drug paclitaxel in the DEB arm. Nine of the 11 trials were industry-sponsored. Four companies manufactured the DEB devices (Bard, Bavaria Medizin, Biotronik, and Medtronic). The trials examined both anatomic and clinical endpoints. There was heterogeneity in the frequency of stent deployment and the type and duration of antiplatelet therapy between trials. Using GRADE assessment criteria, the quality of the evidence presented was moderate for the outcomes of target lesion revascularization and change in Rutherford category, and high for amputation, primary vessel patency, binary restenosis, death, and change in ankle-brachial index (ABI). Most participants were followed up for 12 months, but one trial reported outcomes at five years.There were better outcomes for DEBs for up to two years in primary vessel patency (odds ratio (OR) 1.47, 95% confidence interval (CI) 0.22 to 9.57 at six months; OR 1.92, 95% CI 1.45 to 2.56 at 12 months; OR 3.51, 95% CI 2.26 to 5.46 at two years) and at six months and two years for late lumen loss (mean difference (MD) -0.64 mm, 95% CI -1.00 to -0.28 at six months; MD -0.80 mm, 95% CI -1.44 to -0.16 at two years). DEB were also superior to uncoated balloon angioplasty for up to five years in target lesion revascularization (OR 0.28, 95% CI 0.17 to 0.47 at six months; OR 0.40, 95% CI 0.31 to 0.51 at 12 months; OR 0.28, 95% CI 0.18 to 0.44 at two years; OR 0.21, 95% CI 0.09 to 0.51 at five years) and binary restenosis rate (OR 0.44, 95% CI 0.29 to 0.67 at six months; OR 0.38, 95% CI 0.15 to 0.98 at 12 months; OR 0.26, 95% CI 0.10 to 0.66 at two years; OR 0.12, 95% CI 0.05 to 0.30 at five years). There was no significant difference between DEB and uncoated angioplasty in amputation, death, change in ABI, change in Rutherford category and quality of life (QoL) scores, or functional walking ability, although none of the trials were powered to detect a significant difference in these clinical endpoints. We carried out two subgroup analyses to examine outcomes in femoropopliteal and tibial interventions as well as in people with CLI (4 or greater Rutherford class), and showed no advantage for DEBs in tibial vessels at six and 12 months compared with uncoated balloon angioplasty. There was also no advantage for DEBs in CLI compared with uncoated balloon angioplasty at 12 months. Based on a meta-analysis of 11 trials with 1838 participants, there is evidence of an advantage for DEBs compared with uncoated balloon angioplasty in several anatomic endpoints such as primary vessel patency (high-quality evidence), binary restenosis rate (moderate-quality evidence), and target lesion revascularization (low-quality evidence) for up to 12 months. Conversely, there is no evidence of an advantage for DEBs in clinical endpoints such as amputation, death, or change in ABI, or change in Rutherford category during 12 months' follow-up. Well-designed randomized trials with long-term follow-up are needed to compare DEBs with uncoated balloon angioplasties adequately for both anatomic and clinical study endpoints before the widespread use of this expensive technology can be justified.

Society for Vascular Surgery limb stage and patient risk correlate with outcomes in an amputation prevention program.

PubMed

Causey, Marlin W; Ahmed, Ayman; Wu, Bian; Gasper, Warren J; Reyzelman, Alex; Vartanian, Shant M; Hiramoto, Jade S; Conte, Michael S

2016-06-01

Clinical decision making and accurate outcomes comparisons in advanced limb ischemia require improved staging systems. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System (Wound extent, Ischemia, and foot Infection [WIfI]) was designed to stratify limb outcomes based on three major factors-wound extent, ischemia, and foot infection. The Project or Ex-Vivo vein graft Engineering via Transfection III (PREVENT) III (PIII) risk score was developed to stratify patients by expected amputation-free survival (AFS) after surgical revascularization. This study was designed to prospectively assess limb and patient-based staging for predicting outcomes of hospitalized patients in an amputation prevention program. This study undertook a retrospective analysis of prospectively gathered registry data of consecutive patients with limb-threatening conditions admitted to a fully integrated vascular/podiatry service over a 16-month period. Upon admission, limb risk was stratified using the WIfI system and patient risk was categorized using PIII classification. Patients were assessed for perioperative and postdischarge outcomes, and their relationship to staging at admission was analyzed. There were 174 threatened limbs (143 hospitalized patients) stratified by WIfI stage (1%-12%, 2%-28%, 3%-24%, 4%-28%, 5%-3%, unstaged-5%) and PIII risk (34% low, 49% moderate, and 17% high risk). Diabetes and end-stage renal disease were associated with WIfI stage (P = .006 and P = .018) and PIII risk (P = .003 and P < .001). Perioperative (30-day) events included 3% mortality, 8% major adverse cardiovascular events and 2.4% major amputation. There were 119 limbs (71%) that underwent revascularization, including 108 infrainguinal reconstructions (endovascular or open revascularization). Rate of revascularization increased with WIfI stage (P < .001), concomitant with the number of podiatric procedures, minor amputations, and initial hospital duration of stay (all P < .001). Increased WIfI stage was associated with major adverse limb events (P = .018), reduced limb salvage (P = .037), and decreased AFS (P = .048). In contrast, PIII risk category was associated with mortality (P < .001) and AFS (P < .001). Among infrainguinal reconstruction procedures, there was a similar distribution of endovascular (46%) and surgical (54%) interventions. Freedom from major adverse limb events was best for autogenous vein bypass (P = .025), and surgical revascularization was associated with improved limb salvage among the most severely threatened limbs (WIfI stage 4: 95% limb salvage for open bypass vs 68% limb salvage for endovascular; P = .026). Among patients hospitalized with limb-threatening conditions and treated by a multidisciplinary amputation prevention team, PIII risk correlates with mortality whereas WIfI stage strongly predicts initial hospital duration of stay, and key mid-term limb outcomes. Surgical revascularization performed best in the limbs at greatest risk (WIfI stage 4), and autogenous vein bypass was the preferred conduit for open bypass. These data support the use of WIfI and PIII as complementary staging tools in the management of chronic limb-threatening ischemia. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Mid-term outcomes of orbital atherectomy combined with drug-coated balloon angioplasty for treatment of femoropopliteal disease.

PubMed

Foley, T Raymond; Cotter, Ryan P; Kokkinidis, Damianos G; Nguyen, Daniel D; Waldo, Stephen W; Armstrong, Ehrin J

2017-05-01

To assess the intraprocedural and mid-term outcomes of orbital atherectomy (OA) combined with drug-coated balloon (DCB) angioplasty for the treatment of calcified femoropopliteal disease. In this single-center cohort, 89 patients (139 lesions) were treated with DCB angioplasty for claudication or critical limb ischemia (CLI). Angiographic characteristics and procedural outcomes were reviewed for patients treated with or without adjunctive OA. Lesion calcification was graded using two previously published scoring systems, the angiographic calcium score (ACS) and the peripheral artery calcification scoring system (PACSS). Among 139 lesions, 40 (29%) were treated with OA + DCB. Mean lesion length was 135 ± 100 mm for lesions treated with OA + DCB and 139 ± 100 mm for DCB alone (P = 0.9). Moderate to severe calcification was present in 83% of patients treated with OA, compared to 42% of patients treated with DCB alone (P < 0.001). Lesions treated with OA + DCB were less likely to require bailout stenting (18% vs. 39%, P =0.01). Rates of embolization (0% in OA + DCB vs. 2% in DCB only, P = 0.4), dissection (13% vs. 14%, P = 0.8), and perforation (0%) did not differ significantly between groups. The freedom from TLR at 1 year was 82% in both groups (P = 0.6) while primary patency was 81% in-patients treated with DCB alone and 77% in-patients treated with DCB with concomitant OA (P = 0.8). In this single-center analysis of patients undergoing DCB angioplasty for claudication or CLI, OA was most often used for the treatment of severely calcified lesions. These lesions were more likely to be treated with scoring balloons and less likely to require bailout stenting. At 1 year, target lesion revascularization and primary patency was similar in patients treated with and without adjunctive OA, despite the higher lesion complexity among those receiving the combination procedure. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

[A persistent sciatic artery revealed by acute ischemia of the right lower limb: A case report].

PubMed

Benleghib, N; Boukabache, L; Aziza, B; Boudine, L; Boulacel, A; Boussafsaf, B

2017-09-19

The Persistent Sciatic Artery (PSA) is an unusual anatomical variation due to the persistence of an embryological artery, which should disappear before the 3rd month of intrauterine life. The reported case is that of a woman who developed an acute ischemia of the right lower limb, revealing the presence of persistent sciatic artery. Diagnosis was made only belatedly by means of angio-CT. The amputation was the inevitable choice of treatment. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Use of the Boomerang catalyst advantage closure device to facilitate complex multistaged percutaneous revascularization procedures for the treatment of critical limb ischemia.

PubMed

Garcia, Joel A; Casserly, Ivan P

2009-07-01

An increasing spectrum of complex peripheral arterial disease may be successfully treated using percutaneous revascularization techniques. A pair of challenging peripheral revascularization procedures in patients with critical limb ischemia is presented, where an array of interventional tools and techniques were required, and the off-label use of the Boomerang catalyst system closure device was important in managing a variety of complex arterial access issues and ultimately allowing procedural success. Copyright 2009 Wiley-Liss, Inc.

Preamputation evaluation of lower-limb skeletal muscle perfusion with H(2) (15)O positron emission tomography.

PubMed

Scremin, Oscar U; Figoni, Stephen F; Norman, Keith; Scremin, A M Erika; Kunkel, Charles F; Opava-Rutter, Dorene; Schmitter, Eric D; Bert, Alberto; Mandelkern, Mark

2010-06-01

To establish whether muscle blood flow (MBF) measurements with O-water positron emission tomography could reliably identify patients with critical limb ischemia and detect and quantify a distal deficit in skeletal MBF in these cases. O-water positron emission tomography scans were performed at rest or during unloaded ankle plantar and dorsiflexion exercise of the diseased leg in 17 subjects with leg ischemia or on a randomly selected leg of 18 age-matched healthy control subjects. TcPO2 was evaluated with Novametrix monitors and perfusion of skin topically heated to 44 degrees C and adjacent nonheated areas with a Moor Instruments laser Doppler imaging scanner. The enhancement of MBF induced by exercise was significantly lower in ischemic than in normal legs, and the sensitivity and specificity of this phenomenon were similar to those of laser Doppler imaging or TcPO2 in identifying ischemia subjects. In addition, the exercise MBF deficit was predominant at the distal-leg levels, indicating the ability of the technique to help determine the correct level of amputation. Skeletal MBF of legs with severe ischemia can be detected accurately with O-water positron emission tomography and could add valuable information about viability of skeletal muscle in the residual limb when deciding the level of an amputation.

Efficacy of regional saturation of oxygen monitor using near-infrared spectroscopy for lower limb ischemia during minimally invasive cardiac surgery.

PubMed

Toya, Teppei; Fujita, Tomoyuki; Fukushima, Satuki; Shimahara, Yusuke; Kume, Yuta; Yamashita, Kizuku; Matsumoto, Yorihiko; Kawamoto, Naonori; Kobayashi, Junjiro

2018-06-25

Lower limb ischemia with an occlusive cannula is a potential complication of minimally invasive cardiac surgery (MICS). We evaluated intraoperative local oxygen supply-demand balance by monitoring regional saturation of oxygen (rSO 2 ) using near-infrared spectroscopy (NIRS), and analyzed the correlation between cannula size and fluctuation range of rSO 2 . Fifty-four patients undergoing MICS surgery using femoral artery cannulation from April 2015 to August 2016 were enrolled. The rSO 2 of both the cannulated and uncannulated lower limbs were measured using NIRS. The association between the decline of rSO 2 from baseline (delta-rSO 2 ) and the ratio of the cannula diameter to the femoral artery diameter (Cd/FAd) was analyzed. Of the 54 patients, 16 (30%) (Group 1) showed values over 0.65 for Cd/FAd, and the remaining 38 (70%) (Group 2) showed values under 0.65. No patient developed postoperative lower limb ischemia. No patient was treated with an ipsilateral distal perfusion cannula. There were significant differences between Group 1 and Group 2 in the decrease of rSO 2 at the point of cannulation on the cannulated limb. In the lower limb on the cannulated side, delta-rSO 2 showed a significant decrease in Group 1 compared to Group 2 (Group 1 vs Group 2: 19.9 vs 11.0%; p < 0.001). Delta-rSO 2 was significantly correlated with body surface aera (BSA), but not with gender or age. Decreasing rSO 2 correlates with the Cd/FAd index. Low BSA, Cd/Fad > 0.65 is considered as the risk factor for decline of rSO 2 in cannulated limb in MICS.

Impact of Duplex arterial mapping on decision making in non-acute ischemic limb patients.

PubMed

Elbadawy, A; Aly, H; Ibrahim, M; Bakr, H

2015-12-01

The aim of this study was to demonstrate the impact of Duplex arterial mapping on decision making in non-acute ischemic limb patient group reporting pain onset between 15 days and 3 months. We prospectively evaluated patients presented with critical limb ischemia who reported pain onset of duration between 15 days and 3 months in one-year period. Our series included thirty cases (mean age=61.3 years old), as Duplex arterial mapping was the sole preoperative imaging tool performed in all of them. All patients, in whom duplex indicated thrombosis in long occluded segments, were candidates for fluoroscopically guided thrombectomy. When Duplex defined chronic arterial occlusions, patients underwent endovascular or bypass revascularisation procedures. Impact of Duplex wall interrogation on decision-making between the two groups (subacute and chronic) was measured. Duplex arterial mapping categorized correctly all 30 patients into either subacute ischemia with removable clot (N.=14) or chronic ischemia (N.=16). Fluoroscopic guided thrombectomy was performed in 14 cases when Duplex advised long occluded arterial segments as indicted by intact intima with echogenic thrombus inside. Bypass surgery was performed in 8 patients. Percutaneous transluminal angioplasty (PTA) was done in 7 cases and thrombendartrectomy of common femoral artery in a single case. One-year patency rate in our series was 86.6%. It was 71.4% in thrombosis group. Limb salvage rate was 93.3%. Duplex arterial mapping could be used to differentiate the subacute ischemia with removable thrombus and chronic arterial occlusions guiding for the best revascularization procedure accordingly.

Combined morphine and limb remote ischemic perconditioning provides an enhanced protection against myocardial ischemia/reperfusion injury by antiapoptosis.

PubMed

Wang, Shi-Yu; Cui, Xin-Long; Xue, Fu-Shan; Duan, Ran; Li, Rui-Ping; Liu, Gao-Pu; Yang, Gui-Zhen; Sun, Chao

2016-05-01

Both morphine and limb remote ischemic perconditioning (RIPer) can protect against myocardial ischemia/reperfusion injury (IRI). This experiment was designed to assess whether combined morphine and limb RIPer could provide and enhanced protection against myocardial IRI in an in vivo rat model. One hundred male Sprague-Dawley rats were randomly allocated to six groups: sham, ischemia/reperfusion (IR), ischemic preconditioning, RIPer, morphine (M), and combined morphine and remote ischemic perconditioning (M + RIPer). Ventricular arrhythmias that occurred during ischemia and early reperfusion were scored, and serum creatine kinase isoenzyme and cardiac troponin I levels were assayed. The infarct size was determined by Evans blue and triphenyl tetrazolium chloride staining. The apoptosis in the myocardial ischemic core, ischemic border, and nonischemic areas was assessed through real-time polymerase chain reaction for Bax and Bcl-2 and with the transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay. The infarct size, serum cardiac troponin I level, incidence, and score of the arrhythmias during the initial reperfusion were significantly reduced in the M + RIPer group compared with the IR group but did not differ significantly between the ischemic preconditioning and M + RIPer groups. Transferase-mediated deoxyuridine triphosphate-biotin nick end labeling-positive cells were significantly decreased, and the Bcl-2/Bax ratio was significantly increased in the M + RIPer group compared with the IR group. This experiment demonstrates that combined morphine and limb RIPer provides an enhanced protection against myocardial IRI by the Bcl-2-linked apoptotic signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Novel Method to Assess Arterial Insufficiency in Rodent Hindlimb

PubMed Central

Ziegler, Matthew A.; DiStasi, Matthew R.; Miller, Steven J.; Dalsing, Michael C.; Unthank, Joseph L.

2015-01-01

Background Lack of techniques to assess maximal blood flow capacity thwarts the use of rodent models of arterial insufficiency to evaluate therapies for intermittent claudication. We evaluated femoral vein outflow (VO) in combination with stimulated muscle contraction as a potential method to assess functional hindlimb arterial reserve and therapeutic efficacy in a rodent model of subcritical limb ischemia. Materials and methods VO was measured with perivascular flow probes at rest and during stimulated calf muscle contraction in young healthy rats (Wistar Kyoto, WKY; lean Zucker, LZR) and rats with cardiovascular risk factors (Spontaneously Hypertensive, SHR; Obese Zucker, OZR) with acute and/or chronic femoral arterial occlusion. Therapeutic efficacy was assessed by administration of Ramipril or Losartan to SHR after femoral artery excision. Results VO measurement in WKY demonstrated the utility of this method to assess hindlimb perfusion at rest and during calf muscle contraction. While application to diseased models (OZR, SHR) demonstrated normal resting perfusion compared to contralateral limbs, a significant reduction in reserve capacity was uncovered with muscle stimulation. Administration of Ramipril and Losartan demonstrated significant improvement in functional arterial reserve. Conclusion The results demonstrate that this novel method to assess distal limb perfusion in small rodents with subcritical limb ischemia is sufficient to unmask perfusion deficits not apparent at rest, detect impaired compensation in diseased animal models with risk factors, and assess therapeutic efficacy. The approach provides a significant advance in methods to investigate potential mechanisms and novel therapies for subcritical limb ischemia in pre-clinical rodent models. PMID:26850199

Molecular Imaging of the Paracrine Proangiogenic Effects of Progenitor Cell Therapy in Limb Ischemia

PubMed Central

Ryu, Jae Choon; Davidson, Brian P.; Xie, Aris; Qi, Yue; Zha, Daogang; Belcik, J. Todd; Caplan, Evan S.; Woda, Juliana M.; Hedrick, Catherine C.; Hanna, Richard N.; Lehman, Nicholas; Zhao, Yan; Ting, Anthony; Lindner, Jonathan R.

2013-01-01

Background Stem cells are thought to enhance vascular remodeling in ischemic tissue in part through paracrine effects. Using molecular imaging, we tested the hypothesis that treatment of limb ischemia with multipotential adult progenitor cells (MAPC) promotes recovery of blood flow through the recruitment of pro-angiogenic monocytes. Methods and Results Hindlimb ischemia was produced in mice by iliac artery ligation and MAPC were administered intramuscularly on day 1. Optical imaging of luciferase-transfected MAPC indicated that cells survived for 1 week. Contrast-enhanced ultrasound on day 3, 7 and 21 showed a more complete recovery of blood flow and greater expansion of microvascular blood volume in MAPC-treated mice than in controls. Fluorescent microangiography demonstrated more complete distribution of flow to microvascular units in MAPC-treated mice. On ultrasound molecular imaging, expression of endothelial P-selectin and intravascular recruitment of CX3CR-1-positive monocytes was significantly higher in MAPC-treated than control groups at day 3 and 7 after arterial ligation. Muscle immunohistology showed a >10-fold greater infiltration of monocytes in MAPC-treated than control-treated ischemic limbs at all time points. Intravital microscopy of ischemic or TNF-α-treated cremaster muscle demonstrated that MAPC migrate to peri-microvascular locations and potentiate selectin-dependent leukocyte rolling. In vitro migration of human CD14+ monocytes was 10-fold greater in response to MAPC-conditioned than basal media. Conclusions In limb ischemia, MAPC stimulate the recruitment of pro-angiogenic monocytes through endothelial activation and enhanced chemotaxis. These responses are sustained beyond MAPC lifespan suggesting that paracrine effects promote flow recovery by rebalancing the immune response toward a more regenerative phenotype. PMID:23307829

Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning

PubMed Central

Ren, Chuancheng; Gao, Xuwen; Steinberg, Gary K.; Zhao, Heng

2009-01-01

Remote ischemic preconditioning is an emerging concept for stroke treatment, but its protection against focal stroke has not been established. We tested whether remote preconditioning, performed in the ipsilateral hind limb, protects against focal stroke and explored its protective parameters. Stroke was generated by a permanent occlusion of the left distal middle cerebral artery (MCA) combined with a 30 minute occlusion of the bilateral common carotid arteries (CCA) in male rats. Limb preconditioning was generated by 5 or 15 minute occlusion followed with the same period of reperfusion of the left hind femoral artery, and repeated for 2 or 3 cycles. Infarct was measured 2 days later. The results showed that rapid preconditioning with 3 cycles of 15 minutes performed immediately before stroke reduced infarct size from 47.7±7.6% of control ischemia to 9.8±8.6%; at 2 cycles of 15 minutes, infarct was reduced to 24.7±7.3%; at 2 cycles of 5 minutes, infarct was not reduced. Delayed preconditioning with 3 cycles of 15 minutes conducted 2 days before stroke also reduced infarct to 23.0 ±10.9%, but with 2 cycles of 15 minutes it offered no protection. The protective effects at these two therapeutic time windows of remote preconditioning are consistent with those of conventional preconditioning, in which the preconditioning ischemia is induced in the brain itself. Unexpectedly, intermediate preconditioning with 3 cycles of 15 minutes performed 12 hours before stroke also reduced infarct to 24.7±4.7%, which contradicts the current dogma for therapeutic time windows for the conventional preconditioning that has no protection at this time point. In conclusion, remote preconditioning performed in one limb protected against ischemic damage after focal cerebral ischemia. PMID:18201834

Longitudinal outcomes after tibioperoneal angioplasty alone compared to tibial stenting and atherectomy for critical limb ischemia.

PubMed

Reynolds, Shaun; Galiñanes, Edgar Luis; Dombrovskiy, Viktor Y; Vogel, Todd R

2013-10-01

There are limited data available evaluating longitudinal outcomes after tibioperoneal angioplasty (TA) alone compared to adjunctive tibial procedures including stenting and atherectomy. Using the Centers for Medicare & Medicaid Services inpatient claims (2005-2007), patients evaluated TA only, TA plus stent placement (TA + S), and TA plus atherectomy (TA + A). A total of 2080 patients with critical limb ischemia underwent percutaneous tibioperoneal intervention for the indication of ulceration. Procedures included TA (56.3%), TA + S (16.2%), and TA + A (27.5%). Rates of amputation were not statistically different between the groups at 30, 90, and 365 days after the intervention. Mean total hospital charges were TA ($35,867), TA + A ($41,698; P = .0004), and TA + S ($51,040; P < .0001). Patients undergoing TA alone compared to concomitant stenting or atherectomy for ulceration demonstrated no improvement in limb salvage. Future analysis of adjunctive tibioperoneal interventions is essential to temper cost, as they fail to improve long-term limb salvage.

Cutting balloon angioplasty of the popliteal and infrapopliteal vessels for symptomatic limb ischemia.

PubMed

Ansel, Gary M; Sample, Nancy S; Botti III, Charles F; Tracy, Amy J; Silver, Mitchell J; Marshall, Brian J; George, Barry S

2004-01-01

Options for lower limb percutaneous revascularization are limited especially for complex vessel obstruction. Cutting balloon angioplasty (CBA) has been described in the coronary literature as effective for complex disease. We analyzed our peripheral vascular database and report procedural outcomes along with the clinical success at a mean of 1-year follow-up in 73 patients with symptomatic lower limb ischemia undergoing CBA. CBA was successfully completed in all 73 patients (93 vessels; 100%) with predilation necessary in 4% of vessels. Severe intimal dissection or inadequate hemodynamic result necessitated in adjunctive stenting in 20%. There were no incidents of vessel perforation or surgical target vessel revascularization. One patient (1.5%) died during the periprocedural period due to renal failure. After mean follow-up of 1 year (6-21 months), 89.5% of threatened limbs were salvaged. CBA is a safe and feasible option for the treatment of popliteal and infrapopliteal vessels. Copyright 2004 Wiley-Liss, Inc.

Lumbar sympathectomy versus prostanoids for critical limb ischaemia due to non-reconstructable peripheral arterial disease.

PubMed

Sen, Indrani; Agarwal, Sunil; Tharyan, Prathap; Forster, Rachel

2018-04-16

Peripheral arterial disease (PAD) is a common circulatory problem that can lead to reduced blood flow to the limbs, which may result in critical limb ischaemia (CLI), a painful manifestation that occurs when a person is at rest. The mainstay of treatment for CLI is surgical or endovascular repair. However, when these means of treatment are not suitable, due to anatomical reasons or comorbidities, treatment for pain is limited. Lumbar sympathectomy and prostanoids have both been shown to reduce pain from CLI in people who suffer from non-reconstructable PAD, but there is currently insufficient evidence to determine if one treatment is superior. Due to the severity of the rest pain caused by CLI, and its impact on quality of life, it is important that people are receiving the best pain relief treatment available, therefore interest in this area of research is high. To compare the efficacy of lumbar sympathectomy with prostanoid infusion in improving symptoms and function and avoiding amputation in people with critical limb ischaemia (CLI) due to non-reconstructable peripheral arterial disease (PAD). The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched 29 March 2017) and CENTRAL (2017, Issue 2). The CIS also searched clinical trials databases for ongoing or unpublished studies. Randomised controlled trials (RCTs), with parallel treatment groups, that compared lumbar sympathectomy (surgical or chemical) with prostanoids (any type and dosage) in people with CLI due to non-reconstructable PAD. Three review authors independently selected trials, extracted data and assessed risk of bias. Any disagreements were resolved by discussion. We performed fixed-effect model meta-analyses, when there was no overt sign of heterogeneity, with risk ratios (RRs) and 95% confidence intervals (CIs). We graded the quality of evidence according to GRADE. We included a single study in this review comparing lumbar sympathectomy with prostanoids for the treatment of CLI in people with non-reconstructable PAD. The single study included 200 participants with Buerger's disease, a form of PAD, 100 in each treatment group, but only 162 were actually included in the analyses. The study compared an open surgical technique for lumbar sympathectomy with the prostanoid, iloprost, and followed participants for 24 weeks.Risk of bias was low for most evaluated domains. Due to the nature of the treatment, blinding of the participants and those providing the treatment would be impossible as a surgical procedure was compared with intravenous injections. It was not mentioned if blinded assessors evaluated the study outcomes, therefore, we judged subjective outcomes (i.e. pain reduction) to be at unclear risk of detection bias and objective outcomes (i.e. ulcer healing, amputation and mortality) at low risk of detection bias. We also rated the risk of attrition bias as unclear; 38 out of 200 (19%) participants were not included in the analysis without clear explanation (16 of 100 in the iloprost arm and 22 of 100 in the sympathectomy arm). The quality of evidence was low due to serious imprecision because the study numbers were low and there was only one study included.The single included study reported on the outcome of complete healing without pain or major amputation, which fell under three separate outcomes for our review: relief of rest pain, complete ulcer healing and avoidance of major amputation. We chose to keep the outcome as a singularly reported outcome in order to not introduce bias into the outcomes, which may have been the case if reported separately. The limited evidence suggests participants who received prostaglandins had improved complete ulcer healing without rest pain or major amputation when compared with those who received lumbar sympathectomy (RR 1.63, 95% CI 1.30 to 2.05), but as it was the only included study, we rated the data as low-quality and could not draw any overall conclusions. The study authors stated that more participants who received prostaglandins reported adverse effects, such as headache, flushing, nausea and abdominal discomfort, but only one participant experienced severe enough adverse effects to drop out. Five participants who underwent lumbar sympathectomy reported minor wound infection (low-quality evidence). There was no reported mortality in either of the treatment groups (low-quality evidence).The included study did not report on claudication distances, quality of life or functional status, ankle brachial pressure index (ABPI), tissue oxygenation or toe pressures, or progression to minor amputation, complications or provide any cost-effectiveness data. Low-quality evidence from a single study in a select group of participants (people with Buerger's disease) suggests that prostaglandins are superior to open surgical lumbar sympathectomy for complete ulcer healing without rest pain or major amputation, but possibly incur more adverse effects. Further studies are needed to better understand if prostaglandins truly are more efficacious than open surgical lumbar sympathectomy and if there are any concerns with adverse effects. It would be of great importance for future studies to include other forms of PAD (as Buerger's disease is a select type of PAD), other methods of sympathectomy as well as data on quality of life, complications and cost-effectiveness.

Critical Ischemia Times and the Effect of Novel Preservation Solutions HTK-N and TiProtec on Tissues of a Vascularized Tissue Isograft.

PubMed

Messner, Franka; Hautz, Theresa; Blumer, Michael J F; Bitsche, Mario; Pechriggl, Elisabeth J; Hermann, Martin; Zelger, Bettina; Zelger, Bernhard; Öfner, Dietmar; Schneeberger, Stefan

2017-09-01

We herein investigate critical ischemia times and the effect of novel preservation solutions such as new histidine-tryptophan-ketoglutarate (HTK-N) and TiProtec on the individual tissues of a rat limb isograft. Orthotopic hind-limb transplantations were performed in male Lewis rats after 2 hours, 6 hours, or 10 hours of cold ischemia (CI). Limbs were flushed and stored in HTK-N, TiProtec, HTK, or saline solution. Muscle, nerve, vessel, skin, and bone samples were procured on day 10 for histology, immunohistochemistry, confocal and electron microscopy, and quantitative real-time polymerase chain reaction analysis. Histomorphology of the muscle showed a mainly perivascular inflammatory infiltrate, fibrotic degeneration, and neovascularization after 6 hours and 10 hours of CI. However, centrally aligned nuclei observed in muscle fibers suggest for muscle regeneration in these samples. In addition to Wallerian degeneration, nerve injury was significantly aggravated (P = 0.032) after prolonged CI. Proinflammatory and regulatory cytokines were most significantly upregulated after 2-hour CI. Our data suggest no superiority of novel perfusates HTK-N and TiProtec in terms of tissue preservation, compared with HTK and saline. Limiting CI time for less than 6 hours is the most significant factor to reduce tissue damage in vascularized tissue transplantation. Signs of muscle regeneration give rise that ischemic muscle damage in limb transplantation might be reversible to a certain extent.

Microfibrillar-associated protein 4 variation in symptomatic peripheral artery disease.

PubMed

Hemstra, Line Ea; Schlosser, Anders; Lindholt, Jes Sanddal; Sorensen, Grith L

2018-06-08

Symptomatic peripheral artery disease (PAD) is an atherosclerotic occlusive disease affecting the lower extremities. The cause of symptomatic PAD is atherosclerosis, vascular dysfunctions, impaired angiogenesis and neointima formation. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein, which is highly expressed in the heart and arteries and recently introduced as a potential mediator of pathological vascular remodeling and neointima formation. We aimed to investigate the relationship between serum MFAP4 (sMFAP4) and symptomatic PAD outcomes. A total of 286 PAD patients were analyzed if they had either intermittent claudication or critical lower-extremity ischemia (CLI) and followed for 7 years. The level of serum MFAP4 (sMFAP4) was measured by alphaLISA. Kaplan-Meier, Cox proportional hazard and logistic regression analysis were used to analyze the associations between upper tertile sMFAP4 and symptomatic PAD outcomes. Patients with upper tertile sMFAP4 had an odds ratio (OR) of 2.65 (p < 0.001) for having CLI diagnosis. Further analysis indicated that patients with upper tertile sMFAP4 had a hazard ratio (HR) of 1.97 (p = 0.04) for cardiovascular death during the 7-years follow-up. However, analysis of 2-year primary patency showed that patients with upper tertile sMFAP4 had decreased risk of vascular occlusion after reconstructive surgery with HR of 0.15 (p = 0.02). sMFAP4 has potential as a prognostic marker for cardiovascular death, primary patency of reconstructed vessels and CLI diagnosis in symptomatic PAD patients. Confirmation of observations in larger cohorts is warranted.

Carbon dioxide water-bath treatment augments peripheral blood flow through the development of angiogenesis.

PubMed

Xu, Yan-Jun; Elimban, Vijayan; Dhalla, Naranjan S

2017-08-01

In this study, we investigated the effects of CO 2 water-bath therapy on blood flow and angiogenesis in the ischemic hind limb, as well as some plasma angiogenic factors in peripheral ischemic model. The hind limb ischemia was induced by occluding the femoral artery for 2 weeks in rats and treated with or without CO 2 water-bath therapy at 37 °C for 4 weeks (20 min treatment every day for 5 days per week). The peak blood flow and minimal and mean blood flow in the ischemic skeletal muscle were markedly increased by the CO 2 water-bath therapy. This increase in blood flow was associated with development of angiogenesis in the muscle, as well as reduction in the ischemia-induced increase in plasma malondialdehyde levels. Although plasma vascular endothelial growth factor and nitric oxide levels were increased in animals with peripheral ischemia, the changes in these biomarkers were not affected by CO 2 water-bath therapy. These results suggest that augmentation of blood flow in the ischemic hind limb by CO 2 water-bath therapy may be due to the development of angiogenesis and reduction in oxidative stress.

Nanoparticle-mediated delivery of pioglitazone enhances therapeutic neovascularization in a murine model of hindlimb ischemia.

PubMed

Nagahama, Ryoji; Matoba, Tetsuya; Nakano, Kaku; Kim-Mitsuyama, Shokei; Sunagawa, Kenji; Egashira, Kensuke

2012-10-01

Critical limb ischemia is a severe form of peripheral artery disease (PAD) for which neither surgical revascularization nor endovascular therapy nor current medicinal therapy has sufficient therapeutic effects. Peroxisome proliferator activated receptor-γ agonists present angiogenic activity in vitro; however, systemic administration of peroxisome proliferator-activated receptor-γ agonists is hampered by its side effects, including heart failure. Here, we demonstrate that the nanoparticle (NP)-mediated delivery of the peroxisome proliferator activated receptor-γ agonist pioglitazone enhances its therapeutic efficacy on ischemia-induced neovascularization in a murine model. In a nondiabetic murine model of hindlimb ischemia, a single intramuscular injection of pioglitazone-incorporated NP (1 µg/kg) into ischemic muscles significantly improved the blood flow recovery in the ischemic limbs, significantly increasing the number of CD31-positive capillaries and α-smooth muscle actin-positive arterioles. The therapeutic effects of pioglitazone-incorporated NP were diminished by the peroxisome proliferator activated receptor-γ antagonist GW9662 and were not observed in endothelial NO synthase-deficient mice. Pioglitazone-incorporated NP induced endothelial NO synthase phosphorylation, as demonstrated by Western blot analysis, as well as expression of multiple angiogenic growth factors in vivo, including vascular endothelial growth factor-A, vascular endothelial growth factor-B, and fibroblast growth factor-1, as demonstrated by real-time polymerase chain reaction. Intramuscular injection of pioglitazone (1 µg/kg) was ineffective, and oral administration necessitated a >500 μg/kg per day dose to produce therapeutic effects equivalent to those of pioglitazone-incorporated NP. NP-mediated drug delivery is a novel modality that may enhance the effectiveness of therapeutic neovascularization, surpassing the effectiveness of current treatments for peripheral artery disease with critical limb ischemia.

Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet–Fed Mice

PubMed Central

Ryan, Terence E.; Schmidt, Cameron A.; Green, Thomas D.; Spangenburg, Espen E.; Neufer, P. Darrell

2016-01-01

Patients with type 2 diabetes respond poorly to treatments for peripheral arterial disease (PAD) and are more likely to present with the most severe manifestation of the disease, critical limb ischemia. The underlying mechanisms linking type 2 diabetes and the severity of PAD manifestation are not well understood. We sought to test whether diet-induced mitochondrial dysfunction and oxidative stress would increase the susceptibility of the peripheral limb to hindlimb ischemia (HLI). Six weeks of high-fat diet (HFD) in C57BL/6 mice was insufficient to alter skeletal muscle mitochondrial content and respiratory function or the size of ischemic lesion after HLI, despite reducing blood flow. However, 16 weeks of HFD similarly decreased ischemic limb blood flow, but also exacerbated limb tissue necrosis, increased the myopathic lesion size, reduced muscle regeneration, attenuated muscle function, and exacerbated ischemic mitochondrial dysfunction. Mechanistically, mitochondrial-targeted overexpression of catalase prevented the HFD-induced ischemic limb necrosis, myopathy, and mitochondrial dysfunction, despite no improvement in limb blood flow. These findings demonstrate that skeletal muscle mitochondria are a critical pathological link between type 2 diabetes and PAD. Furthermore, therapeutically targeting mitochondria and oxidant burden is an effective strategy to alleviate tissue loss and ischemic myopathy during PAD. PMID:27284110

Mesenchymal Stem Cell-Based Therapy Improves Lower Limb Movement After Spinal Cord Ischemia in Rats.

PubMed

Takahashi, Shinya; Nakagawa, Kei; Tomiyasu, Mayumi; Nakashima, Ayumu; Katayama, Keijiro; Imura, Takeshi; Herlambang, Bagus; Okubo, Tomoe; Arihiro, Koji; Kawahara, Yumi; Yuge, Louis; Sueda, Taijiro

2018-05-01

Spinal cord ischemia is a devastating complication after thoracic and thoracoabdominal aortic operations. In this study, we aimed to investigate the effects of mesenchymal stem cells (MSCs), which have regenerative capability and exert paracrine actions on damaged tissues, injected into rat models of spinal cord ischemia-reperfusion injury. Forty-five Sprague-Dawley rats were divided into sham, phosphate-buffered saline (PBS), and MSC groups. Spinal cord ischemia was induced in the latter two groups by balloon occlusion of the thoracic aorta. MSCs and PBS were then immediately injected into the left carotid artery of the MSC and PBS groups, respectively. Hindlimb motor function was evaluated at 6 and 24 hours. The spinal cord was removed at 24 hours after ischemia-reperfusion injury, and histologic and immunohistochemical analyses and real-time polymerase chain reaction assessments were performed. Rats in the MSC and PBS groups showed flaccid paraparesis/paraplegia postoperatively. Hindlimb function was significantly better at 6 and 24 hours after ischemia-reperfusion injury in the MSC group than in the PBS group (p < 0.05). The number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive neuron cells in the spinal cord and the ratio of Bax to Bcl2 were significantly larger (p < 0.05) in the PBS group than in the MSC group. The injected MSCs were observed in the spinal cord 24 hours after ischemia-reperfusion injury. The MSC therapy by transarterial injection immediately after spinal cord ischemia-reperfusion injury may improve lower limb function by preventing apoptosis of neuron cells in the spinal cord. Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Attenuation of Hind-Limb Ischemia in Mice with Endothelial-Like Cells Derived from Different Sources of Human Stem Cells

PubMed Central

Chan, Yau-Chi; Ng, Joyce H. L.; Au, Ka-Wing; Wong, Lai-Yung; Siu, Chung-Wah; Tse, Hung-Fat

2013-01-01

Functional endothelial-like cells (EC) have been successfully derived from different cell sources and potentially used for treatment of cardiovascular diseases; however, their relative therapeutic efficacy remains unclear. We differentiated functional EC from human bone marrow mononuclear cells (BM-EC), human embryonic stem cells (hESC-EC) and human induced pluripotent stem cells (hiPSC-EC), and compared their in-vitro tube formation, migration and cytokine expression profiles, and in-vivo capacity to attenuate hind-limb ischemia in mice. Successful differentiation of BM-EC was only achieved in 1/6 patient with severe coronary artery disease. Nevertheless, BM-EC, hESC-EC and hiPSC-EC exhibited typical cobblestone morphology, had the ability of uptaking DiI-labeled acetylated low-density-lipoprotein, and binding of Ulex europaeus lectin. In-vitro functional assay demonstrated that hiPSC-EC and hESC-EC had similar capacity for tube formation and migration as human umbilical cord endothelial cells (HUVEC) and BM-EC (P>0.05). While increased expression of major angiogenic factors including epidermal growth factor, hepatocyte growth factor, vascular endothelial growth factor, placental growth factor and stromal derived factor-1 were observed in all EC cultures during hypoxia compared with normoxia (P<0.05), the magnitudes of cytokine up-regulation upon hypoxic were more dramatic in hiPSC-EC and hESC-EC (P<0.05). Compared with medium, transplanting BM-EC (n = 6), HUVEC (n = 6), hESC-EC (n = 8) or hiPSC-EC (n = 8) significantly attenuated severe hind-limb ischemia in mice via enhancement of neovascularization. In conclusion, functional EC can be generated from hECS and hiPSC with similar therapeutic efficacy for attenuation of severe hind-limb ischemia. Differentiation of functional BM-EC was more difficult to achieve in patients with cardiovascular diseases, and hESC-EC or iPSC-EC are readily available as “off-the-shelf” format for the treatment of tissue ischemia. PMID:23472116

Fatigue-related firing of muscle nociceptors reduces voluntary activation of ipsilateral but not contralateral lower limb muscles.

PubMed

Kennedy, David S; Fitzpatrick, Siobhan C; Gandevia, Simon C; Taylor, Janet L

2015-02-15

During fatiguing upper limb exercise, maintained firing of group III/IV muscle afferents can limit voluntary drive to muscles within the same limb. It is not known if this effect occurs in the lower limb. We investigated the effects of group III/IV muscle afferent firing from fatigued ipsilateral and contralateral extensor muscles and ipsilateral flexor muscles of the knee on voluntary activation of the knee extensors. In three experiments, we examined voluntary activation of the knee extensors by measuring changes in superimposed twitches evoked by femoral nerve stimulation. Subjects attended on 2 days for each experiment. On one day a sphygmomanometer cuff occluded blood flow of the fatigued muscles to maintain firing of group III/IV muscle afferents. After a 2-min extensor contraction (experiment 1; n = 9), mean voluntary activation was lower with than without maintained ischemia (47 ± 19% vs. 87 ± 8%, respectively; P < 0.001). After a 2-min knee flexor maximal voluntary contraction (MVC) (experiment 2; n = 8), mean voluntary activation was also lower with than without ischemia (59 ± 21% vs. 79 ± 9%; P < 0.01). After the contralateral (left) MVC (experiment 3; n = 8), mean voluntary activation of the right leg was similar with or without ischemia (92 ± 6% vs. 93 ± 4%; P = 0.65). After fatiguing exercise, activity in group III/IV muscle afferents reduces voluntary activation of the fatigued muscle and nonfatigued antagonist muscles in the same leg. However, group III/IV muscle afferents from the fatigued left leg had no effect on the unfatigued right leg. This suggests that any "crossover" of central fatigue in the lower limbs is not mediated by group III/IV muscle afferents. Copyright © 2015 the American Physiological Society.

Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation.

PubMed

Hsieh, Ming-Jer; Liu, Hsien-Ta; Wang, Chao-Nin; Huang, Hsiu-Yun; Lin, Yuling; Ko, Yu-Shien; Wang, Jong-Shyan; Chang, Vincent Hung-Shu; Pang, Jong-Hwei S

2017-03-01

BPC 157, a pentadecapeptide with extensive healing effects, has recently been suggested to contribute to angiogenesis. However, the underlying mechanism is not yet clear. The present study aimed to explore the potential therapeutic effect and pro-angiogenic mechanism of BPC 157. As demonstrated by the chick chorioallantoic membrane (CAM) assay and endothelial tube formation assay, BPC 157 could increase the vessel density both in vivo and in vitro, respectively. BPC 157 could also accelerate the recovery of blood flow in the ischemic muscle of the rat hind limb as detected by laser Doppler scanning, indicating the promotion of angiogenesis. Histological analysis of the hind limb muscle confirmed the increased number of vessels and the enhanced vascular expression of vascular endothelial growth factor receptor 2 (VEGFR2) in rat with BPC 157 treatment. In vitro study using human vascular endothelial cells further confirmed the increased mRNA and protein expressions of VEGFR2 but not VEGF-A by BPC 157. In addition, BPC 157 could promote VEGFR2 internalization in vascular endothelial cells which was blocked in the presence of dynasore, an inhibitor of endocytosis. BPC 157 time dependently activated the VEGFR2-Akt-eNOS signaling pathway which could also be suppressed by dynasore. The increase of endothelial tube formation induced by BPC 157 was also inhibited by dynasore. This study demonstrates the pro-angiogenic effects of BPC 157 that is associated with the increased expression, internalization of VEGFR2, and the activation of VEGFR2-Akt-eNOS signaling pathway. BPC 157 promotes angiogenesis in CAM assay and tube formation assay. BPC 157 accelerates the blood flow recovery and vessel number in rats with hind limb ischemia. BPC 157 up-regulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture. BPC 157 promotes VEGFR2 internalization in association with VEGFR2-Akt-eNOS activation. BPC 157 promotes angiogenesis in CAM assay and tube formation assay. BPC 157 accelerates the blood flow recovery and vessel number in rats with hind limb ischemia. BPC 157 up-regulates VEGFR2 expression in rats with hind limb ischemia and endothelial cell culture. BPC 157 promotes VEGFR2 internalization in association with VEGFR2-Akt-eNOS activation.

Carbon dioxide as a substitute for iodine contrast in arteriography during embolectomy

PubMed Central

Wolosker, Nelson; Teivelis, Marcelo Passos; Mendes, Cynthia de Almeida; Nishinari, Kenji; Ribeiro, Mariângela de Freitas; Kuzniec, Sergio

2015-01-01

Acute limb ischemia can be potentially harmful to the limb and life threatening. Renal failure is a possible outcome associated with release of products of ischemic limb reperfusion. Some authors reported the benefit of performing angiography after embolectomy, even though iodine contrast is also nephrotoxic. We report a case of embolectomy on a patient with renal insufficiency in whom carbon dioxide was used as a substitute for iodine contrast. PMID:26061074

Retrograde Ascending Aortic Dissection after Stent Grafting for Stanford Type B Aortic Dissection with Severe Limb Ischemia.

PubMed

Higuchi, Yoshiro; Tochii, Masato; Takami, Yoshiyuki; Kobayashi, Akihiro; Yanagisawa, Tsutomu; Amano, Kentaro; Sakurai, Yusuke; Ishida, Michiko; Ishikawa, Hiroshi; Hattori, Koji; Takagi, Yasushi

2017-03-24

We report a rare case of retrograde Stanford type A aortic dissection after endovascular repair for complicated Stanford type B aortic dissection. A 45-year-old man presented with a sudden onset of back pain and was transferred to our hospital. Computed tomography demonstrated acute Stanford type B aortic dissection with lower limb ischemia. Emergency endovascular surgery was planned for repair of the Stanford type B aortic dissection. The patient suddenly developed recurrent chest pain 10 days after the initial procedure. Computed tomography revealed retrograde Stanford type A aortic dissection involving the ascending aorta and aortic arch. The patient underwent a successful emergency total aortic arch replacement.

The Society for Vascular Surgery lower extremity threatened limb classification system based on Wound, Ischemia, and foot Infection (WIfI) correlates with risk of major amputation and time to wound healing.

PubMed

Zhan, Luke X; Branco, Bernardino C; Armstrong, David G; Mills, Joseph L

2015-04-01

The purpose of this study was to evaluate whether the new Society for Vascular Surgery (SVS) Wound, Ischemia, and foot Infection (WIfI) classification system correlates with important clinical outcomes for limb salvage and wound healing. A total of 201 consecutive patients with threatened limbs treated from 2010 to 2011 in an academic medical center were analyzed. These patients were stratified into clinical stages 1 to 4 on the basis of the SVS WIfI classification. The SVS objective performance goals of major amputation, 1-year amputation-free survival (AFS) rate, and wound healing time (WHT) according to WIfI clinical stages were compared. The mean age was 58 years (79% male, 93% with diabetes). Forty-two patients required major amputation (21%); 159 (78%) had limb salvage. The amputation group had a significantly higher prevalence of advanced stage 4 patients (P < .001), whereas the limb salvage group presented predominantly as stages 1 to 3. Patients in clinical stages 3 and 4 had a significantly higher incidence of amputation (P < .001), decreased AFS (P < .001), and delayed WHT (P < .002) compared with those in stages 1 and 2. Among patients presenting with stage 3, primarily as a result of wound and ischemia grades, revascularization resulted in accelerated WHT (P = .008). These data support the underlying concept of the SVS WIfI, that an appropriate classification system correlates with important clinical outcomes for limb salvage and wound healing. As the clinical stage progresses, the risk of major amputation increases, 1-year AFS declines, and WHT is prolonged. We further demonstrated benefit of revascularization to improve WHT in selected patients, especially those in stage 3. Future efforts are warranted to incorporate the SVS WIfI classification into clinical decision-making algorithms in conjunction with a comorbidity index and anatomic classification. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

CXCR4 Overexpression in Human Adipose Tissue-Derived Stem Cells Improves Homing and Engraftment in an Animal Limb Ischemia Model.

PubMed

Kim, MiJung; Kim, Dong-Ik; Kim, Eun Key; Kim, Chan-Wha

2017-02-16

We investigated the effects of transplantation of CXCR4-overexpressing adipose tissue-derived stem cells (ADSCs) into a mouse diabetic hindlimb ischemia model on homing and engraftment as early as 48 h after transplant. CXCR4-overexpressing ADSCs were intramuscularly or intravenously injected into diabetic mice with hindlimb ischemia. After 48 h, muscle tissues in the femur and tibia were collected, and the CXCR4 expression pattern was analyzed by immunofluorescence staining. The homing and engraftment of transplanted CXCR4-overexpressing ADSCs into the ischemic area were significantly increased, and intravenous (systemic) injection resulted in the more effective delivery of stem cells to the target site 48 h posttransplantation. Furthermore, CXCR4-overexpressing ADSCs more efficiently contributed to long-term engraftment and muscle tissue regeneration than normal ADSCs in a limb ischemia model. In addition, the homing and engraftment of ADSCs were correlated with the CXCR4 transfection efficiency. These results demonstrated that enhanced CXCR4 signaling could significantly improve the early homing and engraftment of ADSCs into ischemic areas as well as the long-term engraftment and ultimate muscle tissue regeneration.

[Limb remote ischemic preconditioning attenuates liver ischemia reperfusion injury by activating autophagy via modulating PPAR-γ pathway].

PubMed

Ruan, Wei; Liu, Qing; Chen, Chan; Li, Suobei; Xu, Junmei

2016-09-28

To investigate the effect of limb remote ischemic preconditioning (RIPC) on hepatic ischemia/reperfusion (IR) injury and the underlying mechanisms.
 Rats were subjected to partial hepatic IR (60 min ischemia followed by 24 hours reperfusion) with or without RIPC, which was achieved by 3 cycles of 10 min-occlusion and 10 min-
reperfusion at the bilateral femoral arteries interval 30 min before ischemia. Some rats were treated with a new PPAR-γ inhibitor, T0070907, before RIPC.
 At the end of reperfusion, liver injury was significantly increased (increases in Suzike's injury score, AST and ALT release), concomitant with elevated oxidative stress (increases in MDA formation, MPO activity, as well as the decrease in SOD activity) and inflammation (increases in TNF-α and IL-6 levels, decrease in IL-10 content). RIPC improved liver function and reduced histologic damage, accompanied by the increased PPAR-γ activation and autophagosome formation as well as the reduced autophagosome clearance. The beneficial effects of RIPC were markedly attenuated by T0070907, an inhibitor of PPAR-γ.
 RIPC exerts the protective effects on liver by activation of autophagy via PPAR-γ.

Use of isovolemic hemodilution in the management of arterial ischemia in patients with polycythemia.

PubMed

Shah, D M; Buchbinder, D; Balko, A; Karmody, A M; Leather, R P

1981-08-01

The management of patients with both polycythemia and limb-threatening ischemia presents many difficulties because in this population, vascular surgical procedures carry a particularly high incidence of hemorrhagic and thromboembolic complications. We evaluated the use of acute isovolemic hemodilution in 12 polycythemic patients who required urgent surgery due to severe ischemia and threatened limb loss. Within 48 hours, blood was withdrawn in units of 500 ml and simultaneously replaced with 1,500 ml of lactated Ringer's solution until a hematocrit of 35 to 40 percent was achieved. After hemodilution, two patients had such a marked improvement that no further therapeutic measures were required immediately. Four patients showed definite improvement in pulmonary vascular resistance tracings and segmental Doppler pressures, but ischemia was not fully ameliorated. These patients together with the remaining six patients underwent vascular surgery within 1 to 14 days after hemodilution. A hematocrit of 32 to 40 percent was maintained during the perioperative period. All arterial reconstructions were successfully completed and there were no perioperative failures. No pulmonary emboli, myocardial infarctions, or deaths occurred in this period. These results indicate that in polycythemic patients, urgent vascular surgery can be performed more safely with the concomitant use of acute isovolemic hemodilution.

An injectable elastin-based gene delivery platform for dose-dependent modulation of angiogenesis and inflammation for critical limb ischemia.

PubMed

Dash, Biraja C; Thomas, Dilip; Monaghan, Michael; Carroll, Oliver; Chen, Xizhe; Woodhouse, Kimberly; O'Brien, Timothy; Pandit, Abhay

2015-10-01

Critical limb ischemia is a major clinical problem. Despite rigorous treatment regimes, there has been only modest success in reducing the rate of amputations in affected patients. Reduced level of blood flow and enhanced inflammation are the two major pathophysiological changes that occur in the ischemic tissue. The objective of this study was to develop a controlled dual gene delivery system capable of delivering therapeutic plasmid eNOS and IL-10 in a temporal manner. In order to deliver multiple therapeutic genes, an elastin-like polypeptide (ELP) based injectable system was designed. The injectable system was comprised of hollow spheres and an in situ-forming gel scaffold of elastin-like polypeptide capable of carrying gene complexes, with an extended manner release profile. In addition, the ELP based injectable system was used to deliver human eNOS and IL-10 therapeutic genes in vivo. A subcutaneous dose response study showed enhanced blood vessel density in the treatment groups of eNOS (20 μg) and IL-10 (10 μg)/eNOS (20 μg) and reduced inflammation with IL-10 (10 μg) alone. Next, we carried out a hind-limb ischemia model comparing the efficacy of the following interventions; Saline; IL-10, eNOS and IL-10/eNOS. The selected dose of eNOS, exhibited enhanced angiogenesis. IL-10 treatment groups showed reduction in the level of inflammatory cells. Furthermore, we demonstrated that eNOS up-regulated major proangiogenic growth factors such as vascular endothelial growth factors, platelet derived growth factor B, and fibroblast growth factor 1, which may explain the mechanism of this approach. These factors help in formation of a stable vascular network. Thus, ELP injectable system mediating non-viral delivery of human IL10-eNOS is a promising therapy towards treating limb ischemia. Copyright © 2015 Elsevier Ltd. All rights reserved.

Reproducable Paraplegia by Thoracic Aortic Occlusion in a Murine Model of Spinal Cord Ischemia-reperfusion

PubMed Central

Bell, Marshall T.; Reece, T. Brett; Smith, Phillip D.; Mares, Joshua; Weyant, Michael J.; Cleveland, Joseph C.; Freeman, Kirsten A.; Fullerton, David A.; Puskas, Ferenc

2014-01-01

Background Lower extremity paralysis continues to complicate aortic interventions. The lack of understanding of the underlying pathology has hindered advancements to decrease the occurrence this injury. The current model demonstrates reproducible lower extremity paralysis following thoracic aortic occlusion. Methods Adult male C57BL6 mice were anesthetized with isoflurane. Through a cervicosternal incision the aorta was exposed. The descending thoracic aorta and left subclavian arteries were identified without entrance into pleural space. Skeletonization of these arteries was followed by immediate closure (Sham) or occlusion for 4 min (moderate ischemia) or 8 min (prolonged ischemia). The sternotomy and skin were closed and the mouse was transferred to warming bed for recovery.  Following recovery, functional analysis was obtained at 12 hr intervals until 48 hr. Results Mice that underwent sham surgery showed no observable hind limb deficit. Mice subjected to moderate ischemia for 4 min had minimal functional deficit at 12 hr followed by progression to complete paralysis at 48 hr. Mice subjected to prolonged ischemia had an immediate paralysis with no observable hind-limb movement at any point in the postoperative period. There was no observed intraoperative or post operative mortality. Conclusion Reproducible lower extremity paralysis whether immediate or delayed can be achieved in a murine model. Additionally, by using a median sternotomy and careful dissection, high survival rates, and reproducibility can be achieved. PMID:24637534

Reproducable paraplegia by thoracic aortic occlusion in a murine model of spinal cord ischemia-reperfusion.

PubMed

Bell, Marshall T; Reece, T Brett; Smith, Phillip D; Mares, Joshua; Weyant, Michael J; Cleveland, Joseph C; Freeman, Kirsten A; Fullerton, David A; Puskas, Ferenc

2014-03-03

Lower extremity paralysis continues to complicate aortic interventions. The lack of understanding of the underlying pathology has hindered advancements to decrease the occurrence this injury. The current model demonstrates reproducible lower extremity paralysis following thoracic aortic occlusion. Adult male C57BL6 mice were anesthetized with isoflurane. Through a cervicosternal incision the aorta was exposed. The descending thoracic aorta and left subclavian arteries were identified without entrance into pleural space. Skeletonization of these arteries was followed by immediate closure (Sham) or occlusion for 4 min (moderate ischemia) or 8 min (prolonged ischemia). The sternotomy and skin were closed and the mouse was transferred to warming bed for recovery. Following recovery, functional analysis was obtained at 12 hr intervals until 48 hr. Mice that underwent sham surgery showed no observable hind limb deficit. Mice subjected to moderate ischemia for 4 min had minimal functional deficit at 12 hr followed by progression to complete paralysis at 48 hr. Mice subjected to prolonged ischemia had an immediate paralysis with no observable hind-limb movement at any point in the postoperative period. There was no observed intraoperative or post operative mortality. Reproducible lower extremity paralysis whether immediate or delayed can be achieved in a murine model. Additionally, by using a median sternotomy and careful dissection, high survival rates, and reproducibility can be achieved.

Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury.

PubMed

Huang, Rong-Shuang; Zhou, Jiao-Jiao; Feng, Yu-Ying; Shi, Min; Guo, Fan; Gou, Shen-Ju; Salerno, Stephen; Ma, Liang; Fu, Ping

2017-09-20

Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway. C57BL/6 mice were injected with a 50% glycerin solution at bilateral back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate (PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine levels, creatine kinase, the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and hematoxylin and eosin stainings of kidney tissues were tested. The infiltration of macrophage, mRNA levels, and protein expression of TLR4 and NF-κB were investigated by immunofluorescence double-staining techniques, reverse transcriptase-quantitative polymerase chain reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-κB expressions were also detected. In an in vivo study, using CLI-095 or PDTC to block TLR4/NF-κB, functional and histologic results showed that the inhibition of TLR4 or NF-κB alleviated glycerol-induced renal damages (P < 0.01). CLI-095 or PDTC administration suppressed proinflammatory cytokine (TNF-α, IL-6, and IL-1β) production and macrophage infiltration into the kidney (P < 0.01). Moreover, in an in vitro study, CLI-095 or PDTC suppressed myoglobin-induced expression of TLR4, NF-κB, and proinflammatory cytokine levels in macrophage RAW264.7 cells (P < 0.01). The pharmacological inhibition of TLR4/NF-κB exhibited protective effects on rhabdomyolysis-induced AKI by the regulation of proinflammatory cytokine production and macrophage infiltration.

Criteria predictive of limb viability at 1 year in patients with chronic severe ischemia--TcPO2 and demographic parameters.

PubMed

Chomard, D; Habault, P; Eveno, D; Le Lamer, S; Ledemeney, M; Haon, C

2000-09-01

Following an earlier study, the investigators sought to identify and define objective prognostic criteria of viability at 1 year of a limb with severe chronic ischemia. A study was undertaken in 116 patients (118 limbs) (74 men and 42 women), with a mean age of 71.9 years for men and 81.6 years for women. Static transcutaneous oxygen pressure (TcPO2) was measured with a verticalization sensitization test and inhalation of oxygen on JO and viability of the limb noted 1 year later. Logistic analysis was made of 13 oximetry parameters and two demographic parameters (age and gender). Results were analyzed in absolute terms and by tissue oxygenation ratio (TOR) (ratio between absolute TcPO2 at the foot and at a chest reference electrode). Six factors appeared to be prognostic factors of limb viability at 1 year, statistically significant at 6% according to threshold values: age, verticalization TcPO2, TcPO2 after 1 minute's inhalation of oxygen, TcPO2 after 4 minutes' inhalation of oxygen, and slope of TcPO2 and slope of TOR between 1 and 4 minutes' inhalation. A 1 year viability index integrating these criteria is suggested.

Enhanced angiogenic effect of adipose-derived stromal cell spheroid with low-level light therapy in hind limb ischemia mice.

PubMed

Park, In-Su; Chung, Phil-Sang; Ahn, Jin Chul

2014-11-01

The aim of this study was to investigate the effects of low-level laser therapy (LLLT) on transplanted human adipose-derived mesenchymal stem cells (hASCs) spheroid in a hind limb ischemia animal model. LLLT, hASCs spheroid and hASCs spheroid transplantation with LLLT (spheroid + LLLT) were applied to the ischemic hind limbs in athymic mice. The survival, differentiation and secretion of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF), and hepatocyte growth factor (HGF) of the spheroid ASCs were evaluated by immunohistochemistry and western blots. Spheroid + LLLT group had enhanced the tissue regeneration, including angiogenesis, compared with the ASC group. The spheroid ASCs contributed to tissue regeneration via differentiation and secretion of growth factors. In the spheroid + LLLT group, the survival of spheroid hASCs increased with a concomitant decrease in apoptosis of spheroid hASCs in the ischemic hind limb. The secretion of growth factors was stimulated in the spheroid + LLLT group compared with the ASCs and spheroid group. These data suggested that LLLT is an effective biostimulator of spheroid hASCs in tissue regeneration that enhanced the survival of ASCs and stimulated the secretion of growth factors in the ischemic hind limb. Copyright © 2014 Elsevier Ltd. All rights reserved.

[The use of genetic angiogenesis inductors in surgical treatment of chronic lower limb ischemia].

PubMed

Gavrilenko, A V; Voronov, D A; Bochkov, N P

2013-01-01

The efficacy and safety of gene-engineering recombinant constructions with endothelial growth factor gene and angiogenin for the treatment of the chronic lower limb ischemia were studied. 134 patients were included in prospective controlled study. The main group, who received both traditional treatment and genetic therapy, consisted of 74 patients. The rest 60 patients were included into the control group. Of 74 patients from the main group, genetic therapy was used together with conservative means in 39 patients and with reconstructive vascular operations in 35 patients. The gene-engineering angiogenesis stimulation therapy proved to be effective and safe. The combination of angiogenesis genetic stimulation with reconstructive vascular surgery demonstrated significantly better results, then monotherapy.

Marrow-isolated adult multilineage inducible cells embedded within a biologically-inspired construct promote recovery in a mouse model of peripheral vascular disease.

PubMed

Grau-Monge, Cristina; Delcroix, Gaëtan J-R; Bonnin-Marquez, Andrea; Valdes, Mike; Awadallah, Ead Lewis Mazen; Quevedo, Daniel F; Armour, Maxime R; Montero, Ramon B; Schiller, Paul C; Andreopoulos, Fotios M; D'Ippolito, Gianluca

2017-02-17

Peripheral vascular disease is one of the major vascular complications in individuals suffering from diabetes and in the elderly that is associated with significant burden in terms of morbidity and mortality. Stem cell therapy is being tested as an attractive alternative to traditional surgery to prevent and treat this disorder. The goal of this study was to enhance the protective and reparative potential of marrow-isolated adult multilineage inducible (MIAMI) cells by incorporating them within a bio-inspired construct (BIC) made of two layers of gelatin B electrospun nanofibers. We hypothesized that the BIC would enhance MIAMI cell survival and engraftment, ultimately leading to a better functional recovery of the injured limb in our mouse model of critical limb ischemia compared to MIAMI cells used alone. Our study demonstrated that MIAMI cell-seeded BIC resulted in a wide range of positive outcomes with an almost full recovery of blood flow in the injured limb, thereby limiting the extent of ischemia and necrosis. Functional recovery was also the greatest when MIAMI cells were combined with BICs, compared to MIAMI cells alone or BICs in the absence of cells. Histology was performed 28 days after grafting the animals to explore the mechanisms at the source of these positive outcomes. We observed that our critical limb ischemia model induces an extensive loss of muscular fibers that are replaced by intermuscular adipose tissue (IMAT), together with a highly disorganized vascular structure. The use of MIAMI cells-seeded BIC prevented IMAT infiltration with some clear evidence of muscular fibers regeneration.

MIAMI cells embedded within a biologically-inspired construct promote recovery in a mouse model of peripheral vascular disease

PubMed Central

Grau-Monge, Cristina; Delcroix, Gaëtan J.-R; Bonnin-Marquez, Andrea; Valdes, Mike; Awadallah, Ead Lewis Mazen; Quevedo, Daniel F.; Armour, Maxime R.; Montero, Ramon B.; Schiller, Paul C.; Andreopoulos, Fotios M.; D’Ippolito, Gianluca

2017-01-01

Peripheral vascular disease is one of the major vascular complications in individuals suffering from diabetes and in the elderly that is associated with significant burden in terms of morbidity and mortality. Stem cell therapy is being tested as an attractive alternative to traditional surgery to prevent and treat this disorder. The goal of this study was to enhance the protective and reparative potential of marrow-isolated adult multilineage inducible (MIAMI) cells by incorporating them within a bio-inspired construct (BIC) made of 2 layers of gelatin B electrospun nanofibers. We hypothesized that the BIC would enhance MIAMI cell survival and engraftment, ultimately leading to a better functional recovery of the injured limb in our mouse model of critical limb ischemia compared to MIAMI cells used alone. Our study demonstrated that MIAMI cell-seeded BIC resulted in a wide range of positive outcomes with an almost full recovery of blood flow in the injured limb, thereby limiting the extent of ischemia and necrosis. Functional recovery was also the greatest when MIAMI cells were combined with BICs, compared to MIAMI cells alone or BICs in the absence of cells. Histology was performed 28 days after grafting the animals to explore the mechanisms at the source of these positive outcomes. We observed that our critical limb ischemia model induces an extensive loss of muscular fibers that are replaced by intermuscular adipose tissue (IMAT), together with a highly disorganized vascular structure. The use of MIAMI cells-seeded BIC prevented IMAT infiltration with some clear evidence of muscular fibers regeneration. PMID:28211362

Frequency of cancer in patients operated on for acute peripheral arterial thrombosis and the impact on prognosis.

PubMed

Nicolajsen, Chalotte Winther; Dickenson, Maja Holch; Budtz-Lilly, Jacob; Eldrup, Nikolaj

2015-12-01

Little is known about acute peripheral arterial thrombosis in patients with concomitant cancer. Small studies suggest that revascularization in this patient group is associated with thrombosis and increased risk of amputation and death. We investigated the frequency of cancer in patients operated on for acute peripheral arterial thrombosis and the long-term risk of amputation, mortality, myocardial infarction, and stroke in a national cohort. This was a prospective case/noncase study comprising all Danish citizens undergoing vascular surgery for acute arterial thrombosis from 1986 to 2012 with up to 26 years of follow-up. A total of 7840 patients were treated surgically for acute arterial thrombosis; 2384 (30.4%) were previously diagnosed with cancer or developed cancer during the observation period. Risk of amputation was not significantly different in patients with or without cancer, except in patients with cancer diagnosed <24 months before acute limb ischemia (hazard ratio, 2.0). Mortality was significantly greater in all patients having or developing cancer within 24 months after surgery (hazard ratio, 1.2-2.2). The frequencies of myocardial infarction and stroke were similar to those among patients without cancer. One of five patients operated on for acute limb ischemia has a diagnosis of cancer, and a further 3.4% will develop cancer within 24 months. The data further show that patients with acute limb ischemia and concomitant cancer can be successfully revascularized and that the majority of these patients preserve their limb. Cancer should therefore not contravene interventional treatment. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter.

PubMed

Ezzati, Mojgan; Bainbridge, Alan; Broad, Kevin D; Kawano, Go; Oliver-Taylor, Aaron; Rocha-Ferreira, Eridan; Alonso-Alconada, Daniel; Fierens, Igor; Rostami, Jamshid; Jane Hassell, K; Tachtsidis, Ilias; Gressens, Pierre; Hristova, Mariya; Bennett, Kate; Lebon, Sophie; Fleiss, Bobbi; Yellon, Derek; Hausenloy, Derek J; Golay, Xavier; Robertson, Nicola J

2016-08-01

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White female newborn piglets were randomized to: (i) no intervention (n = 8); (ii) RIPostC - with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI (n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate (p = 0.005) and increased whole brain phosphorus-31 MRS ATP (p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter (p = 0.03), internal capsule (p = 0.002) and corpus callosum (p = 0.021); there was reduced microglial activation in corpus callosum (p = 0.001) and more surviving oligodendrocytes in corpus callosum (p = 0.029) and periventricular white matter (p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter. © The Author(s) 2015.

Peripheral Stent Thrombosis Leading to Acute Limb Ischemia and Major Amputation: Incidence and Risk Factors in the Aortoiliac and Femoropopliteal Arteries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katsanos, Konstantinos, E-mail: katsanos@med.upatras.gr; Al-Lamki, Said A. M.; Parthipun, Aneeta

PurposeTo report the real-world incidence and risk factors of stent thrombosis in the aortoiliac and femoropopliteal arteries in case of bare nitinol stent (BNS) or covered nitinol stent (CNS) placement from a single-centre retrospective audit.Materials and MethodsMedical records of consecutive patients treated with peripheral stent placement for claudication or critical limb ischemia were audited for definite stent thrombosis defined as imaging confirmed stent thrombosis that presented as acute limb-threatening ischemia. Cases were stratified between aortoiliac and femoropopliteal anatomy. Cox regression analysis was employed to adjust for baseline clinical and procedural confounders and identify predictors of stent thrombosis and major limbmore » loss.Results256 patients (n = 277 limbs) were analysed over a 5-year period (2009–2014) including 117 aortoiliac stents (34 CNS; 12.8 ± 5.0 cm and 83 BNS; 7.8 ± 4.0 cm) and 160 femoropopliteal ones (60 CNS; 21.1 ± 11.0 cm and 100 BNS; 17.5 ± 11.9 cm). Median follow-up was 1 year. Overall stent thrombosis rate was 6.1% (17/277) after a median of 43 days (range 2–192 days) and affected almost exclusively the femoropopliteal segment (12/60 in the CNS cohort vs. 4/100 in the BNS; p = 0.001). Annualized stent thrombosis rates (per 100 person-years) were 12.5% in case of CNS and 1.4% in case of BNS (HR 6.3, 95% CI 2.4–17.9; p = 0.0002). Corresponding major amputations rates were 8.7 and 2.5%, respectively (HR 4.5, 95% CI 2.7–27.9; p = 0.0006). On multivariable analysis, critical leg ischemia and CNS placement were the only predictors of stent thrombosis. Diabetes, critical leg ischemia, femoropopliteal anatomy, long stents and CNS were independent predictors of major amputations.ConclusionsPlacement of long femoropopliteal covered nitinol stents is associated with an increased incidence of acute stent thrombosis and ensuing major amputation. Risks are significantly lower in the aortoiliac vessels and with use of bare nitinol stents.« less

Improving Ischemia Reperfusion Injury in Vascularized Composite Tissue Allotransplantation Via Histone Deacetylase Modulation

DTIC Science & Technology

2017-10-01

of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other...average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed...IRI) in scenarios relevant to limb transplantation using mouse models for experimentation. Limitations in tolerated ischemia times limits the scope

Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation.

PubMed

Belcik, J Todd; Mott, Brian H; Xie, Aris; Zhao, Yan; Kim, Sajeevani; Lindner, Nathan J; Ammi, Azzdine; Linden, Joel M; Lindner, Jonathan R

2015-04-01

Ultrasound can increase tissue blood flow, in part, through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation and sought to characterize the biological mediators. Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in nonischemic mice after unilateral 10-minute exposure to intermittent ultrasound alone (mechanical index, 0.6 or 1.3) or ultrasound with lipid microbubbles (2×10(8) IV). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (P<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3- and 10-fold higher than control for mechanical index 0.6 and 1.3, respectively; P<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase attenuated flow augmentation produced by ultrasound and microbubbles by 70% (P<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide production and muscle phospho-endothelial nitric oxide synthase increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40%-50% reduction in flow), ultrasound (mechanical index, 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control nonischemic limb. Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of endothelial nitric oxide synthase. © 2015 American Heart Association, Inc.

AUGMENTATION OF LIMB PERFUSION AND REVERSAL OF TISSUE ISCHEMIA PRODUCED BY ULTRASOUND-MEDIATED MICROBUBBLE CAVITATION

PubMed Central

Belcik, J. Todd; Mott, Brian H.; Xie, Aris; Zhao, Yan; Kim, Sajeevani; Lindner, Nathan J.; Ammi, Azzdine; Linden, Joel M.; Lindner, Jonathan R.

2015-01-01

Background Ultrasound can increase tissue blood flow in part through the intravascular shear produced by oscillatory pressure fluctuations. We hypothesized that ultrasound-mediated increases in perfusion can be augmented by microbubble contrast agents that undergo ultrasound-mediated cavitation, and sought to characterize the biologic mediators. Methods and Results Contrast ultrasound perfusion imaging of hindlimb skeletal muscle and femoral artery diameter measurement were performed in non-ischemic mice after unilateral 10 min exposure to intermittent ultrasound alone (mechanical index [MI] 0.6 or 1.3) or ultrasound with lipid microbubbles (2×108 I.V.). Studies were also performed after inhibiting shear- or pressure-dependent vasodilator pathways, and in mice with hindlimb ischemia. Ultrasound alone produced a 2-fold increase (p<0.05) in muscle perfusion regardless of ultrasound power. Ultrasound-mediated augmentation in flow was greater with microbubbles (3-fold and 10-fold higher than control for MI 0.6 and 1.3, respectively; p<0.05), as was femoral artery dilation. Inhibition of endothelial nitric oxide synthase (eNOS) attenuated flow augmentation produced by ultrasound and microbubbles by 70% (p<0.01), whereas inhibition of adenosine-A2a receptors and epoxyeicosatrienoic acids had minimal effect. Limb nitric oxide (NO) production and muscle phospho-eNOS increased in a stepwise fashion by ultrasound and ultrasound with microbubbles. In mice with unilateral hindlimb ischemia (40–50% reduction in flow), ultrasound (MI 1.3) with microbubbles increased perfusion by 2-fold to a degree that was greater than the control non-ischemic limb. Conclusions Increases in muscle blood flow during high-power ultrasound are markedly amplified by the intravascular presence of microbubbles and can reverse tissue ischemia. These effects are most likely mediated by cavitation-related increases in shear and activation of eNOS. PMID:25834183

Quantifying the vascular response to ischemia with speckle variance optical coherence tomography

PubMed Central

Poole, Kristin M.; McCormack, Devin R.; Patil, Chetan A.; Duvall, Craig L.; Skala, Melissa C.

2014-01-01

Longitudinal monitoring techniques for preclinical models of vascular remodeling are critical to the development of new therapies for pathological conditions such as ischemia and cancer. In models of skeletal muscle ischemia in particular, there is a lack of quantitative, non-invasive and long term assessment of vessel morphology. Here, we have applied speckle variance optical coherence tomography (OCT) methods to quantitatively assess vascular remodeling and growth in a mouse model of peripheral arterial disease. This approach was validated on two different mouse strains known to have disparate rates and abilities of recovering following induction of hind limb ischemia. These results establish the potential for speckle variance OCT as a tool for quantitative, preclinical screening of pro- and anti-angiogenic therapies. PMID:25574425

Protease-activated receptor (PAR)2, but not PAR1, is involved in collateral formation and anti-inflammatory monocyte polarization in a mouse hind limb ischemia model.

PubMed

van den Hengel, Lisa G; Hellingman, Alwine A; Nossent, Anne Yael; van Oeveren-Rietdijk, Annemarie M; de Vries, Margreet R; Spek, C Arnold; van Zonneveld, Anton Jan; Reitsma, Pieter H; Hamming, Jaap F; de Boer, Hetty C; Versteeg, Henri H; Quax, Paul H A

2013-01-01

In collateral development (i.e. arteriogenesis), mononuclear cells are important and exist as a heterogeneous population consisting of pro-inflammatory and anti-inflammatory/repair-associated cells. Protease-activated receptor (PAR)1 and PAR2 are G-protein-coupled receptors that are both expressed by mononuclear cells and are involved in pro-inflammatory reactions, while PAR2 also plays a role in repair-associated responses. Here, we investigated the physiological role of PAR1 and PAR2 in arteriogenesis in a murine hind limb ischemia model. PAR1-deficient (PAR1-/-), PAR2-deficient (PAR2-/-) and wild-type (WT) mice underwent femoral artery ligation. Laser Doppler measurements revealed reduced post-ischemic blood flow recovery in PAR2-/- hind limbs when compared to WT, while PAR1-/- mice were not affected. Upon ischemia, reduced numbers of smooth muscle actin (SMA)-positive collaterals and CD31-positive capillaries were found in PAR2-/- mice when compared to WT mice, whereas these parameters in PAR1-/- mice did not differ from WT mice. The pool of circulating repair-associated (Ly6C-low) monocytes and the number of repair-associated (CD206-positive) macrophages surrounding collaterals in the hind limbs were increased in WT and PAR1-/- mice, but unaffected in PAR2-/- mice. The number of repair-associated macrophages in PAR2-/- hind limbs correlated with CD11b- and CD115-expression on the circulating monocytes in these animals, suggesting that monocyte extravasation and M-CSF-dependent differentiation into repair-associated cells are hampered. PAR2, but not PAR1, is involved in arteriogenesis and promotes the repair-associated response in ischemic tissues. Therefore, PAR2 potentially forms a new pro-arteriogenic target in coronary artery disease (CAD) patients.

Late recurrent peripheral upper limb ischemia after non-union of a clavicle fracture.

PubMed

Stella, Marco; Santolini, Emmanuele; Briano, Stefania; Santolini, Federico

2015-12-01

A 74-year-old woman was referred to our hospital due to recurrent episodes of upper limb ischemia. Her past medical history included a clavicle non-union developed after a clavicle midshaft fracture that had occurred 30 years previously. After a long asymptomatic period, she started showing symptoms of chronic ischemia to the left arm that were misdiagnosed. Thoracic outlet syndrome (TOS) is a rare but possible complication of mal-union and non-union of clavicle fractures; symptoms related to arterial involvement (ATOS) amount to less than 1% of all existing forms of thoracic outlet syndrome. In case of clavicle non-union, local instability plays a key role in determining the initial injury to the vessels and the recurrence of symptoms. Restoration of local bone stability and anatomy, obtained by compression plating and autologous bone grafting, combined with an appropriate vascular surgery, is essential to achieve a clinical resolution of symptoms and to avoid the recurrence of symptomatology as seen in the herein case. Copyright © 2015 Elsevier Ltd. All rights reserved.

Poly ADP-Ribose Polymerase Inhibition Ameliorates Hind Limb Ischemia Reperfusion Injury in a Murine Model of Type 2 Diabetes

PubMed Central

Long, Chandler A.; Boloum, Valy; Albadawi, Hassan; Tsai, Shirling; Yoo, Hyung-Jin; Oklu, Rahmi; Goldman, Mitchell H.; Watkins, Michael T.

2013-01-01

Introduction Diabetes is known to increase poly-ADP-ribose-polymerase (PARP) activity and posttranslational poly-ADP-ribosylation of several regulatory proteins involved in inflammation and energy metabolism. These experiments test the hypothesis that PARP inhibition will modulate hind limb ischemia reperfusion (IR) in a mouse model of type-II diabetes; ameliorate the ribosylation and the activity/transnuclear localization of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Methods db/db mice underwent 1.5hrs of hind limb ischemia followed by 1, 7, or 24hrs reperfusion. The treatment group received the PARP inhibitor PJ34 (PJ34) over a 24hrs period; the untreated group received Lactated ringer’s (LR) at the same time points. IR muscles were analyzed for indices of PARP activity, fiber injury, metabolic activity, inflammation, GAPDH activity /intracellular localization and poly-ADP-ribosylation of GAPDH. Results PARP activity was significantly lower in the PJ34 treated groups compared to the LR group at 7 and 24 hours reperfusion. There was significantly less muscle fiber injury in the PJ34 treated group compared to LR treated mice at 24 hrs reperfusion. PJ34 lowered levels of select proinflammatory molecules at 7hrs and 24hrs IR. There were significant increases in metabolic activity only at 24 hours IR in the PJ34 group, which temporally correlated with increase in GAPDH activity, decreased GAPDH poly ADP-ribosylation and nuclear translocation of GAPDH. Conclusions PJ34 reduced PARP activity, GAPDH ribosylation, GAPDH translocation, ameliorated muscle fiber injury, and increased metabolic activity following hind limb IR injury in a murine model of type-II diabetes. PARP inhibition might be a therapeutic strategy following IR in diabetic humans. PMID:23549425

Heme oxygenase-1 mediates the protective effects of ischemic preconditioning on mitigating lung injury induced by lower limb ischemia-reperfusion in rats.

PubMed

Peng, Tsui-Chin; Jan, Woan-Ching; Tsai, Pei-Shan; Huang, Chun-Jen

2011-05-15

Lower limb ischemia-reperfusion (I/R) imposes oxidative stress, elicits inflammatory response, and subsequently induces acute lung injury. Ischemic preconditioning (IP), a process of transient I/R, mitigates the acute lung injury induced by I/R. We sought to elucidate whether the protective effects of IP involve heme oxygenase-1 (HO-1). Adult male rats were randomized to receive I/R, I/R plus IP, I/R plus IP plus the HO-1 inhibitor tin protoporphyrin (SnPP) (n = 12 in each group). Control groups were run simultaneously. I/R was induced by applying rubber band tourniquet high around each thigh for 3 h followed by reperfusion for 3 h. To achieve IP, three cycles of bilateral lower limb I/R (i.e., ischemia for 10 min followed by reperfusion for 10 min) were performed. IP was performed immediately before I/R. After sacrifice, degree of lung injury was determined. Histologic findings, together with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that I/R induced acute lung injury. I/R also caused significant inflammatory response (increases in chemokine, cytokine, and prostaglandin E(2) concentrations), imposed significant oxidative stress (increases in nitric oxide and malondialdehyde concentrations), and up-regulated HO-1 expression in lung tissues. IP significantly enhanced HO-1 up-regulation and, in turn, mitigated oxidative stress, inflammatory response, and acute lung injury induced by I/R. In addition, the protective effects of IP were counteracted by SnPP. The protective effects of IP on mitigating acute lung injury induced by lower limb I/R are mediated by HO-1. Copyright © 2011 Elsevier Inc. All rights reserved.

Shifting paradigms in the treatment of lower extremity vascular disease: a report of 1000 percutaneous interventions.

PubMed

DeRubertis, Brian G; Faries, Peter L; McKinsey, James F; Chaer, Rabih A; Pierce, Matthew; Karwowski, John; Weinberg, Alan; Nowygrod, Roman; Morrissey, Nicholas J; Bush, Harry L; Kent, K Craig

2007-09-01

Catheter-based revascularization has emerged as an alternative to surgical bypass for lower extremity vascular disease and is a frequently used tool in the armamentarium of the vascular surgeon. In this study we report contemporary outcomes of 1000 percutaneous infra-inguinal interventions performed by a single vascular surgery division. We evaluated a prospectively maintained database of 1000 consecutive percutaneous infra-inguinal interventions between 2001 and 2006 performed for claudication (46.3%) or limb-threatening ischemia (52.7%; rest pain in 27.7% and tissue loss in 72.3%). Treatments included angioplasty with or without stenting, laser angioplasty, and atherectomy of the femoral, popliteal, and tibial vessels. Mean age was 71.4 years and 57.3% were male; comorbidities included hypertension (84%), coronary artery disease (51%), diabetes (58%), tobacco use (52%), and chronic renal insufficiency (39%). Overall 30-day mortality was 0.5%. Two-year primary and secondary patencies and rate of amputation were 62.4%, 79.3%, and 0.5%, respectively, for patients with claudication. Two-year primary and secondary patencies and limb salvage rates were 37.4%, 55.4%, and 79.3% for patients with limb-threatening ischemia. By multivariable Cox PH modeling, limb-threat as procedural indication (P < 0.0001), diabetes (P = 0.003), hypercholesterolemia (P = 0.001), coronary artery disease (P = 0.047), and Transatlantic Inter-Society Consensus D lesion complexity (P = 0.050) were independent predictors of recurrent disease. For patients that developed recurrent disease, 7.5% required no further intervention, 60.3% underwent successful percutaneous reintervention, 11.7% underwent bypass and 20.5% underwent amputation. Patency rates were identical for the initial procedure and subsequent reinterventions (P = 0.97). Percutaneous therapy for peripheral vascular disease is associated with minimal mortality and can achieve 2-year secondary patency rates of nearly 80% in patients with claudication. Although patency is diminished in patients with limb-threat, limb-salvage rates remain reasonable at close to 80% at 2 years. Percutaneous infra-inguinal revascularization carries a low risk of morbidity and mortality, and should be considered first-line therapy in patients with chronic lower extremity ischemia.

Limb myokymia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Albers, J.W.; Allen, A.A.; Bastron, J.A.

Thirty-eight patients with myokymic discharges localized to limb muscles on needle electromyography had various neurologic lesions, both acute and chronic. Of the 38 patients, 27 had had previous radiation therapy and the clinical diagnosis of radiation-induced plexopathy, myelopathy, or both. For the remaining 11 patients, the diagnoses included multiple sclerosis, inflammatory polyradiculoneuropathy, ischemic neuropathy, inflammatory myopathy, and chronic disorders of the spinal cord and peripheral nerves. The clinical presentations and results of local ischemia, peripheral nerve block, and percutaneous stimulation suggest that most limb myokymic discharges arise focally at the site of a chronic peripheral nerve lesion.

Myocardial and Peripheral Ischemia Causes an Increase in Circulating Pregnancy-Associated Plasma Protein-A in Non-atherosclerotic, Non-heparinized Pigs.

PubMed

Steffensen, Lasse Bach; Poulsen, Christian Bo; Shim, Jeong; Bek, Marie; Jacobsen, Kevin; Conover, Cheryl A; Bentzon, Jacob Fog; Oxvig, Claus

2015-12-01

The usefulness of circulating pregnancy-associated plasma protein-A (PAPP-A) as a biomarker for acute coronary syndrome (ACS) is widely debated. We used the pig as a model to assess PAPP-A dynamics in the setting of myocardial ischemia. Induction of myocardial ischemia by ligation of the left anterior descending (LAD) coronary artery caused a systemic rise in PAPP-A. However, the ischemic myocardium was excluded as the source of PAPP-A. Interestingly, induction of ischemia in peripheral tissues by ligation of the left femoral artery caused a systemic rise in PAPP-A originating from the left hind limb. This is the first study to demonstrate PAPP-A elevations in the absence of atherosclerosis or heparin during myocardial ischemia. Our findings thus add to the current discussion of the usefulness of PAPP-A as a biomarker for ACS.

Revascularization of ischemic limbs after transplantation of human bone marrow cells with high aldehyde dehydrogenase activity

PubMed Central

Capoccia, Benjamin J.; Robson, Debra L.; Levac, Krysta D.; Maxwell, Dustin J.; Hohm, Sarah A.; Neelamkavil, Marian J.; Bell, Gillian I.; Xenocostas, Anargyros; Link, Daniel C.; Piwnica-Worms, David; Nolta, Jan A.

2009-01-01

The development of cell therapies to treat peripheral vascular disease has proven difficult because of the contribution of multiple cell types that coordinate revascularization. We characterized the vascular regenerative potential of transplanted human bone marrow (BM) cells purified by high aldehyde dehydrogenase (ALDHhi) activity, a progenitor cell function conserved between several lineages. BM ALDHhi cells were enriched for myelo-erythroid progenitors that produced multipotent hematopoietic reconstitution after transplantation and contained nonhematopoietic precursors that established colonies in mesenchymal-stromal and endothelial culture conditions. The regenerative capacity of human ALDHhi cells was assessed by intravenous transplantation into immune-deficient mice with limb ischemia induced by femoral artery ligation/transection. Compared with recipients injected with unpurified nucleated cells containing the equivalent of 2- to 4-fold more ALDHhi cells, mice transplanted with purified ALDHhi cells showed augmented recovery of perfusion and increased blood vessel density in ischemic limbs. ALDHhi cells transiently recruited to ischemic regions but did not significantly integrate into ischemic tissue, suggesting that transient ALDHhi cell engraftment stimulated endogenous revascularization. Thus, human BM ALDHhi cells represent a progenitor-enriched population of several cell lineages that improves perfusion in ischemic limbs after transplantation. These clinically relevant cells may prove useful in the treatment of critical ischemia in humans. PMID:19324906

Endogenous developmental endothelial locus-1 limits ischemia-related angiogenesis by blocking inflammation

PubMed Central

Klotzsche - von Ameln, Anne; Cremer, Sebastian; Hoffmann, Jedrzej; Schuster, Peggy; Khedr, Sherif; Korovina, Irina; Troulinaki, Maria; Neuwirth, Ales; Sprott, David; Chatzigeorgiou, Antonios; Economopoulou, Matina; Orlandi, Alessia; Hain, Andreas; Zeiher, Andreas M.; Deussen, Andreas; Hajishengallis, George; Dimmeler, Stefanie; Chavakis, Triantafyllos; Chavakis, Emmanouil

2017-01-01

We have recently identified endothelial cell-secreted developmental endothelial locus-1 (Del-1) as an endogenous inhibitor of β2-integrin–dependent leukocyte infiltration. Del-1 was previously also implicated in angiogenesis. Here, we addressed the role of endogenously produced Del-1 in ischemia-related angiogenesis. Intriguingly, Del-1–deficient mice displayed increased neovascularization in two independent ischemic models (retinopathy of prematurity and hind-limb ischemia), as compared to Del-1–proficient mice. On the contrary, angiogenic sprouting in vitro or ex vivo (aortic ring assay) and physiological developmental retina angiogenesis were not affected by Del-1 deficiency. Mechanistically, the enhanced ischemic neovascularization in Del-1-deficiency was linked to higher infiltration of the ischemic tissue by CD45+ hematopoietic and immune cells. Moreover, Del-1-deficiency promoted β2-integrin–dependent adhesion of hematopoietic cells to endothelial cells in vitro, and the homing of hematopoietic progenitor cells and of immune cell populations to ischemic muscles in vivo. Consistently, the increased hind limb ischemia-related angiogenesis in Del-1 deficiency was completely reversed in mice lacking both Del-1 and the β2-integrin LFA-1. Additionally, enhanced retinopathy-associated neovascularization in Del-deficient mice was reversed by LFA-1 blockade. Our data reveal a hitherto unrecognized function of endogenous Del-1 as a local inhibitor of ischemia-induced angiogenesis by restraining LFA-1–dependent homing of pro-angiogenic hematopoietic cells to ischemic tissues. Our findings are relevant for the optimization of therapeutic approaches in the context of ischemic diseases. PMID:28447099

Infiltration of plasma rich in growth factors enhances in vivo angiogenesis and improves reperfusion and tissue remodeling after severe hind limb ischemia.

PubMed

Anitua, Eduardo; Pelacho, Beatriz; Prado, Roberto; Aguirre, José Javier; Sánchez, Mikel; Padilla, Sabino; Aranguren, Xabier L; Abizanda, Gloria; Collantes, María; Hernandez, Milagros; Perez-Ruiz, Ana; Peñuelas, Ivan; Orive, Gorka; Prosper, Felipe

2015-03-28

PRGF is a platelet concentrate within a plasma suspension that forms an in situ-generated fibrin-matrix delivery system, releasing multiple growth factors and other bioactive molecules that play key roles in tissue regeneration. This study was aimed at exploring the angiogenic and myogenic effects of PRGF on in vitro endothelial cells (HUVEC) and skeletal myoblasts (hSkMb) as well as on in vivo mouse subcutaneously implanted matrigel and on limb muscles after a severe ischemia. Human PRGF was prepared and characterized. Both proliferative and anti-apoptotic responses to PRGF were assessed in vitro in HUVEC and hSkMb. In vivo murine matrigel plug assay was conducted to determine the angiogenic capacity of PRGF, whereas in vivo ischemic hind limb model was carried out to demonstrate PRGF-driven vascular and myogenic regeneration. Primary HUVEC and hSkMb incubated with PRGF showed a dose dependent proliferative and anti-apoptotic effect and the PRGF matrigel plugs triggered an early and significant sustained angiogenesis compared with the control group. Moreover, mice treated with PRGF intramuscular infiltrations displayed a substantial reperfusion enhancement at day 28 associated with a fibrotic tissue reduction. These findings suggest that PRGF-induced angiogenesis is functionally effective at expanding the perfusion capacity of the new vasculature and attenuating the endogenous tissue fibrosis after a severe-induced skeletal muscle ischemia. Copyright © 2015 Elsevier B.V. All rights reserved.

Distal vein patch as a form of autologus modification for infragenicular prosthetic bypass.

PubMed

Totic, Dragan; Rustempasic, Nedzad; Djedovic, Muhamed; Solakovic, Sid; Vukas, Haris; Aslani, Ilijas; Krvavac, Alma; Rudalija, Dzejra; Ahmetasevic, Alen

2013-01-01

Preferred graft for infragenicular bypass is autologus vein. The problem is when there is not available autologus vein. Literature suggest that in these situations, prosthetic graft with some form of modification of distal anastomosis with autogenic tissue is valuable adjunctive. Frequently used modifications are Miller's cuff, Taylor's patch and St. Mary's boot. Recently, there are reports on "Distal vein patch" as a form of autologus modification which, due to its simplicity and patency rate, attracted attention. The aim of this study was to evaluate benefits of this novel modification by comparing its patencies with other autologus modification of distal anastomosis. Study was performed on 60 patients, diabetics, with critical limb ischemia (CLI). Patients were divided in two groups: Group with distal vein patch modification; and group with some other form modification - control group. Patients were followed at least 22 months. We examined patency of grafts by physical examination or using Color Doppler. For statistical purposes we used KIaplan Meier analysis and curve. Significance was determined by Mann-Whitney, Fisher's exact, Pearsons chi square or Student T test as appropriate. P value less than 0,05 was considered significant. Groups were fairly matched relative to demographics, risk factors, operative intervention and distal anastomosis site. There was not statistical difference in two year primary patency between distal vein patch and control group--50% vs 53% respectivly (X2 = 0,08; p = 0,773). Also, there was not statistically significant difference in extremity survival (77% vs 77%) and patient survival between groups (89% vs 93%; X2 = 2,458; p = 0,117). This study proved equivalent patencies of infragenicular prosthetic bypasses performed using distal vein patch technique as with any other modification of distal anastomosis.

Long term effects of below-the-knee angioplasty in diabetic patients with critical ischemia of lower limbs referred to Sina Hospital during 2010-2011.

PubMed

Zafarghandi, Mohammad-Reza; Nazari, Iraj; Taghavi, Morteza; Rashidi, Abbas; Dardashti, Sanaz Karimi; Sadid, Donya; Esmaili, Leyli; Mahmoodi, Seyed Mostafa; Mousavi, Masood

2015-03-01

Despite significant advances in the treatment of diabetic foot ulcers and below-the-knee critical ischemia, there are ongoing efforts to achieve a method with low complication, high success rate and persistence of long-term effects. The aim of the study was to examine the outcome of angioplasty in patients with below-the-knee critical ischemia referred to Hospital. This semi-experimental study conducted on diabetics patients treated with PTA (Percutaneous transluminal angioplasty) with critical ischemia of lower limbs referred to Sina Hospital. After discharge, the patients were followed weekly for the first month and then monthly up to 12 months. The procedure short-term effects were examined through evaluation of wound healing as well as patients' recovery and pain relief, after one month. Given the distribution type, parametric and non-parametric test were used to compare the results before and after treatment. Pearson's correlation coefficient was used to determine the correlation between variables. Twenty four patients participated in this study. The mean ankle-brachial index (ABI) at baseline was 0.55 ± 0.17. A month after angioplasty, the index increased statistically significant to 0.93 ± 0.16. The mean health score expressed by the patients at baseline was 5.48 ± 1.39. A month after angioplasty, it was significantly increased (6.32 ± 1.24). The mean pain score before enrollment was 6.68 ± 2.52 (according to VAS scale). There was a significant decrease over time (3.45 ± 1.13). The overall mean score of all patients at Rutherford Classification was 3.88 ± 0.63 at baseline. During the 1st month and 6th month follow-up, it was changed to Class 0 that was statistically significant in the first month. This study represents the mid-term outcomes of PTA. Although PTA treatment was associated with improved pain scores, satisfaction with health, classification of limb ischemia and diabetic foot ulcers, the effects only remain short-term and mid-term. However, long-term efficacy of PTA needs to be investigated further.

Assessment of Minimum Important Difference and Substantial Clinical Benefit with the Vascular Quality of Life Questionnaire-6 when Evaluating Revascularisation Procedures in Peripheral Arterial Disease.

PubMed

Nordanstig, J; Pettersson, M; Morgan, M; Falkenberg, M; Kumlien, C

2017-09-01

Patient reported outcomes are increasingly used to assess outcomes after peripheral arterial disease (PAD) interventions. VascuQoL-6 (VQ-6) is a PAD specific health-related quality of life (HRQoL) instrument for routine clinical practice and clinical research. This study assessed the minimum important difference for the VQ-6 and determined thresholds for the minimum important difference and substantial clinical benefit following PAD revascularisation. This was a population-based observational cohort study. VQ-6 data from the Swedvasc Registry (January 2014 to September 2016) was analysed for revascularised PAD patients. The minimum important difference was determined using a combination of a distribution based and an anchor-based method, while receiver operating characteristic curve analysis (ROC) was used to determine optimal thresholds for a substantial clinical benefit following revascularisation. A total of 3194 revascularised PAD patients with complete VQ-6 baseline recordings (intermittent claudication (IC) n = 1622 and critical limb ischaemia (CLI) n = 1572) were studied, of which 2996 had complete VQ-6 recordings 30 days and 1092 a year after the vascular intervention. The minimum important difference 1 year after revascularisation for IC patients ranged from 1.7 to 2.2 scale steps, depending on the method of analysis. Among CLI patients, the minimum important difference after 1 year was 1.9 scale steps. ROC analyses demonstrated that the VQ-6 discriminative properties for a substantial clinical benefit was excellent for IC patients (area under curve (AUC) 0.87, sensitivity 0.81, specificity 0.76) and acceptable in CLI (AUC 0.736, sensitivity 0.63, specificity 0.72). An optimal VQ-6 threshold for a substantial clinical benefit was determined at 3.5 scale steps among IC patients and 4.5 in CLI patients. The suggested thresholds for minimum important difference and substantial clinical benefit could be used when evaluating VQ-6 outcomes following different interventions in PAD and in the design of clinical trials. Copyright © 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Daily tympanometry for high-resolution measurement of the time between onset of cold-like illness and middle ear effusion.

PubMed

Doyle, William J; Winther, Birgit; Alper, Cuneyt M

2008-06-01

Tympanometry is a simple method to assess middle ear pressure (MEP) and the presence of middle ear effusion (MEE), a marker of otitis media (OM). To determine whether daily parental tympanometry and illness sign recording in their children can be used to define the time between onsets of cold-like illness (CLI) and MEE at high resolution. Prospective, longitudinal, 7 month, daily follow-up on 169 children aged 1 through 8.6 years. Tympanograms and illness were recorded daily by a parent. Tympanograms were examined, rejected if artifactual, and MEP data were entered into a database, with "flat tympanograms" coded as -400 mm H2O = MEE. The incidence and burden of CLIs (>2 days) were calculated, and for each CLI, the presence/absence of concurrent MEE (>2 days) was determined. For each child, the average MEP for CLI and nonCLI days was calculated. Paired CLI and tympanometric results were aligned and the days between event onsets determined. Stepwise regression was used to assign risk predictors for the measured outcomes. A total of 566 CLIs were recorded, and the average CLI burden/child was 16%. Age was a significant predictor of CLI incidence/child, and age, history of colds, and daily environment were predictors of CLI-burden/child. Of the 433 evaluable CLI episodes, MEE was a complication in 37%, and MEE with a CLI was predicted by age, OM history, and environment. MEP was significantly more negative during CLI episodes, and the magnitude was predicted by age, race, and OM history. The average difference in MEE-CLI onsets was 1.2 +/- 4.0 days; approximately 32% of MEEs occurred prior to CLI onset and 17% on the same day as CLI onset. CLIs adversely affect the middle ear-ambient pressure balance and are frequently associated with MEE episodes. The distribution in onsets between those events suggests that chemoprophylaxis of a child with a newly identified CLI to prevent MEE would have a low expected efficiency.

[Neurolitic block of the lumbar sympathetic chain improves chronic pain in a patient with critical lower limb ischemia].

PubMed

Barreto Junior, Elton Pereira de Sá; Nascimento, Jedson Dos Santos; de Castro, Anita Perpetua Carvalho Rocha

Sympathectomy is one of the therapies used in the treatment of chronic obstructive arterial disease (COAD). Although not considered as first-line strategy, it should be considered in the management of pain difficult to control. This clinical case describes the evolution of a patient with inoperable COAD who responded properly to the lumbar sympathetic block. A female patient, afro-descendant, 69 years old, ASA II, admitted to the algology service due to refractory ischemic pain in the lower limbs. The patient had undergone several surgical procedures and conservative treatments without success. Vascular surgery considered the case as out of therapeutic possibility, unless limb amputation. At that time, sympathectomy was indicated. After admission to the operating room, the patient was monitored, positioned and sedated. The blockade was performed with the aid of radioscopy, bilaterally, at L2-L3-L4 right and L3 left levels. On the right side, at each level cited, 3mL of absolute alcohol with 0.25% bupivacaine were injected without vasoconstrictor, and on the left side only local anesthetic. The procedure was performed uneventfully. The patient was discharged with complete remission of the pain. Neurolitic block of the lumbar sympathetic chain is an effective and safe treatment option for pain control in patients with critical limb ischemia patients in whom the only possible intervention would be limb amputation. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

Reticulon 4B (Nogo-B) is necessary for macrophage infiltration and tissue repair.

PubMed

Yu, Jun; Fernández-Hernando, Carlos; Suarez, Yajaira; Schleicher, Michael; Hao, Zhengrong; Wright, Paulette L; DiLorenzo, Annarita; Kyriakides, Themis R; Sessa, William C

2009-10-13

Blood vessel formation during ischemia and wound healing requires coordination of the inflammatory response with genes that regulate blood vessel assembly. Here we show that the reticulon family member 4B, aka Nogo-B, is upregulated in response to ischemia and is necessary for blood flow recovery secondary to ischemia and wound healing. Mice lacking Nogo-B exhibit reduced arteriogenesis and angiogenesis that are linked to a decrease in macrophage infiltration and inflammatory gene expression in vivo. Bone marrow-derived macrophages isolated from Nogo knock-out mice have reduced spreading and chemotaxis due to impaired Rac activation. Bone marrow reconstitution experiments show that Nogo in myeloid cells is necessary to promote macrophage homing and functional recovery after limb ischemia. Thus, endogenous Nogo coordinates macrophage-mediated inflammation with arteriogenesis, wound healing, and blood flow control.

Bilateral persistent sciatic arteries complicated with chronic lower limb ischemia

PubMed Central

Wang, Bin; Liu, Zhenjie; Shen, Laigen

2011-01-01

INTRODUCTION Persistent sciatic artery (PSA) is a rare vascular anomaly associated with a higher rate of aneurysm formation or thromboembolic complications causing lower extremity ischemia. PRESENTATION Of Case A 15-year-old female patient with bilateral PSA presented with lower extremity ischemia. Considering the age and symptoms of the patient, we did not perform any intervention, but continued surveillance with duplex ultrasonography in case of the high incidence of aneurysmal formation or thromboembolic event. DISCUSSION Epidemiology, development, anatomical structure, diagnosis and treatments of PSAs are discussed. CONCLUSION PSAs, are prone to early atheromatous degeneration and aneurysm formation. Treatment of a PSA mainly dependent on the symptoms is either by surgical procedures or by endovascular interventions. PMID:22096762

Clindamycin Affects Group A Streptococcus Virulence Factors and Improves Clinical Outcome.

PubMed

Andreoni, Federica; Zürcher, Claudia; Tarnutzer, Andrea; Schilcher, Katrin; Neff, Andrina; Keller, Nadia; Marques Maggio, Ewerton; Poyart, Claire; Schuepbach, Reto A; Zinkernagel, Annelies S

2017-01-15

Group A Streptococcus (GAS) has acquired an arsenal of virulence factors, promoting life-threatening invasive infections such as necrotizing fasciitis. Current therapeutic regimens for necrotizing fasciitis include surgical debridement and treatment with cell wall-active antibiotics. Addition of clindamycin (CLI) is recommended, although clinical evidence is lacking. Reflecting the current clinical dilemma, an observational study showed that only 63% of the patients with severe invasive GAS infection received CLI. This work thus aimed to address whether CLI improves necrotizing fasciitis outcome by modulating virulence factors of CLI-susceptible and CLI-resistant GAS in vitro and in vivo. Treatment with CLI reduced extracellular DNase Sda1 and streptolysin O (SLO) activity in vivo, whereas subinhibitory CLI concentrations induced expression and activity of SLO, DNase, and Streptococcus pyogenes cell envelope protease in vitro. Our in vivo results suggest that CLI should be administered as soon as possible to patients with necrotizing fasciitis, while our in vitro studies emphasize that a high dosage of CLI is essential. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Case Series of HIV Infection-Associated Arteriopathy: Diagnosis, Management, and Outcome Over a 5-Year period at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University.

PubMed

Orrapin, Saritphat; Reanpang, Termpong; Orrapin, Saranat; Arwon, Supapong; Kattipathanapong, Thanate; Lekwanavijit, Suree; Rerkasem, Kittipan

2015-09-01

Patients infected with human immunodeficiency virus (HIV) can present with 4 pathology types: drug-induced vasospasm (ergotism), arterial limb ischemia, critical limb ischemia, and aneurysm. Although these problems are common vascular problems, they result in increased morbidity and mortality in HIV-infected patients, especially aneurysm. Patients with these problems tend to be diagnosed with difficulty because of atypical symptoms and signs. Because of lack of data in treatment outcome literature, our report explores and provides information on HIV infection-related arteriopathy. There were 17 patients in our 5-year review. There was no death in patients except the aneurysm type. The survival of aneurysm patients was significantly lower than from other pathologies (P = .003). Our case series showed good short-term outcome, and patients were not at risk for less beneficial surgical procedures. © The Author(s) 2015.

[The modern principles of management of intermittent claudication].

PubMed

Gamzatov, T H; Svetlikov, A V

2016-01-01

Number of patients with peripheral arterial disease, despite various national public health programs, remains high and has no steady downward trend over the past few decades. Despite recent advances in drug therapy, сonservative approach in the management of peripheral arterial disease is often neglected by vascular surgeons. However, vast majority of patients with intermittent claudication, who receive comprehensive conservative treatment, including risk factor modification, exercise and drug therapy, may get significant improvement in quality of life by partial or complete relief of symptoms related to the disease. Patients strictly adhering to medical recommendations has favorable prognosis and progression of disease to the stage of critical limb ischemia is very unlikely. Noncompliant patients and those who continue smoking in particular, often experience progression of symptoms related to the disease. That may result in the need for surgical intervention aiming to prevent or delay the onset of critical limb ischemia.

Monitoring somatosensory evoked potentials in spinal cord ischemia-reperfusion injury

PubMed Central

Ji, Yiming; Meng, Bin; Yuan, Chenxi; Yang, Huilin; Zou, Jun

2013-01-01

It remains unclear whether spinal cord ischemia-reperfusion injury caused by ischemia and other non-mechanical factors can be monitored by somatosensory evoked potentials. Therefore, we monitored spinal cord ischemia-reperfusion injury in rabbits using somatosensory evoked potential detection technology. The results showed that the somatosensory evoked potential latency was significantly prolonged and the amplitude significantly reduced until it disappeared during the period of spinal cord ischemia. After reperfusion for 30–180 minutes, the amplitude and latency began to gradually recover; at 360 minutes of reperfusion, the latency showed no significant difference compared with the pre-ischemic value, while the somatosensory evoked potential amplitude in-creased, and severe hindlimb motor dysfunctions were detected. Experimental findings suggest that changes in somatosensory evoked potential latency can reflect the degree of spinal cord ischemic injury, while the amplitude variations are indicators of the late spinal cord reperfusion injury, which provide evidence for the assessment of limb motor function and avoid iatrogenic spinal cord injury. PMID:25206629

Limb remote ischemic post-conditioning mitigates brain recovery in a mouse model of ischemic stroke by regulating reactive astrocytic plasticity.

PubMed

Cheng, Xue; Zhao, Haiping; Yan, Feng; Tao, Zhen; Wang, Rongliang; Han, Ziping; Li, Guangwen; Luo, Yumin; Ji, Xunming

2018-05-01

Maladaptive alterations of astrocytic plasticity may cause brain edema in the acute stage of stroke and glial scar formation in the recovery stage. The present study was designed to investigate the potential regulation of limb remote ischemic post-conditioning (RIPC) on astrocytic plasticity in experimental cerebral ischemia-reperfusion injury. Cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h in C57BL/6 mice, who were treated with RIPC immediately after reperfusion. The results showed that RIPC decreased hemispheric swelling, infarct volume and brain atrophy, and increased neurological function recovery and survival rates of ischemic mice at 3 and 14 d after cerebral ischemia-reperfusion, respectively. Moreover, the proportion of astrocyte subtypes was adjusted by RIPC treatment, demonstrated by decreased expression of the fibrous type (glial fibrillary acidic protein, GFAP) and increased expression of the protoplasmic type (glutamine synthetase, GS) in the ipsilateral side of the mouse brain at 14 d after cerebral ischemia-reperfusion. RIPC treatment adjusted the proportion of GFAP subtypes by downregulating the protein level of GFAPα, as well as upregulating the GFAPδ/GFAPα ratio in the ipsilateral side at 3 and 14 d after reperfusion. Notably, RIPC inhibited the phosphorylation of signal transducer and activators of transcriptions 3 (p-STAT3) in the ipsilateral side at 3 and 14 d after cerebral ischemia-reperfusion. Taken together, the results show that RIPC treatment could regulate reactive astrocytic plasticity and inhibition of STAT3 phosphorylation to promote neurological function recovery following ischemic stroke. Copyright © 2018 Elsevier B.V. All rights reserved.

Changes in muscle tissue oxygenation during stagnant ischemia in septic patients.

PubMed

Pareznik, Roman; Knezevic, Rajko; Voga, Gorazd; Podbregar, Matej

2006-01-01

To determine changes in the rate of thenar muscles tissue deoxygenation during stagnant ischemia in patients with severe sepsis and septic shock. Prospective observational study in the medical ICU of a general hospital. Consecutive patients admitted to ICU with septic shock (n=6), severe sepsis (n=6), localized infection (n=3), and healthy volunteers (n=15). Upper limb ischemia was induced by rapid automatic pneumatic cuff inflation around upper arm. Thenar muscle tissue oxygen saturation (StO2) was measured continuously by near-infrared spectroscopy before and during upper limb ischemia. StO(2) before intervention was comparable in patients with septic shock, severe sepsis, or localized infection and healthy volunteers (89 [65, 92]% vs. 82 [72, 91]% vs. 87 [85, 92]% vs. 83 [79, 93]%, respectively; p>0.1). The rate of StO(2) decrease during stagnant ischemia after initial hemodynamic stabilization was slower in septic shock patients than in those with severe sepsis or localized infection and in controls (-7.0 [-3.6, -11.0] %/min vs. -10.4 [-7.8, -13.3] %/min vs. -19.5 [-12.3, -23.3] vs. -37.4 [-27.3, -56.2] %/min, respectively; p=0.041). At ICU discharge the rate of StO2 decrease did not differ between the septic shock, severe sepsis, and localized infection groups (-17.0 [-9.3, -28.9] %/min vs. -19.9 [-13.3, -23.6] %/min vs. -23.1 [-20.7, -26.2] %/min, respectively), but remained slower than in controls (p<0.01). The rate of StO2 decrease was correlated with Sequential Organ Failure Assessment (SOFA) score (r=0.739, p<0.001). After hemodynamic stabilization thenar muscle tissue oxygen saturation during stagnant ischemia decreases slower in septic shock patients than in patients with severe sepsis or localized infection and in healthy volunteers. During ICU stay and improvement of sepsis the muscle tissue deoxygenation rate increases in survivors of both septic shock and severe sepsis and was correlated with SOFA score.

Comparison of LDPI to SPECT perfusion imaging using (99m)Tc-sestamibi and (99m)Tc-pyrophosphate in a murine ischemic hind limb model of neovascularization.

PubMed

Hendrikx, Geert; Vries, Mark H; Bauwens, Matthias; De Saint-Hubert, Marijke; Wagenaar, Allard; Guillaume, Joël; Boonen, Levinia; Post, Mark J; Mottaghy, Felix M

2016-12-01

We aimed to determine the accuracy of laser Doppler perfusion imaging (LDPI) in an animal model for hind limb ischemia. We used a murine (C57Bl/6 mice) ischemic hind limb model in which we compared LDPI with the clinically used (99m)Tc-sestamibi SPECT perfusion imaging (n = 7). In addition, we used the SPECT tracer (99m)Tc-pyrophosphate ((99m)Tc-PyP) to image muscular damage (n = 6). LDPI indicated a quick and prominent decrease in perfusion immediately after ligation, subsequently recovering to 21.9 and 25.2 % 14 days later in the (99m)Tc-sestamibi and (99m)Tc-PyP group, respectively. (99m)Tc-sestamibi SPECT scans also showed a quick decrease in perfusion. However, nearly full recovery was reached 7 days post ligation. Muscular damage, indicated by the uptake of (99m)Tc-PyP, was highest at day 3 and recovered to baseline levels at day 14 post ligation. Postmortem histology supported these findings, as a significantly increased collateral diameter was found 7 and 14 days after ligation and peak macrophage infiltration and TUNEL positivity was found on day 3 after ligation. Here, we indicate that LDPI strongly underestimates perfusion recovery in a hind limb model for profound ischemia.

Resurrection of the in situ saphenous vein bypass. 1000 cases later.

PubMed Central

Leather, R P; Shah, D M; Chang, B B; Kaufman, J L

1988-01-01

Distal bypasses for the terminal stages of atherosclerotic occlusive disease manifest by chronic limb-threatening ischemia are among the most challenging arterial reconstructive procedures of surgeons today. The length and low flow rates of distal bypasses often exceed the functional limits of synthetic and even free vein grafts. However, the saphenous vein, when used in situ, provides a unique, viable, physiologically active, and hence antithrombogenic endothelial flow surface that is ideally suited for such bypasses. This paper presents the experience of the Albany Medical Center Hospital with the first 1000 in situ bypasses performed by the valve incision method over a 12-year period. Limb-threatening ischemia was the most common indication for surgery (91%). An in situ bypass was attempted in over 95% of unselected limbs and were completed in situ and in toto in 94%. 66% of the bypasses were carried out to the infrapopliteal level, and in more than 50% of the limbs, the distal vein diameter was less than 3.5 mm. The 30-day patency rate was 95%, and the cumulative patency rates, by life table analysis at 1, 2, 3, 4, and 5 years, were 90%, 86%, 84%, 80%, and 76%, respectively. The vein diameter, specific outflow vessel, level of distal anastomosis (length of bypass), inguinal inflow source used, and instrumental evolution had no significant effect on immediate or long-term bypass performance. PMID:3178331

Remote limb ischemic preconditioning (rIPC) activates antioxidant and antiapoptotic genes and inhibits proinflammatory cytokine genes in renal ischemia/reperfusion injury.

PubMed

Hussein, Abdelaziz M; Harraz, Ahmed M; Awadalla, Amira; Barakat, Nashwa; Khater, Shery; Shokeir, Ahmed A

2016-01-01

The mechanisms underlying the renoprotective effect for remote limb ischemic preconditioning (rIPC) against renal ischemia/reperfusion injury need further elucidation. In our work, one hundred and twenty male Sprague Dawley rats were randomized into 3 groups; sham, I/R group (left renal 45 min ischemia) and rIPC (as I/R group with 3 cycles of left femoral ischemic PC just before renal ischemia). Rats were sacrificed at 2 h, 24 h, 48 h and 7 days. Serum creatinine and urea were measured at the baseline and endpoints. Also, histopathological examination and assessment of the expression of inflammatory cytokines e.g. TNF-α, IL-1β and ICAM-1 and antioxidant genes: Nrf2, HO-1 and NQO-1 and anti-apoptotic gene Bcl-2 in left kidney were done by the end of experiment. The results of this study demonstrated that, rIPC caused significant improvement in serum creatinine and BUN levels and in the expression of antioxidant genes and Bcl-2 antiapoptotic gene with significant attenuation of pro-inflammatory cytokines and histopathological damage score at all-time points compared to I/R group (p ≤ 0.05). In conclusion, inhibition of inflammatory cytokine (TNF-α, IL-1β and ICAM-1) formation and activation of antioxidant genes: Nrf2, HO-1 and NQO-1 and anti-apoptotic gene Bcl-2 could be possible underlying mechanisms for the renoprotective effect of rIPC.

Impact of type 2 diabetes mellitus on in-hospital-mortality after major cardiovascular events in Spain (2002-2014).

PubMed

de Miguel-Yanes, José M; Jiménez-García, Rodrigo; Hernández-Barrera, Valentín; Méndez-Bailón, Manuel; de Miguel-Díez, Javier; Lopez-de-Andrés, Ana

2017-10-10

Diabetes mellitus has long been associated with cardiovascular events. Nevertheless, the higher burden of traditional cardiovascular risk factors reported in high-income countries is offset by a more widespread use of preventive measures and revascularization or other invasive procedures. The aim of this investigation is to describe trends in number of cases and outcomes, in-hospital mortality (IHM) and length of hospital stay (LHS), of hospital admissions for major cardiovascular events between type 2 diabetes (T2DM) and matched non-diabetes patients. Retrospective study using National Hospital Discharge Database, analyzed in 4 years 2002, 2006, 2010, 2014, in Spain. We included patients (≥ 40 years old) with a primary diagnosis of myocardial infarction, ischemic and hemorrhagic stroke, aortic aneurysm and dissection and acute lower limb ischemia in people with T2DM. Cases were matched with controls (without T2DM) by ICD-9-CM codes, sex, age, province of residence and year. We selected 130,011 matched couples (50,427 with myocardial infarction, 60,236 with stroke, 2599 with aortic aneurysm and dissection and 16,749 with acute lower limb ischemia. Among T2DM patients we found increasing numbers of admissions overtime for stroke (10,794 in 2002 vs 17,559 in 2014), aortic aneurysm and dissection (390 vs 841) and acute lower limb ischemia (3854 vs. 4548). People were progressively older (except for myocardial infarction), had more comorbidities (especially T2DM patients), and were more frequently coded overtime for cardiovascular risk factors (smoking, obesity, hypertension, lipid disorders) and renal diseases. LHS and IHM declined overtime, though IHM only did it significantly in T2DM patients. Multivariable adjustment showed that T2DM patients had a significantly 15% higher mortality rate during admission for myocardial infarction, a 6% higher mortality for stroke, and a 6% higher mortality rate for "all cardiovascular events combined", than non-diabetic matched controls. The number of hospital admissions for stroke, aortic aneurysm and dissection and acute lower limb ischemia increased overtime, but remained stable for myocardial infarction. T2DM is associated to higher IHM after major cardiovascular events. Further research is needed to help us understand the reasons for an apparently increased mortality in T2DM patients when admitted to hospital for some major cardiovascular events.

Inhibition of Aldehyde Dehydrogenase-Activity Expands Multipotent Myeloid Progenitor Cells with Vascular Regenerative Function.

PubMed

Cooper, Tyler T; Sherman, Stephen E; Kuljanin, Miljan; Bell, Gillian I; Lajoie, Gilles A; Hess, David A

2018-05-01

Blood-derived progenitor cell transplantation holds potential for the treatment of severe vascular diseases. Human umbilical cord blood (UCB)-derived hematopoietic progenitor cells purified using high aldehyde dehydrogenase (ALDH hi ) activity demonstrate pro-angiogenic functions following intramuscular (i.m.) transplantation into immunodeficient mice with hind-limb ischemia. Unfortunately, UCB ALDH hi cells are rare and prolonged ex vivo expansion leads to loss of high ALDH-activity and diminished vascular regenerative function. ALDH-activity generates retinoic acid, a potent driver of hematopoietic differentiation, creating a paradoxical challenge to expand UCB ALDH hi cells while limiting differentiation and retaining pro-angiogenic functions. We investigated whether inhibition of ALDH-activity during ex vivo expansion of UCB ALDH hi cells would prevent differentiation and expand progeny that retained pro-angiogenic functions after transplantation into non-obese diabetic/severe combined immunodeficient mice with femoral artery ligation-induced unilateral hind-limb ischemia. Human UCB ALDH hi cells were cultured under serum-free conditions for 9 days, with or without the reversible ALDH-inhibitor, diethylaminobenzaldehyde (DEAB). Although total cell numbers were increased >70-fold, the frequency of cells that retained ALDH hi /CD34+ phenotype was significantly diminished under basal conditions. In contrast, DEAB-inhibition increased total ALDH hi /CD34+ cell number by ≥10-fold, reduced differentiation marker (CD38) expression, and enhanced the retention of multipotent colony-forming cells in vitro. Proteomic analysis revealed that DEAB-treated cells upregulated anti-apoptotic protein expression and diminished production of proteins implicated with megakaryocyte differentiation. The i.m. transplantation of DEAB-treated cells into mice with hind-limb ischemia stimulated endothelial cell proliferation and augmented recovery of hind-limb perfusion. DEAB-inhibition of ALDH-activity delayed hematopoietic differentiation and expanded multipotent myeloid cells that accelerated vascular regeneration following i.m. transplantation in vivo. Stem Cells 2018;36:723-736. © AlphaMed Press 2018.

A novel approach to therapeutic angiogenesis for patients with critical limb ischemia by sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel: an initial report of the phase I-IIa study.

PubMed

Marui, Akira; Tabata, Yasuhiko; Kojima, Shinsuke; Yamamoto, Masaya; Tambara, Keiichi; Nishina, Takeshi; Saji, Yoshiaki; Inui, Ken-ichi; Hashida, Tohru; Yokoyama, Sumiko; Onodera, Rie; Ikeda, Tadashi; Fukushima, Masanori; Komeda, Masashi

2007-08-01

Limb ischemia remains a challenge. To overcome shortcomings or limitations of gene therapy or cell transplantation, a sustained release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel has been developed. A phase I-IIa study was performed, in which 7 patients had critical limb ischemia. They were intramuscularly injected with 200 microg of bFGF-incorporated gelatin hydrogel microspheres into the gastrocnemius of the ischemic limb. End-points were safety and feasibility of treatment after 4 and 24 weeks. One patient was excluded from the study for social reasons, but only after symptomatic improvements. In the evaluation of the other 6 patients, significant improvements were observed in the distance walked in 6 min (295+/-42 m vs 491+/-85 m for pretreatment vs after 24 weeks, p=0.023) and in transcutaneous oxygen pressure (53.5+/-5.2 mmHg vs 65.5+/-4.0 mmHg, p=0.03). The rest pain scale also improved (3.5+/-0.2 vs 1.0+/-0.6, p=0.022). The ankle-brachial pressure index improved at 4 weeks but not at 24 weeks. Among 5 patients who had a non-healing foot ulcer, the ulcer was completely healed in 3 patients, reduced in 1, and there was no change in 1 patient at 24 weeks. The blood levels of bFGF were undetected or within the normal level in all patients. The sustained release of bFGF from gelatin hydrogel might be simple, safe, and effective to achieve therapeutic angiogenesis because it did not need genetic materials or collection of implanted cells, and because it did not have any general effects, which was supported by there being no elevation of the bFGF serum level.

Subintimal angioplasty with the aid of a re-entry device for TASC C and D lesions of the SFA.

PubMed

Setacci, C; Chisci, E; de Donato, G; Setacci, F; Iacoponi, F; Galzerano, G

2009-07-01

The aim of this prospective study was to assess the clinical effectiveness and related midterm patency of subintimal angioplasty (SAP) in patients suffering from critical limb ischaemia (CLI) in a single tertiary care university centre. The secondary aim was to evaluate the safety and clinical effectiveness of using a re-entry device when re-canalisation by SAP was unsuccessful. From January 2005 to December 2007, consecutive patients suffering from CLI (Rutherford clinical categories: 4-6) were treated with SAP. All patients included in the study had occluded SFA (TASC C and D) and underwent clinical and ultrasound follow-up examinations at day 30 and at 3, 6, 9 and 12 months, and then yearly. A re-entry device (Outback, Cordis Corporation, Miami Lakes, Florida, USA in all cases) was only used when re-canalisation by simple SAP was unsuccessful, and stenting was used when residual stenosis was >30% or there was a flow-limiting dissection. Factors that could modify the outcome were analysed. In this study, 145 patients were treated, with a technical success rate of 83.5% (121 of 145) for simple SAP. Stenting was performed in 43% (n=62) of successful SAP procedures. No death occurred in the perioperative period, while the 30-day mortality was 4.8% (7 of 145). The re-entry device (Outback) was used in 24 cases (16.5%). The technical success of the re-entry device was 79% (19 of 24), with a 90% success rate of stent placement at the site of re-entry. Complications occurred in 6.2% of all procedures (n=9) (three arterial perforations (2.1%), three distal embolisations (2.1%), two femoral artery pseudo-aneurysms (1.4%) and one arterio-venous fistula (0.7%)). Factors capable of independently affecting the patency were renal insufficiency (p=0.03), current smoking (p=0.01) and diabetes (p=0.04). The primary patency at 1 and 3 years was 70% and 34% and the secondary patency at 1 and 3 years was 77% and 43%, respectively. At the same time intervals, the limb-salvage rate was 88% and 49%. SAP with the aid of a re-entry device for TASC C and D lesions of the SFA seems to be safe and clinically effective in patients suffering from CLI, according to the experience at our centre. Further follow-up and more data are necessary to confirm these findings.

Combined therapy for critical limb ischaemia: Biomimetic PLGA microcarriers potentiates the pro-angiogenic effect of adipose tissue stromal vascular fraction cells.

PubMed

Hoareau, Laurence; Fouchet, Florian; Planesse, Cynthia; Mirbeau, Sophie; Sindji, Laurence; Delay, Emmanuel; Roche, Régis; Montero-Menei, Claudia N; Festy, Franck

2018-06-01

We propose a regenerative solution in the treatment of critical limb ischaemia (CLI). Poly-lactic/glycolic acid microcarriers were prepared and coated with laminin to be sterilized through γ-irradiation of 25 kGy at low temperature. Stromal vascular fraction (SVF) cells were extracted through enzymatic digestion of adipose tissue. Streptozotocin-induced diabetic mice underwent arteriotomy and received an administration of SVF cells combined or not with biomimetic microcarriers. Functional evaluation of the ischaemic limb was then reported, and tissue reperfusion was evaluated through fluorescence molecular tomography. Microcarriers were stable and functional after γ-irradiation until at least 12 months of storage. Mice that received an injection of SVF cells in the ischaemic limb have 22% of supplementary blood supply within this limb 7 days after surgery compared with vehicle, whereas no difference was observed at Day 14. With the combined therapy, the improvement of blood flow is significantly higher compared with vehicle, of about 31% at Day 7 and of about 11% at Day 14. Injection of SVF cells induces a significant 27% decrease of necrosis compared with vehicle. This effect is more important when SVF cells were mixed with biomimetic microcarriers: -37% compared with control. Although SVF cells injection leads to a non-significant 22% proprioception recovery, the combined therapy induces a significant recovery of about 27% compared with vehicle. We show that the combination of SVF cells from adipose tissue with laminin-coated poly-lactic/glycolic acid microcarriers is efficient for critical limb ischaemia therapy in a diabetic mouse model. Copyright © 2018 John Wiley & Sons, Ltd.

Vascular complications following intra-aortic balloon pump implantation: an updated review

PubMed Central

de Jong, Monique M; Lorusso, Roberto; Al Awami, Fatima; Matteuci, Francesco; Parise, Orlando; Lozekoot, Pieter; Bonacchi, Massimo; Maessen, Jos G; Johnson, Daniel M; Gelsomino, Sandro

2017-01-01

Background: The use of the intra-aortic balloon pump (IABP) as a support device remains controversial due to the fact that a number of studies have shown no benefit in end mortality whilst using this device. One of the reasons for this could be the increase in vascular complications when using the pump. Therefore, the aim of the present review was to assess the current literature available with regards to IABP vascular complications during the clinical situation. Methods: A literature search was performed, searching for IABP complications in adult human studies between 1990 and 2016. Results: A total of 20 reports were identified as fitting the criteria of this study. The majority of vascular complications were limb ischemia, bleeding or mesenteric ischemia. The overall incidence of vascular complications ranged from 0.94% to 31.1%. Diabetes, peripheral vascular disease and hypertension, as well as smoking were all identified as risk factors for complications following IABP. Furthermore, studies supported the use of sheathless balloon insertion to reduce the risk of complications. Conclusion: Major vascular complications, including limb and mesenteric ischemia as well as bleeding and hemorrhage, have been associated with IABP. However, the incidence of these complications was generally low. Further studies are still required to truly understand the risk/benefit associated with the use of IABP. PMID:28816093

A functional murine model of hindlimb demand ischemia.

PubMed

Peck, Michael A; Crawford, Robert S; Abularrage, Christopher J; Patel, Virendra I; Conrad, Mark F; Yoo, Jin Hyung; Watkins, Michael T; Albadawi, Hassan

2010-05-01

To date, murine models of treadmill exercise have been used to study general exercise physiology and angiogenesis in ischemic hindlimbs. The purpose of these experiments was to develop a murine model of demand ischemia in an ischemic limb to mimic claudication in humans. The primary goal was to determine whether treadmill exercise reflected a hemodynamic picture which might be consistent with the hyperemic response observed in humans. Aged hypercholesterolemic ApoE null mice (ApoE(-/-), n = 13) were subjected to femoral artery ligation (FAL) and allowed to recover from the acute ischemic response. Peripheral perfusion of the hindlimbs at rest was determined by serial evaluation using laser Doppler imaging (LDI) on days 0, 7, and 14 following FAL. During the experiments, mice were also assessed on an established five-point clinical ischemic score, which assessed the degree of digital amputation, necrosis, and cyanosis compared to the nonischemic contralateral limb. After stabilization of the LDI ratio (ischemic limb flux/contralateral nonischemic limb flux) and clinical ischemic score, mice underwent 2 days of treadmill training (10 min at 10 m/min, incline of 10 degrees ) followed by 60 min of daily treadmill exercise (13 m/min, incline of 10 degrees ) through day 25. An evaluation of preexercise and postexercise perfusion using LDI was performed on two separate occasions following the onset of daily exercise. During the immediate 15 min postexercise evaluation, LDI scanning was obtained in quadruplicate, to allow identification of peak flux ratios. Statistical analysis included unpaired t-tests and analysis of variance. After FAL, the LDI flux ratio reached a nadir between days 1 and 2, then stabilized by day 14 and remained stable through day 25. The clinical ischemic score stabilized at day 7 and remained stable throughout the rest of the experiment. Based on stabilization of both the clinical ischemic score and LDI ratio, exercise training began on day 15. The peak 15 min postexercise LDI ratio increased significantly compared to the preexercise ratio on day 17 (0.48 +/- 0.04 vs. 0.34 +/- 0.04, p < 0.05) and day 25 (0.37 +/- 0.03 vs. 0.27 +/- 0.03, p < 0.01). Within 2 hr of exercise, the LDI ratio returned to preexercise levels on both days 17 and 25. Clinical and hemodynamic stabilization of limb perfusion is evident by 14 days after FAL. FAL followed by demand ischemia results in a reversible relative hyperemic response similar to that observed in exercising human claudicants. A murine model of FAL associated with demand ischemia may be useful to evaluate the metabolic, inflammatory, and flow-related changes associated with claudication in humans. Copyright 2010 Annals of Vascular Surgery Inc. All rights reserved.

Features of the temperature response to a double cuff-occlusion of the upper limbs: remote ischemic preconditioning aspect

NASA Astrophysics Data System (ADS)

Sagaidachnyi, A. A.; Fomin, A. V.; Mayskov, D. I.; Skripal, A. V.; Usanov, D. A.

2018-04-01

The essence of the phenomenon of ischemic preconditioning is increasing myocardium resistance to long periods of ischemia that occurs after several short ischemia-reperfusion periods. The aim of this pilot study was to determine the temperature and vascular response in double brachial occlusions and to assess the prospects of using this maneuver for remote ischemic preconditioning. Infrared thermography-based measurements were used to assess hemodynamics both left and right hands during the baseline, ischemia and hyperemia periods. Double ischemia with a period of 2 min was implemented by a cuff compression of the brachial artery of the right hand. A study group was constituted of eight men and six women without cardiovascular abnormalities at the age of 22 to 35 years. As a result, we have determined that a temperature and vascular response to ischemia of right hand is accompanied by the vascular reaction of the contralateral left hand, especially after the inflation and deflation of the cuff. These vascular reactions are reproducible, systemic and appear to be at least neurological in nature. An experimental confirmation of the systemic vascular «training effect» after multiple brachial ischemia-reperfusion periods is a subject of further investigations.

An evaluation of the International Society for Animal Genetics recommended parentage and identification panel for the domestic pigeon (Columba livia domestica).

PubMed

de Groot, M; van Haeringen, W A

2017-08-01

In this study, the International Society for Animal Genetics (ISAG) recommended panel for the identification of the domestic pigeon (Columba livia domestica) is characterized based on commonly used statistical parameters. The marker panel is based on 16 short tandem repeat (STR) loci (PIGN15, PIGN10, PIGN57, PIGN26, CliμD16, CliμD19, PIGN12, CliμD17, CliμT17, PIGN04, CliμD01, CliμD11, CliμD35, CliμT02, CliμT13, CliμT43). The alleles of the 16 loci consist of a mixture of tri-, tetra-, penta- and hexameric repeat patterns. A sex determination marker was included in the multiplex for quality control. The repeat sequence of the PIGN markers was previously unpublished and therefore sequenced to reveal the sequence pattern. In total, 1421 pigeons were genotyped on 16 STR loci to generate allele frequency data for each locus. For all 16 markers combined, a PE1 (combined non-exclusion probability, first parent) of 0.9986 and PE2 (combined non-exclusion probability, second parent) of >0.9999 was observed. Comparing the alleged father and mother, a PE value of >0.9999 was observed. Two of the markers, CliμD19 and PIGN12, were found to have relatively high Hardy-Weinberg equilibrium and F(null) values. Therefore these markers may be considered to be replaced by other STRs. Another point of discussion may be to add a gender identification marker to the recommended ISAG panel. Not only can this serve as an extra identification marker, but this can also confirm the sex of a sample, because it is challenging to determine the sex based on phenotypical characteristics, especially for chicks. In conclusion, the set of 16 STR markers can be used in routine parentage verification and the identification of individuals. © 2017 Stichting International Foundation for Animal Genetics.

Subintimal recanalization of femoropopliteal occlusive lesions in patients with critical ischemia: 66 cases.

PubMed

Mousnier, Aurélien; Jean-Baptiste, Elixène; Sadaghianloo, Nirvana; Declemy, Serge; Brizzi, Sophie; Hassen-Khodja, Réda

2013-05-01

Subintimal recanalization allows for the treatment of percutaneously extended occlusive lesions. The aim of this study was to evaluate the feasibility and short- and mid-term results of subintimal recanalization in the treatment of femoropopliteal occlusive lesions in patients with critical ischemia. Between January 2009 and December 2010, consecutive patients with critical ischemia presenting with femoropopliteal arterial occlusion were included in this study. These patients underwent subintimal recanalization, and all patients had clinical and ultrasound follow-up. Sixty-six procedures were performed on 66 patients (mean age, 79±10 yrs). All patients were American Society of Anesthesiologists classification 3 or 4. Thirty-two patients had diabetes and 27 had chronic renal insufficiency. More than two-thirds (76%) of the lesions had a Trans-Atlantic Inter-Society Classification of C or D. The mean occlusion length was 13.5±7 cm. The rate of technical success was 85%. The peroperative complication rate was 4.5%. There were no cases of operative mortality. Occlusion length was the only predictive factor of restenosis (P=0.049). At 1 year, primary and secondary patency rates were 56% and 70%, respectively, for a 92% rate of limb salvage. The subintimal recanalization technique is feasible and minimally invasive. At 1 year postprocedure, the primary patency is poor, but this technique is associated with a high rate of limb salvage. It is suitable for the treatment of critical ischemia, taking into account the often precarious clinical backgrounds of these patients. Copyright © 2013 Elsevier Inc. All rights reserved.

[Postconditioning can reduce long-term lung injury after lower limb ischemia-reperfusion].

PubMed

Garbaisz, Dávid; Turóczi, Zsolt; Fülöp, András; Rosero, Olivér; Arányi, Péter; Ónody, Péter; Lotz, Gábor; Rakonczay, Zoltán; Balla, Zsolt; Harsányi, László; Szijártó, Attila

2013-06-01

Operation on the infrarenal aorta could cause ischemic-reperfusion (IR) injury in local tissues and remote organs (e.g. the lung). Our aim was to reduce long-term lung damage, after lower limb IR with postconditioning. Male Wistar rats underwent 180 minutes of bilateral lower limb ischemia. Animals were divided into three groups: Sham-operated, IR, Postconditioned (PostC) and further to two subgroups according to reperfusion time: 24 h and 72 h. Serum free radical and IL-6 levels, histological changes, Wet/Dry (W/D) ratio, tissue myeloperoxidase (MPO) activity and Hsp72 levels were investigated. Postconditioning can reduce histological changes in the lung. Free radical levels are significantly lower in PostC groups than in IR groups (42.9 ± 8.0 vs. 6.4 ± 3.4; 27.3 ± 4.4 vs. 8.3 ± 4.0 RLU%; p < 0.05). IL-6 level (238.4 ± 31.1 vs. 209.1 ± 18.8; 190.0 ± 8.8 vs. 187.0 ± 14.9 pg/ml) and Hsp72 expression did not show any significant difference. Compared to the IR group, lung MPO activity did not change in the PostC groups. W/D ratio in PostC groups is significantly lower at all measured time-points (68% vs. 65%; 72% vs. 68%; p < 0.05). Postconditioning may reduce long-term damages of the lung after lower limb ischemic-reperfusion injury.

[The use of vascular prothesis Gore Viabahn in the managment of the lower limbs ischemia].

PubMed

Pupka, Artur; Szyber, Przemysław Piotr; Skóra, Jan; Pawłowski, Stanisław

2011-01-01

The chronic lower limbs ischaemia is caused mainly by arteriosclerosis. After insufficient conservative treatment only the surgical intervention can salvage the limb. The revascularisation surgery can be performed by open surgery with implantation of the prosthetic bypass or by endovascular angioplasty with stent. This second method seems to be the best alternative for the patients with several concomitant systemic diseases. Nevertheless it is limited by presence of the long-distance arteriosclerotic lesions. The resolve of that problem is use of new generation of long endovascular covered stents. They can be succesfuly used in aorto-femoral and femoro-popliteal segment. Their efficiacy is simmilar to traditional prosthetic grafts.

A New Approach: Regional Nerve Blockade for Angioplasty of the Lower Limb

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marcus, A.J., E-mail: Adrian.Marcus@bcf.nhs.uk; Lotzof, K.; Kamath, B.S.K.

2006-04-15

Purpose. An audit study investigated the pilot use of regional nerve block analgesia (as an alternative to sedative/opiate, general or central neuraxial anesthesia) performed by radiologists with the assistance of imaging techniques during complex prolonged angiography. Methods. Radiologists were trained by anesthetic consultants to administer and use lower limb peripheral nerve block for difficult prolonged angioplasty procedures for patients with severe lower limb rest pain who were unable to lie in the supine position. In a pilot study 25 patients with limb-threatening ischemia received sciatic and femoral nerve blockade for angioplasty. The technique was developed and perfected in 12 patientsmore » and in a subsequent 13 patients the details of the angiography procedures, peripheral anesthesia, supplementary analgesia, complications, and pain assessment scores were recorded. Pain scores were also recorded in 11 patients prior to epidural/spinal anesthesia for critical ischemic leg angioplasty. Results. All patients with peripheral nerve blockade experienced a reduction in their ischemic rest pain to a level that permitted angioplasty techniques to be performed without spinal, epidural or general analgesia. In patients undergoing complex angioplasty intervention, the mean pain score by visual analogue scale was 3.7, out of a maximum score of 10. Conclusions. The successful use of peripheral nerve blocks was safe and effective as an alternative to sedative/opiate, epidural or general anesthesia in patients undergoing complex angiography and has optimized the use of radiological and anesthetic department resources. This has permitted the frequent radiological treatment of patients with limb-threatening ischemia and reduced delays caused by the difficulty in enlisting the help of anesthetists, often at short notice, from the busy operating lists.« less

The effects of L-carnitine on spinal cord ischemia/reperfusion injury in rabbits.

PubMed

Tetik, O; Yagdi, T; Islamoglu, F; Calkavur, T; Posacioglu, H; Atay, Y; Ayik, F; Canpolat, L; Yuksel, M

2002-02-01

Paraplegia after distal aortic aneurysm repair remains a persistent clinical problem. We hypothesized that the tolerance of the spinal cord to an ischemic period could be improved with hypothermic Ringer's Lactate containing L-Carnitine. Twenty-eight New Zealand white rabbits were used as spinal cord ischemia models. We separated rabbits into four equal groups and clamped each animal's abdominal aorta distal to the left renal artery. We occluded the aortas above the iliac bifurcation for 30 minutes. In group I, the infrarenal aorta was clamped without infusing any solution. In group II, Ringer's Lactate solution was infused at + 25degrees C for 3 minutes at a rate of 5 ml/min into the isolated aortic segments immediately after cross-clamping and the last 3 minutes of ischemia. In group III, Ringer's Lactate solution at +3 degrees C was given in the same method as that of group II. In group IV, Ringer's Lactate solution at +3 degrees C plus 100 mg/kg of L-carnitine was infused using the same technique. We assessed the neurological status of the hind limbs 24 and 48 hours after operation according to Tarlov's criteria. All animals were sacrificed and spinal cords were harvested for histological analyses. The neurological status in groups III and IV was significantly superior to that of groups I and II. All the animals in group I had complete hind-limb paraplegia. Complete hind-limb paraplegia occurred in 5 rabbits in group II. Two of the 7 animals in group III had spastic paraplegia, and none at all in group IV. Histological analysis of the cross-clamped segments of the rabbits with paraplegia in group I, II and III revealed changes consistent with ischemic injury, while findings were normal for the normal animals in group III and IV. In this model, the infusion of hypothermic Ringer's Lactate contained L-carnitine provided sufficient spinal cord protection against ischemia. Clinically, this may be a useful adjunct for prevention of paraplegia during surgery of the descending aorta.

Cerenkov luminescence imaging: physics principles and potential applications in biomedical sciences.

PubMed

Ciarrocchi, Esther; Belcari, Nicola

2017-12-01

Cerenkov luminescence imaging (CLI) is a novel imaging modality to study charged particles with optical methods by detecting the Cerenkov luminescence produced in tissue. This paper first describes the physical processes that govern the production and transport in tissue of Cerenkov luminescence. The detectors used for CLI and their most relevant specifications to optimize the acquisition of the Cerenkov signal are then presented, and CLI is compared with the other optical imaging modalities sharing the same data acquisition and processing methods. Finally, the scientific work related to CLI and the applications for which CLI has been proposed are reviewed. The paper ends with some considerations about further perspectives for this novel imaging modality.

Topical Nitroglycerine for Neonatal Arterial Associated Peripheral Ischemia following Cannulation: A Case Report and Comprehensive Literature Review

PubMed Central

Mosalli, Rafat; Elbaz, Mohamed; Paes, Bosco

2013-01-01

Arterial cannulation in neonates is usually performed for frequent blood pressure monitoring and blood sampling. The procedure, while easily executed by skilled neonatal staff, can be associated with serious complications such as vasospasm, thrombosis, embolism, hematoma, infection, peripheral nerve damage, ischemia, and tissue necrosis. Several treatment options are available to reverse vascular induced ischemia and tissue damage. Applied interventions depend on the extent of tissue involvement and whether the condition is progressive and deemed life threatening. Standard, noninvasive measures include immediate catheter removal, limb elevation, and warming the contralateral extremity. Topical vasodilators, anticoagulation, thrombolysis, and surgery are considered secondary therapeutic strategies. A comprehensive literature search indicates that topical nitroglycerin has been utilized for the treatment of tissue ischemia in three preterms with umbilical arterial catheters and four with peripheral arterial lines. We report the first successful use of nitroglycerine ointment in a critically ill preterm infant with ischemic hand changes after brachial artery cannulation. PMID:24251058

Measurement of intracellular chloride in guinea-pig vas deferens by ion analysis, 36chloride and micro-electrodes

PubMed Central

Aickin, C. Claire; Brading, Alison F.

1982-01-01

1. Cl-sensitive micro-electrodes were used to measure the intracellular Cl activity (aCli) in smooth muscle cells of the guinea-pig vas deferens. The values obtained were compared with those of intracellular Cl (Cli) found by both ion analysis and 36Cl efflux. 2. Various combinations of filling solution for recording membrane potential (Em), and type of micro-electrode were tested. The most successful, which allowed continuous recording of aCli for several hours, was a double-barrelled electrode using the reference liquid ion exchanger (RLIE; Thomas & Cohen, 1981). However, aCli measured both by simultaneous impalements of separate cells with Cl-sensitive and conventional micro-electrodes, and by double-barrelled micro-electrodes, was about 42 mM in normal Krebs solution. This is five times higher than the value from a passive distribution. ECl was about -24 mV, more than 40 mV positive to Em. 3. On complete removal of extracellular Cl (Clo), aCli fell to an apparent level of about 3 mM. If this represents interference from other anions, the maximum error in ECl measured in normal Krebs solution is 2·5 mV. Replacement of Clo caused a rapid increase in aCli. This must be caused by an active transport of Cl- ions into the cell against their electrochemical gradient. 4. The stabilized values of aCli measured at different levels of Clo agree surprisingly well with aCli estimated from ion analysis and 36Cl efflux, assuming that the intracellular activity coefficient was the same as measured in the normal Krebs solution. The relationship of aCli to Clo was hyperbolic. 5. It is concluded that Cl-sensitive micro-electrodes accurately measure aCli in smooth muscle cells. The remarkable agreement between the direct and indirect methods of measuring Cli suggests that Cl- ions are not bound to a significant extent and that the compartment seen by the micro-electrodes is probably representative of the whole cell. PMID:7108787

20 years of ClO measurements in the Antarctic lower stratosphere

NASA Astrophysics Data System (ADS)

Nedoluha, Gerald E.; Connor, Brian J.; Mooney, Thomas; Barrett, James W.; Parrish, Alan; Gomez, R. Michael; Boyd, Ian; Allen, Douglas R.; Kotkamp, Michael; Kremser, Stefanie; Deshler, Terry; Newman, Paul; Santee, Michelle L.

2016-08-01

We present 20 years (1996-2015) of austral springtime measurements of chlorine monoxide (ClO) over Antarctica from the Chlorine Oxide Experiment (ChlOE1) ground-based millimeter wave spectrometer at Scott Base, Antarctica, as well 12 years (2004-2015) of ClO measurements from the Aura Microwave Limb Sounder (MLS). From August onwards we observe a strong increase in lower stratospheric ClO, with a peak column amount usually occurring in early September. From mid-September onwards we observe a strong decrease in ClO. In order to study interannual differences, we focus on a 3-week period from 28 August to 17 September for each year and compare the average column ClO anomalies. These column ClO anomalies are shown to be highly correlated with the average ozone mass deficit for September and October of each year. We also show that anomalies in column ClO are strongly anti-correlated with 30 hPa temperature anomalies, both on a daily and an interannual timescale. Making use of this anti-correlation we calculate the linear dependence of the interannual variations in column ClO on interannual variations in temperature. By making use of this relationship, we can better estimate the underlying trend in the total chlorine (Cly = HCl + ClONO2 + HOCl + 2 × Cl2 + 2 × Cl2O2 + ClO + Cl). The resultant trends in Cly, which determine the long-term trend in ClO, are estimated to be -0.5 ± 0.2, -1.4 ± 0.9, and -0.6 ± 0.4 % year-1, for zonal MLS, Scott Base MLS (both 2004-2015), and ChlOE (1996-2015) respectively. These trends are within 1σ of trends in stratospheric Cly previously found at other latitudes. The decrease in ClO is consistent with the trend expected from regulations enacted under the Montreal Protocol.

Determinants of midterm functional outcomes, wound healing, and resources used in a hospital-based limb preservation program.

PubMed

Ramanan, Bala; Ahmed, Ayman; Wu, Bian; Causey, Marlin W; Gasper, Warren J; Vartanian, Shant M; Reyzelman, Alexander M; Hiramoto, Jade S; Conte, Michael S

2017-12-01

The objective of this study was to assess midterm functional status, wound healing, and in-hospital resource use among a prospective cohort of patients treated in a tertiary hospital, multidisciplinary Center for Limb Preservation. Data were prospectively gathered on all consecutive admissions to the Center for Limb Preservation from July 2013 to October 2014 with follow-up data collection through January 2016. Limbs were staged using the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) threatened limb classification scheme at the time of hospital admission. Patients with nonatherosclerotic vascular disorders, acute limb ischemia, and trauma were excluded. The cohort included 128 patients with 157 threatened limbs; 8 limbs with unstageable disease were excluded. Mean age (±standard deviation [SD]) was 66 (±13) years, and median follow-up duration (interquartile range) was 395 (80-635) days. Fifty percent (n = 64/128) of patients were readmitted at least once, with a readmission rate of 20% within 30 days of the index admission. Mean total number of admissions per patient (±SD) was 1.9 ± 1.2, with mean (±SD) cumulative length of stay (cLOS) of 17.1 (±17.9) days. During follow-up, 25% of limbs required a vascular reintervention, and 45% developed recurrent wounds. There was no difference in the rate of readmission, vascular reintervention, or wound recurrence by initial WIfI stage (P > .05). At the end of the study period, 23 (26%) were alive and nonambulatory; in 20%, functional status was missing. On both univariate and multivariate analysis, end-stage renal disease and prior functional status predicted ability to ambulate independently (P < .05). WIfI stage was associated with major amputation (P = .01) and cLOS (P = .002) but not with time to wound healing. Direct hospital (inpatient) cost per limb saved was significantly higher in stage 4 patients (P < .05 for all time periods). WIfI stage was associated with cumulative in-hospital costs at 1 year and for the overall follow-up period. Among a population of patients admitted to a tertiary hospital limb preservation service, WIfI stage was predictive of midterm freedom from amputation, cLOS, and hospital costs but not of ambulatory functional status, time to wound healing, or wound recurrence. Patients presenting with limb-threatening conditions require significant inpatient care, have a high frequency of repeated hospitalizations, and are at significant risk for recurrent wounds and leg symptoms at later times. Stage 4 patients require the most intensive care and have the highest initial and aggregate hospital costs per limb saved. However, limb salvage can be achieved in these patients with a dedicated multidisciplinary team approach. Published by Elsevier Inc.

Desert hedgehog promotes ischemia-induced angiogenesis by ensuring peripheral nerve survival.

PubMed

Renault, Marie-Ange; Chapouly, Candice; Yao, Qinyu; Larrieu-Lahargue, Frédéric; Vandierdonck, Soizic; Reynaud, Annabel; Petit, Myriam; Jaspard-Vinassa, Béatrice; Belloc, Isabelle; Traiffort, Elisabeth; Ruat, Martial; Duplàa, Cécile; Couffinhal, Thierry; Desgranges, Claude; Gadeau, Alain-Pierre

2013-03-01

Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves. The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia. We induced hindlimb ischemia in wild-type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle. This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.

Evaluation of 89Zr-rituximab tracer by Cerenkov luminescence imaging and correlation with PET in a humanized transgenic mouse model to image NHL.

PubMed

Natarajan, Arutselvan; Habte, Frezghi; Liu, Hongguang; Sathirachinda, Ataya; Hu, Xiang; Cheng, Zhen; Nagamine, Claude M; Gambhir, Sanjiv Sam

2013-08-01

This research aimed to study the use of Cerenkov luminescence imaging (CLI) for non-Hodgkin's lymphoma (NHL) using 89Zr-rituximab positron emission tomography (PET) tracer with a humanized transgenic mouse model that expresses human CD20 and the correlation of CLI with PET. Zr-rituximab (2.6 MBq) was tail vein-injected into transgenic mice that express the human CD20 on their B cells (huCD20TM). One group (n=3) received 2 mg/kg pre-dose (blocking) of cold rituximab 2 h prior to tracer; a second group (n=3) had no pre-dose (non-blocking). CLI was performed using a cooled charge-coupled device optical imager. We also performed PET imaging and ex vivo studies in order to confirm the in vivo CLI results. At each time point (4, 24, 48, 72, and 96 h), two groups of mice were imaged in vivo and ex vivo with CLI and PET, and at 96 h, organs were measured by gamma counter. huCD20 transgenic mice injected with 89Zr-rituximab demonstrated a high-contrast CLI image compared to mice blocked with a cold dose. At various time points of 4-96 h post-radiotracer injection, the in vivo CLI signal intensity showed specific uptake in the spleen where B cells reside and, hence, the huCD20 biomarker is present at very high levels. The time-activity curve of dose decay-corrected CLI intensity and percent injected dose per gram of tissue of PET uptake in the spleen were increased over the time period (4-96 h). At 96 h, the 89Zr-rituximab uptake ratio (non-blocking vs blocking) counted (mean±standard deviation) for the spleen was 1.5±0.6 for CLI and 1.9±0.3 for PET. Furthermore, spleen uptake measurements (non-blocking and blocking of all time points) of CLI vs PET showed good correlation (R2=0.85 and slope=0.576), which also confirmed the corresponding correlations parameter value (R2=0.834 and slope=0.47) obtained for ex vivo measurements. CLI and PET of huCD20 transgenic mice injected with 89Zr-rituximab demonstrated that the tracer was able to target huCD20-expressing B cells. The in vivo and ex vivo tracer uptake corresponding to the CLI radiance intensity from the spleen is in good agreement with PET. In this report, we have validated the use of CLI with PET for NHL imaging in huCD20TM.

Critical Limb Ischemia in Association with Charcot Neuroarthropathy: Complex Endovascular Therapy for Limb Salvage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palena, Luis Mariano, E-mail: marianopalena@hotmail.com; Brocco, Enrico; Manzi, Marco

2013-05-09

Charcot neuroarthropathy is a low-incidence complication of diabetic foot and is associated with ankle and hind foot deformity. Patients who have not developed deep ulcers are managed with offloading and supportive bracing or orthopedic arthrodesis. In patients who have developed ulcers and severe ankle instability and deformity, below-the-knee amputation is often indicated, especially when deformity and cutaneous involvement result in osteomyelitis. Ischemic association has not been described but can be present as a part of peripheral arterial disease in the diabetic population. In this extreme and advanced stage of combined neuroischemic diabetic foot disease, revascularization strategies can support surgical andmore » orthopedic therapy, thus preventing osteomyelitis and leading to limb and foot salvage.« less

Postischemic Treatment With Ethyl Pyruvate Prevents Adenosine Triphosphate Depletion, Ameliorates Inflammation, and Decreases Thrombosis in a Murine Model of Hind-Limb Ischemia and Reperfusion

PubMed Central

Crawford, Robert S.; Albadawi, Hassan; Atkins, Marvin D.; Jones, John J.; Conrad, Mark F.; Austen, William G.; Fink, Mitchell P.; Watkins, Michael T.

2011-01-01

Introduction Experiments were designed to investigate the effects of ethyl pyruvate (EP) in a murine model of hind-limb ischemia-reperfusion (IR) injury. Methods C57BL6 mice underwent 90 minutes of unilateral ischemia followed by 24 hours of reperfusion using two treatment protocols. For the preischemic treatment (pre-I) protocol, mice (n = 6) were given 300 mg/kg EP before ischemia, followed by 150 mg/kg of EP just before reperfusion and at 6 hours and 12 hours after reperfusion. In a postischemic treatment (post-I) protocol, mice (n = 7) were treated with 300 mg/kg EP at the end of the ischemic period, then 15 minutes later, and 2 hours after reperfusion and 150 mg/kg of EP at 4 hours, 6 hours, 10 hours, 16 hours, and 22 hours after reperfusion. Controls mice for both protocols were treated with lactated Ringers alone at time intervals identical to EP. Skeletal muscle levels of adenosine triphosphate (ATP), interleukin-1β, keratinocyte chemoattractant protein, and thrombin antithrombin-3 complex were measured. Skeletal muscle architectural integrity was assessed microscopically. Results ATP levels were higher in mice treated with EP compared with controls under the both treatment protocols (p = 0.02). Interleukin-1β, keratinocyte chemoattractant protein, thrombin antithrombin-3 complex (p < 0.05), and the percentage of injured fibers (p < 0.0001) were significantly decreased in treated versus control mice under the both protocols. Conclusion Muscle fiber injury and markers of tissue thrombosis and inflammation were reduced, and ATP was preserved with EP in pre-I and post-I protocols. Further investigation of the efficacy of EP to modulate IR injury in a larger animal model of IR injury is warranted. PMID:21217488

Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia.

PubMed

Oda, Shinichiro; Nagahama, Ryoji; Nakano, Kaku; Matoba, Tetsuya; Kubo, Mitsuki; Sunagawa, Kenji; Tominaga, Ryuji; Egashira, Kensuke

2010-08-01

We recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals. Chronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle. Treatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects. The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients. Copyright (c) 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Rearfoot Transcutaneous Oximetry is a Useful Tool to Highlight Ischemia of the Heel

DOE Office of Scientific and Technical Information (OSTI.GOV)

Izzo, Valentina, E-mail: valentina-izzo@virgilio.it; Meloni, Marco, E-mail: meloni.marco@libero.it; Fabiano, Sebastiano, E-mail: sebas575@yahoo.it

PurposeTo demonstrate the usefulness of rearfoot transcutaneous oximetry to assess the peripheral arterial disease in diabetic patients with heel ulcer.MethodsFrom our database of 550 critical limb ischemia diabetic patients followed after a percutaneous transluminal angioplasty, we have selected patients with below the knee arterial disease. Patients were grouped according to the dorsal transcutaneous oximetry value (Group A < 30 mmHg; Group B ≥ 30 mmHg). Patients of Group B had a second oximetry performed at the rearfoot, close to the lesion localized in all cases at the heel. Finally, the analysis of the arterial pattern disease has been done.ResultsWe selected 191 patients: Group A (151 patients),more » dorsal transcutaneous oximetry of 11.8 ± 0.7 mmHg; Group B (40 patients), dorsal transcutaneous oximetry of 44.2 ± 10.1 mmHg. In Group B, rearfoot oximetry was 20.5 ± 5 mmHg, significantly lower than dorsal oximetry (p = 0.0179). The anterior tibial artery was involved in all patients of Group A. In Group B, the anterior tibial artery was involved in 15 subjects and never alone; the posterior tibial artery was involved in 20 subjects and in 11 cases alone. The peroneal artery was affected in 20 subjects and in 14 patients alone.ConclusionWhen a heel lesion is present and the transcutaneous oximetry recorded on the dorsum of the foot does not confirm the presence of critical limb ischemia (not ≤30 mmHg), a second oximetry recorded on the rearfoot is useful to point out ischemia of the peroneal artery and/or of the posterior tibial artery.« less

Influence of Butyrate Loaded Clinoptilolite Dietary Supplementation on Growth Performance, Development of Intestine and Antioxidant Capacity in Broiler Chickens

PubMed Central

Wu, Yanan; Zhou, Yanmin; Lu, Changhui; Ahmad, Hussain; Zhang, Hao; He, Jintian; Zhang, Lili; Wang, Tian

2016-01-01

The study was conducted to evaluate the effects of dietary butyrate loaded clinoptilolite (CLI-B) on growth performance, pancreatic digestive enzymes, intestinal development and histomorphology, as well as antioxidant capacity of serum and intestinal mucosal in chickens. Two hundred forty 1-day-old commercial Arbor Acres broilers were randomly assigned to 4 groups: CON group (fed basal diets), SB group (fed basal diet with 0.05% sodium butyrate), CLI group (fed basal diet with 1% clinoptilolite), and CLI-B group (fed basal diet with 1% CLI-B). The results showed that supplementation of CLI-B significantly decreased (P < 0.05) feed conservation ratio at both 21 and 42 days of age, improved the pancreatic digestive enzymes activities (P < 0.05), increased the villus length and villus/crypt ratio (P < 0.05), and decreased the crypt depth of intestine (P < 0.05) as compared to the other experimental groups. Furthermore, the CLI-B environment improved the antioxidant capacity by increasing the antioxidant enzyme activities (P < 0.05) in intestine mucosal, and decreasing the NO content and iNOS activity (P < 0.05) in serum. In addition, CLI-B supplementation had improved the development of intestine and antioxidant capacity of broilers than supplementation with either clinoptilolite or butyrate sodium alone. In conclusion, 1% CLI-B supplementation improved the health status, intestine development and antioxidant capacity in broiler chickens, thus appearing as an important feed additive for the poultry industry. PMID:27104860

Hemorheological changes in ischemia-reperfusion: an overview on our experimental surgical data.

PubMed

Nemeth, Norbert; Furka, Istvan; Miko, Iren

2014-01-01

Blood vessel occlusions of various origin, depending on the duration and extension, result in tissue damage, causing ischemic or ischemia-reperfusion injuries. Necessary surgical clamping of vessels in vascular-, gastrointestinal or parenchymal organ surgery, flap preparation-transplantation in reconstructive surgery, as well as traumatological vascular occlusions, all present special aspects. Ischemia and reperfusion have effects on hemorheological state by numerous ways: besides the local metabolic and micro-environmental changes, by hemodynamic alterations, free-radical and inflammatory pathways, acute phase reactions and coagulation changes. These processes may be harmful for red blood cells, impairing their deformability and influencing their aggregation behavior. However, there are still many unsolved or non-completely answered questions on relation of hemorheology and ischemia-reperfusion. How do various organ (liver, kidney, small intestine) or limb ischemic-reperfusionic processes of different duration and temperature affect the hemorheological factors? What is the expected magnitude and dynamics of these alterations? Where is the border of irreversibility? How can hemorheological investigations be applied to experimental models using laboratory animals in respect of inter-species differences? This paper gives a summary on some of our research data on organ/tissue ischemia-reperfusion, hemorheology and microcirculation, related to surgical research and experimental microsurgery.

Blood vessel control of macrophage maturation promotes arteriogenesis in ischemia.

PubMed

Krishnasamy, Kashyap; Limbourg, Anne; Kapanadze, Tamar; Gamrekelashvili, Jaba; Beger, Christian; Häger, Christine; Lozanovski, Vladimir J; Falk, Christine S; Napp, L Christian; Bauersachs, Johann; Mack, Matthias; Haller, Hermann; Weber, Christian; Adams, Ralf H; Limbourg, Florian P

2017-10-16

Ischemia causes an inflammatory response that is intended to restore perfusion and homeostasis yet often aggravates damage. Here we show, using conditional genetic deletion strategies together with adoptive cell transfer experiments in a mouse model of hind limb ischemia, that blood vessels control macrophage differentiation and maturation from recruited monocytes via Notch signaling, which in turn promotes arteriogenesis and tissue repair. Macrophage maturation is controlled by Notch ligand Dll1 expressed in vascular endothelial cells of arteries and requires macrophage canonical Notch signaling via Rbpj, which simultaneously suppresses an inflammatory macrophage fate. Conversely, conditional mutant mice lacking Dll1 or Rbpj show proliferation and transient accumulation of inflammatory macrophages, which antagonizes arteriogenesis and tissue repair. Furthermore, the effects of Notch are sufficient to generate mature macrophages from monocytes ex vivo that display a stable anti-inflammatory phenotype when challenged with pro-inflammatory stimuli. Thus, angiocrine Notch signaling fosters macrophage maturation during ischemia.Molecular mechanisms of macrophage-mediated regulation of artery growth in response to ischemia are poorly understood. Here the authors show that vascular endothelium controls macrophage maturation and differentiation via Notch signaling, which in turn promotes arteriogenesis and ischemic tissue recovery.

A simple model for deep tissue attenuation correction and large organ analysis of Cerenkov luminescence imaging

NASA Astrophysics Data System (ADS)

Habte, Frezghi; Natarajan, Arutselvan; Paik, David S.; Gambhir, Sanjiv S.

2014-03-01

Cerenkov luminescence imaging (CLI) is an emerging cost effective modality that uses conventional small animal optical imaging systems and clinically available radionuclide probes for light emission. CLI has shown good correlation with PET for organs of high uptake such as kidney, spleen, thymus and subcutaneous tumors in mouse models. However, CLI has limitations for deep tissue quantitative imaging since the blue-weighted spectral characteristics of Cerenkov radiation attenuates highly by mammalian tissue. Large organs such as the liver have also shown higher signal due to the contribution of emission of light from a greater thickness of tissue. In this study, we developed a simple model that estimates the effective tissue attenuation coefficient in order to correct the CLI signal intensity with a priori estimated depth and thickness of specific organs. We used several thin slices of ham to build a phantom with realistic attenuation. We placed radionuclide sources inside the phantom at different tissue depths and imaged it using an IVIS Spectrum (Perkin-Elmer, Waltham, MA, USA) and Inveon microPET (Preclinical Solutions Siemens, Knoxville, TN). We also performed CLI and PET of mouse models and applied the proposed attenuation model to correct CLI measurements. Using calibration factors obtained from phantom study that converts the corrected CLI measurements to %ID/g, we obtained an average difference of less that 10% for spleen and less than 35% for liver compared to conventional PET measurements. Hence, the proposed model has a capability of correcting the CLI signal to provide comparable measurements with PET data.

Correlation between positron emission tomography and Cerenkov luminescence imaging in vivo and ex vivo using 64Cu-labeled antibodies in a neuroblastoma mouse model.

PubMed

Maier, Florian C; Schmitt, Julia; Maurer, Andreas; Ehrlichmann, Walter; Reischl, Gerald; Nikolaou, Konstantin; Handgretinger, Rupert; Pichler, Bernd J; Thaiss, Wolfgang M

2016-10-11

Antibody-based therapies gain momentum in clinical therapy, thus the need for accurate imaging modalities with respect to target identification and therapy monitoring are of increasing relevance. Cerenkov luminescence imaging (CLI) are a novel method detecting charged particles emitted during radioactive decay with optical imaging. Here, we compare Position Emission Tomography (PET) with CLI in a multimodal imaging study aiming at the fast and efficient screening of monoclonal antibodies (mAb) designated for targeting of the neuroblastoma-characteristic epitope disialoganglioside GD2. Neuroblastoma-bearing SHO mice were injected with a 64Cu-labeled GD2-specific mAb. The tumor uptake was imaged 3 h, 24 h and 48 h after tracer injection with both, PET and CLI, and was compared to the accumulation in GD2-negative control tumors (human embryonic kidney, HEK-293). In addition to an in vivo PET/CLI-correlation over time, we also demonstrate linear correlations of CLI- and γ-counter-based biodistribution analysis. CLI with its comparably short acquisition time can thus be used as an attractive one-stop-shop modality for the longitudinal monitoring of antibody-based tumor targeting and ex vivo biodistribution.These findings suggest CLI as a reliable alternative for PET and biodistribution studies with respect to fast and high-throughput screenings in subcutaneous tumors traced with radiolabeled antibodies. However, in contrast to PET, CLI is not limited to positron-emitting isotopes and can therefore also be used for the visualization of mAb labeled with therapeutic isotopes like electron emitters.

Remote limb ischemic conditioning enhances motor learning in healthy humans

PubMed Central

Cherry-Allen, Kendra M.; Gidday, Jeff M.; Lee, Jin-Moo; Hershey, Tamara

2015-01-01

Brief bouts of sublethal ischemia have been shown to protect exposed tissue (ischemic conditioning) and tissues at remote sites (remote ischemic conditioning) against subsequent ischemic challenges. Given that the mechanisms of this protective phenomenon are multifactorial and epigenetic, we postulated that remote limb ischemic conditioning (RLIC) might enhance mechanisms responsible for neural plasticity, and thereby facilitate learning. Specifically, we hypothesized that conditioning of the nervous system with RLIC, achieved through brief repetitive limb ischemia prior to training, would facilitate the neurophysiological processes of learning, thus making training more effective and more long-lasting. Eighteen healthy adults participated in this study; nine were randomly allocated to RLIC and nine to sham conditioning. All subjects underwent seven consecutive weekday sessions and 2-wk and 4-wk follow-up sessions. We found that RLIC resulted in significantly greater motor learning and longer retention of motor performance gains in healthy adults. Changes in motor performance do not appear to be due to a generalized increase in muscle activation or muscle strength and were not associated with changes in serum brain-derived neurotrophic factor (BDNF) concentration. Of note, RLIC did not enhance cognitive learning on a hippocampus-dependent task. While future research is needed to establish optimal conditioning and training parameters, this inexpensive, clinically feasible paradigm might ultimately be implemented to enhance motor learning in individuals undergoing neuromuscular rehabilitation for brain injury and other pathological conditions. PMID:25867743

Hydrogen peroxide-responsive copolyoxalate nanoparticles for detection and therapy of ischemia-reperfusion injury.

PubMed

Lee, Dongwon; Bae, Soochan; Ke, Qingen; Lee, Jiyoo; Song, Byungjoo; Karumanchi, S Ananth; Khang, Gilson; Choi, Hak Soo; Kang, Peter M

2013-12-28

The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the generation of high level of hydrogen peroxide (H2O2). In this study, we report a novel diagnostic and therapeutic strategy for I/R injury based on H2O2-activatable copolyoxalate nanoparticles using a murine model of hind limb I/R injury. The nanoparticles are composed of hydroxybenzyl alcohol (HBA)-incorporating copolyoxalate (HPOX) that, in the presence of H2O2, degrades completely into three known and safe compounds, cyclohexanedimethanol, HBA and CO2. HPOX effectively scavenges H2O2 in a dose-dependent manner and hydrolyzes to release HBA which exerts intrinsic antioxidant and anti-inflammatory activities both in vitro and in vivo models of hind limb I/R. HPOX nanoparticles loaded with fluorophore effectively and robustly image H2O2 generated in hind limb I/R injury, demonstrating their potential for bioimaging of H2O2-associated diseases. Furthermore, HPOX nanoparticles loaded with anti-apoptotic drug effectively release the drug payload after I/R injury, exhibiting their effectiveness for a targeted drug delivery system for I/R injury. We anticipate that multifunctional HPOX nanoparticles have great potential as H2O2 imaging agents, therapeutics and drug delivery systems for H2O2-associated diseases. © 2013.

Digital image analysis of striated skeletal muscle tissue injury during reperfusion after induced ischemia

NASA Astrophysics Data System (ADS)

Rosero Salazar, Doris Haydee; Salazar Monsalve, Liliana

2015-01-01

Conditions such as surgical procedures or vascular diseases produce arterial ischemia and reperfusion injuries, which generate changes in peripheral tissues and organs, for instance, in striated skeletal muscle. To determine such changes, we conducted an experimental method in which 42 male Wistar rat were selected, to be undergone to tourniquet application on the right forelimb and left hind limb, to induce ischemia during one and three hours, followed by reperfusion periods starting at one hour and it was prolonged up to 32 days. Extensor carpi radialis longus and soleus respectively, were obtained to be processed for histochemical and morphometric analysis. By means of image processing and detection of regions of interest, variations of areas occupied by muscle fibers and intramuscular extracellular matrix (IM-ECM) throughout reperfusion were observed. In extensor carpi radialis longus, results shown reduction in the area occupied by muscle fibers; this change is significant between one hour and three hours ischemia followed by 16 hours, 48 hours and 32 days reperfusión (p˂0.005). To compare only periods of reperfusión that continued to three hours ischemia, were found significant differences, as well. For area occupied by IM-ECM, were identified increments in extensor carpi radialis longus by three hours ischemia and eight to 16 days reperfusion; in soleus, was observed difference by one hour ischemia with 42 hours reperfusion, and three hours ischemia followed by four days reperfusion (p˂0.005). Skeletal muscle develops adaptive changes in longer reperfusion, to deal with induced injury. Descriptions beyond 32 days reperfusion, can determine recovering normal pattern.

Spinal Cord Ischemia Secondary to Hypovolemic Shock

PubMed Central

Kapoor, Siddhant; Koh, Roy KM; Yang, Eugene WR; Hee, Hwan-Tak

2014-01-01

A 44-year-old male presented with symptoms of spinal cord compression secondary to metastatic prostate cancer. An urgent decompression at the cervical-thoracic region was performed, and there were no complications intraoperatively. Three hours postoperatively, the patient developed acute bilateral lower-limb paralysis (motor grade 0). Clinically, he was in class 3 hypovolemic shock. An urgent magnetic resonance imaging (MRI) was performed, showing no epidural hematoma. He was managed aggressively with medical therapy to improve his spinal cord perfusion. The patient improved significantly, and after one week, he was able to regain most of his motor functions. Although not commonly reported, spinal cord ischemia post-surgery should be recognized early, especially in the presence of hypovolemic shock. MRI should be performed to exclude other potential causes of compression. Spinal cord ischemia needs to be managed aggressively with medical treatment to improve spinal cord perfusion. The prognosis depends on the severity of deficits, and is usually favorable. PMID:25558328

Risk Factors for Long-Term Mortality and Amputation after Open and Endovascular Treatment of Acute Limb Ischemia.

PubMed

Genovese, Elizabeth A; Chaer, Rabih A; Taha, Ashraf G; Marone, Luke K; Avgerinos, Efthymios; Makaroun, Michel S; Baril, Donald T

2016-01-01

Acute limb ischemia (ALI) is a highly morbid and fatal vascular emergency with little known about contemporary, long-term patient outcomes. The goal was to determine predictors of long-term mortality and amputation after open and endovascular treatment of ALI. A retrospective review of ALI patients at a single institution from 2005 to 2011 was performed to determine the impact of revascularization technique on 5-year mortality and amputation. For each main outcome 2 multivariable models were developed; the first adjusted for preoperative clinical presentation and procedure type, the second also adjusted for postoperative adverse events (AEs). A total of 445 limbs in 411 patients were treated for ALI. Interventions included surgical thrombectomy (48%), emergent bypass (18%), and endovascular revascularization (34%). Mean age was 68 ± 15 years, 54% were male, and 23% had cancer. Most patients presented with Rutherford classification IIa (54%) or IIb (39%). The etiology of ALI included embolism (27%), in situ thrombosis (28%), thrombosed bypass grafts (32%), and thrombosed stents (13%). Patients treated with open procedures had significantly more advanced ischemia and higher rates of postoperative respiratory failure, whereas patients undergoing endovascular interventions had higher rates of technical failure. Rates of postprocedural bleeding and cardiac events were similar between both treatments. Excluding Rutherford class III patients (n = 12), overall 5-year mortality was 54% (stratified by treatment, 65% for thrombectomy, 63% for bypass, and 36% for endovascular, P < 0.001); 5-year amputation was 28% (stratified by treatment, 18% for thrombectomy, 27% for bypass, and 17% for endovascular, P = 0.042). Adjusting for comorbidities, patient presentation, AEs, and treatment method, the risk of mortality increased with age (hazard ratio [HR] = 1.04, P < 0.001), female gender (HR = 1.50, P = 0.031), cancer (HR = 2.19, P < 0.001), fasciotomy (HR = 1.69, P = 0.204) in situ thrombosis or embolic etiology (HR = 1.73, P = 0.007), cardiac AEs (HR = 2.25, P < 0.001), respiratory failure (HR = 2.72, P < 0.001), renal failure (HR = 4.70, P < 0.001), and hemorrhagic events (HR = 2.25, P = 0.003). Risk of amputation increased with advanced ischemia (Rutherford IIb compared with IIa, HR = 2.57, P < 0.001), thrombosed bypass etiology (HR = 3.53, P = 0.002), open revascularization (OR; HR = 1.95, P = 0.022), and technical failure of primary intervention (HR = 6.01, P < 0.001). After the treatment of ALI, long-term mortality and amputation rates were greater in patients treated with open techniques; OR patients presented with a higher number of comorbidities and advanced ischemia, while also experiencing a higher rate of major postoperative complications. Overall, mortality rates remained high and were most strongly associated with baseline comorbidities, acuity of presentation, and perioperative AEs, particularly respiratory failure. Comparatively, amputation risk was most highly associated with advanced ischemia, thrombosed bypass, and failure of the initial revascularization procedure. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical efficacy of concomitant tibial interventions associated with superficial femoral artery interventions in critical limb ischemia.

PubMed

Smolock, Christopher J; Anaya-Ayala, Javier E; El-Sayed, Hosam F; Naoum, Joseph J; Lumsden, Alan B; Davies, Mark G

2013-01-01

Combined superficial femoral artery (SFA) and tibial angioplasty (TA) are a common treatment for critical limb ischemia. Poor tibial runoff significantly compromises durability and clinical effectiveness of SFA interventions. The aim of this study is to determine clinical and anatomic outcomes of SFA interventions in patients with equally compromised runoff, with and without concomitant TA. The database of patients undergoing endovascular treatment of SFA (1999-2009) was retrospectively queried. Patients with poor runoff, scored>10 by modified Society for Vascular Surgery criteria, were selected. Preoperative angiograms were reviewed to assess distal popliteal and tibial runoff. Kaplan-Meier analyses were performed to assess time-dependent outcomes. Factor analyses were performed for time-dependent variables. A total of 162 limbs with a runoff score>10 (56% men; average age, 69 years) underwent endovascular intervention for symptomatic SFA disease: 61 (54% men) underwent TA but the remaining 101 (57% men) did not. The groups were matched for age, sex, and SFA anatomy (Trans-Atlantic Inter-Society Consensus II C/D lesions: 56% no TA vs 62% TA; P=.5). Presenting symptoms were similar between no TA and TA groups (rest pain: 40% vs 32%; tissue loss: 60% vs 68%; P=.3). Three-year survival favored the TA group (79%±5%) vs no TA (68%±5%; P=.06). Three-year anatomic outcomes in no TA vs TA group, including primary patency (45%±6% vs 63%±8%; P=.04), assisted primary patency (55%±6% vs 75%±7%; P=.03), and secondary patency (57%±6% vs 77%±7%; P=.03) were all superior in the TA group. Target vessel revascularization in no TA vs TA (61%±6% vs 74%±8%; P=.002) and target extremity revascularization (42%±6% vs 59%±8%; P=.06) also favored the TA group. However the comparison of no TA vs TA for clinical success (39%±6% vs 47%±8%; P=.6), freedom from recurrent symptoms (59%±6% vs 60%±9%; P=.1), amputation-free survival (46%±5% vs 63%±7%; P=.06), and limb salvage at 3 years (63%±6% vs 74%±7%; P=.6) were similar. TA in patients with poor runoff has a positive effect on SFA anatomic outcomes. However, clinical success was not affected. Concomitant TA appears not to add clinical benefit to SFA intervention in critical limb ischemia. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine.

PubMed

Steensrud, Tor; Li, Jing; Dai, Xiaojing; Manlhiot, Cedric; Kharbanda, Rajesh K; Tropak, Michael; Redington, Andrew

2010-11-01

We have previously shown that remote ischemic preconditioning (rIPC) by transient limb ischemia leads to the release of a circulating factor(s) that induces potent myocardial protection. Intra-arterial injection of adenosine into a limb also leads to cardioprotection, but the mechanism of its signal transduction is poorly understood. Eleven groups of rabbits received saline control or rIPC or adenosine administration with additional pretreatment with the nitric oxide (NO) synthase blocker N(G)-nitro-l-arginine methyl ester, the NO donor S-nitroso-N-acetylpenicillamine, its non-NO-donating derivative N-acetylpenicillamine, or femoral nerve section. Blood was then drawn from each animal, and the dialysate of the plasma was used to perfuse a naïve heart from an untreated donor. Infarct size was measured after 30 min of global ischemia and 120 min reperfusion. When compared with that of the control, mean infarct size was significantly smaller in groups treated with rIPC alone (P < 0.01) and intra-arterial adenosine (P < 0.01). Pretreatment with N(G)-nitro-l-arginine methyl ester or N-acetylpenicillamine did not affect the level of protection induced by rIPC (P = not significant, compared with rIPC alone) or intra-arterial adenosine (P = not significant, compared with intra-arterial adenosine alone), but prior femoral nerve transection or pretreatment with S-nitroso-N-acetylpenicillamine abolished the cardioprotective effect of intra-arterial adenosine and rIPC. Intra-arterial adenosine, like rIPC, releases a blood-borne cardioprotective factor(s) that is dependent on an intact femoral nerve and is inhibited by pretreatment with a NO donor. These results may be important when designing or assessing the results of clinical trials of adenosine or rIPC cardioprotection, where NO donors are used as part of therapy.

How critical is chronic critical leg ischaemia?

PubMed

Kroese, A J; Stranden, E

1998-01-01

"Critical" according to the Oxford dictionary means: a "turning point" where an acute change for better or worse may be anticipated. Thus, the meaning of the word "critical" complies with its use in relation to ischaemia. We don't really know, prospectively, what will happen to the critically ischaemic limb, whether it will improve or worsen. The answer to the question "How critical is critical leg ischaemia (CLI)?" must be: "We don't know!" The addition of ankle systolic pressure as an objective haemodynamic measurement has not made the definition of the Second European Consensus Group significantly better than the original Fontaine classification, grade III and IV. For clinical practice the Fontaine classification will be sufficient. For scientific purposes macro- and microcirculatory assessments and information about the patient's risk profile should be added.

Multiparametric evaluation of hindlimb ischemia using time-series indocyanine green fluorescence imaging.

PubMed

Guang, Huizhi; Cai, Chuangjian; Zuo, Simin; Cai, Wenjuan; Zhang, Jiulou; Luo, Jianwen

2017-03-01

Peripheral arterial disease (PAD) can further cause lower limb ischemia. Quantitative evaluation of the vascular perfusion in the ischemic limb contributes to diagnosis of PAD and preclinical development of new drug. In vivo time-series indocyanine green (ICG) fluorescence imaging can noninvasively monitor blood flow and has a deep tissue penetration. The perfusion rate estimated from the time-series ICG images is not enough for the evaluation of hindlimb ischemia. The information relevant to the vascular density is also important, because angiogenesis is an essential mechanism for post-ischemic recovery. In this paper, a multiparametric evaluation method is proposed for simultaneous estimation of multiple vascular perfusion parameters, including not only the perfusion rate but also the vascular perfusion density and the time-varying ICG concentration in veins. The target method is based on a mathematical model of ICG pharmacokinetics in the mouse hindlimb. The regression analysis performed on the time-series ICG images obtained from a dynamic reflectance fluorescence imaging system. The results demonstrate that the estimated multiple parameters are effective to quantitatively evaluate the vascular perfusion and distinguish hypo-perfused tissues from well-perfused tissues in the mouse hindlimb. The proposed multiparametric evaluation method could be useful for PAD diagnosis. The estimated perfusion rate and vascular perfusion density maps (left) and the time-varying ICG concentration in veins of the ankle region (right) of the normal and ischemic hindlimbs. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hypothenar hammer syndrome: a case and brief review.

PubMed

Swanson, Keith E; Bartholomew, John R; Paulson, Rolf

2012-04-01

Hypothenar hammer syndrome is an uncommon cause of upper-extremity ischemia that is often overlooked in the absence of a thorough occupational and recreational history. Importantly, it is a reversible cause of hand ischemia that, if missed, can lead to significant morbidity and even amputation. The occupational ramifications and quality of life of those affected can be significant. Its relative rarity, set against the ubiquitous use of the hand as a 'hammer' is noteworthy. Several other causes of hand ischemia can present similarly; therefore, consideration of other etiologies must be thoroughly investigated. Key distinguishing clinical features, in addition to a detailed occupational and recreational history, may include characteristic sparing of the thumb, the absence of a hyperemic phase in 'Raynaud's phenomenon', and a positive Allen's sign. Both non-invasive and invasive diagnostic studies, including bilateral upper-limb segmental pulse volume recordings (PVR), arterial duplex examination, and upper-extremity angiography, are complementary to a thorough history and physical examination. Optimal management strategies are not well defined because of its rarity and resultant lack of quality, evidence-based data. Though most cases can be successfully managed non-operatively, micrographic arterial reconstruction may be limb saving in severe or recalcitrant cases. Newer, experimental strategies including selective sympathetic blockage using botulinum toxin A have been reported in a few recalcitrant cases. The brief case description illustrates the typical presentation and potential treatment strategies employed in a difficult case. A review of relevant literature is also presented.

Endothelial miR-17∼92 cluster negatively regulates arteriogenesis via miRNA-19 repression of WNT signaling.

PubMed

Landskroner-Eiger, Shira; Qiu, Cong; Perrotta, Paola; Siragusa, Mauro; Lee, Monica Y; Ulrich, Victoria; Luciano, Amelia K; Zhuang, Zhen W; Corti, Federico; Simons, Michael; Montgomery, Rusty L; Wu, Dianqing; Yu, Jun; Sessa, William C

2015-10-13

The contribution of endothelial-derived miR-17∼92 to ischemia-induced arteriogenesis has not been investigated in an in vivo model. In the present study, we demonstrate a critical role for the endothelial-derived miR-17∼92 cluster in shaping physiological and ischemia-triggered arteriogenesis. Endothelial-specific deletion of miR-17∼92 results in an increase in collateral density limbs and hearts and in ischemic limbs compared with control mice, and consequently improves blood flow recovery. Individual cluster components positively or negatively regulate endothelial cell (EC) functions in vitro, and, remarkably, ECs lacking the cluster spontaneously form cords in a manner rescued by miR-17a, -18a, and -19a. Using both in vitro and in vivo analyses, we identified FZD4 and LRP6 as targets of miR-19a/b. Both of these targets were up-regulated in 17∼92 KO ECs compared with control ECs, and both were shown to be targeted by miR-19 using luciferase assays. We demonstrate that miR-19a negatively regulates FZD4, its coreceptor LRP6, and WNT signaling, and that antagonism of miR-19a/b in aged mice improves blood flow recovery after ischemia and reduces repression of these targets. Collectively, these data provide insights into miRNA regulation of arterialization and highlight the importance of vascular WNT signaling in maintaining arterial blood flow.

Physiological and Therapeutic Vascular Remodeling Mediated by Hypoxia-Inducible Factor 1

NASA Astrophysics Data System (ADS)

Sarkar, Kakali; Semenza, Gregg L.

Angiogenesis along with arteriogenesis and vasculogenesis is a fundamental process in ischemic repair in adult animals including humans. Hypoxia-inducible factor 1 (HIF-1) plays a central role in mediating adaptive responses to hypoxia/ischemia by expressing angiogenic cytokines/growth factors and their cognate receptors. Angiogenic growth factors are the homing signal for circulating angiogenic cells (CACs), which are mobilized to peripheral blood from bone marrow, recruited to target tissues, and promote vascularization. Impairment of HIF-1-mediated gene transcription contributes to the impaired vascular responses in peripheral vascular disease that are associated with aging and diabetes. Promoting neovascularization in ischemic tissues is a promising strategy for the treatment of peripheral vascular disease when surgical or catheter-based revascularization is not possible. Intramuscular injection of an adenovirus encoding a constitutively active form of HIF-1α (AdCA5), into the ischemic limb of diabetic mice increases the recovery of limb perfusion and function, rescues the diabetes-associated impairment of CACs, and increases vascularization. Administration of AdCA5 overcomes the effect of aging on recovery of blood flow in middle-aged mice following femoral artery ligation in a mouse model of age-dependent critical limb ischemia. Intramuscular injection of AdCA5 along with intravenous injection of bone-marrow-derived angiogenic cells cultured in the presence of prolyl-4-hydroxylase inhibitor dimethyloxalylglycine, increases blood flow and limb salvage in old mice following femoral artery ligation. HIF-1α gene therapy increases homing of bone-marrow-derived cells, whereas induction of HIF-1 in these cells increases their retention in the ischemic tissue by increasing their adhesion to endothelium leading to synergistic effects of combined therapy on improving blood flow.

Results of Infrageniculate Bypasses Using the Profunda Femoris Artery as Inflow Source.

PubMed

Illuminati, Giulio; Calio', Francesco G; Pizzardi, Giulia; Pasqua, Rocco; Masci, Federica; Frezzotti, Francesca; Palumbo, Piergaspare; Vietri, Francesco

2018-02-01

When the common femoral artery is not accessible for infrainguinal bypass grafting, the profunda femoris artery (PFA) can be a valuable alternative inflow source for distal arterial revascularization. The purpose of this retrospective study was to evaluate the results of infrageniculate bypass grafting via the PFA as inflow source for critical limb ischemia. Between 1994 and 2016, 68 patients, 51 men of a mean age of 74 years, underwent an infrageniculate arterial bypass grafting for critical limb ischemia, using the PFA as inflow site. PFA was exposed at the Scarpa's triangle in 38 patients (56%) and at its medio-crural segment in 30 patients (44%). The distal anastomosis was performed on the infragenicular popliteal artery in 33 patients (48%), the peroneal artery in 14 patients (20%), the tibioperoneal trunk in 8 patients (12%), the posterior tibial artery in 8 patients (12%), and the dorsalis pedis artery in 5 patients (8%). The graft material consisted of a reversed great saphenous vein (GSV) in 62 patients (91%) and a 6-mm polytetrafluoroethylene graft in 6 patients (9%). The median duration of follow-up was 51 months (range, 6-72 months). As main results, postoperative mortality and morbidity, overall late patients' survival, primary grafts' patency, and limb salvage rate were considered. Operative mortality and morbidity were 3% and 4%, respectively. Overall patients' survival, primary patency and limb salvage rate, at 36 and 60 months were, respectively, 62% and 53%, 66% and 59%, and 92% and 77%. The PFA, both exposed at the Scarpa's triangle and at mid-thigh, is an excellent inflow source for infrageniculate revascularizations. It should remain an important part of the technical armamentarium of vascular surgeons, even in the endovascular era. Copyright © 2017 Elsevier Inc. All rights reserved.

Alternative Techniques for Treatment of Complex Below-the Knee Arterial Occlusions in Diabetic Patients With Critical Limb Ischemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gandini, Roberto; Uccioli, Luigi; Spinelli, Alessio

The purpose of this study was to describe alternative endovascular (EV) techniques and assess their feasibility and efficacy in minimizing failure rates in limb salvage for the treatment of complex below-the knee (BTK) occlusions that could not be crossed with a conventional antegrade access. Between December 2007 and November 2010, 1,035 patients (557 male) underwent EV treatment for critical limb ischemia in our institution. In 124 (12% [83 male], mean age 68.2 {+-} 0.5 years) patients, transfemoral antegrade revascularization attempt failed, and an alternative approach was used. Follow-up was performed at 1 and 6 months. Results were compared with 56more » patients treated between November 2002 and November 2007, in whom conventional technique was unsuccessful and unconventional techniques were not adopted. Technical success was achieved in 119 (96%) patients. The limb-salvage rates were 96.8% and 83% at 1- and 6-month follow-up, respectively. Sixteen (12.9%) and 33 (26.6%) patients underwent reintervention at 1- and 6-month follow-up, respectively. Transcutaneous oxygen tension increased at 1 month (44.7 {+-} 1.1 vs. 15.7 {+-} 0.8 mmHg; p < 0.001) and remained stable at follow-up. Twenty (16.1%) patients required major amputation. Thirteen (10.4%) patients died during follow-up. In our previous experience, percutaneous transluminal angioplasty failure, amputation, and death rates were 10.9, 39.2, and 23.2%, respectively. Alternative techniques allowed a significant decrease of major amputation and death rates (p = 0.0001 and p = 0.02, respectively). The use of alternative techniques seems feasible in case of a failed antegrade BTK revascularization attempt and could minimize failure rates in the treatment of complex occlusions while providing satisfying clinical success rates at 6 months.« less

A Comparison of the Regional Circulation in the Feet between Dialysis and Non-Dialysis Patients using Indocyanine Green Angiography.

PubMed

Nishizawa, M; Igari, K; Kudo, T; Toyofuku, T; Inoue, Y; Uetake, H

2017-09-01

Peripheral artery disease in dialysis cases is more prone to critical limb ischemia compared to non-dialysis cases, with a significantly high rate of major amputation of the lower limbs. Lesions are distributed on the more distal side in dialysis critical limb ischemia cases. The aim of this study was to investigate the usefulness of indocyanine green angiography to determine differences in the regional circulation in the foot between dialysis and non-dialysis patients. The subjects included 62 cases, among which 20 were dialysis patients and 42 were non-dialysis patients. We compared the indocyanine green angiography parameters for regions of interest in the dialysis and non-dialysis groups, which included the magnitude of intensity from indocyanine green onset to maximum intensity (Imax), the time from indocyanine green onset to maximum intensity (Tmax), the time elapsed from the fluorescence onset to half the maximum intensity (T1/2), and the time from maximum intensity to declining to 90% of the maximum intensity (Td90%). These indocyanine green angiography parameters were measured at region of interest 1 (the Chopart joint), region of interest 2 (the Lisfranc joint), and region of interest 3 (the distal region of the first metatarsal bone). In the comparison between the dialysis and non-dialysis groups, a significant difference was observed regarding Tmax, T1/2, and Td90%, especially in region of interest 3. In this study, we show that regional tissue perfusion is more deteriorated in dialysis patients compared with non-dialysis patients using indocyanine green angiography. Tmax, T1/2, and Td90% could be useful clinical parameters to compare ischemic severity of the lower limb between dialysis and non-dialysis patients.

78 FR 31625 - Bloggerwave, Inc., Cardima, Inc. (n/k/a CLI Liquidating Corporation), Innuity, Inc., Kaleidoscope...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-24

... SECURITIES AND EXCHANGE COMMISSION [File No. 500-1] Bloggerwave, Inc., Cardima, Inc. (n/k/a CLI... Marine, Inc., SBS Interactive Co., and VersaTech, Inc. (n/k/a VersaTech USA), Order of Suspension of.... (n/k/a CLI Liquidating Corporation) because it has not filed any periodic reports since the period...

Quantum circuits for qubit fusion

DOE PAGES

Moussa, Jonathan Edward

2015-12-01

In this article, we consider four-dimensional qudits as qubit pairs and their qudit Pauli operators as qubit Cli ord operators. This introduces a nesting, C 2 1 C C 4 2 C C 2 3, where C m n is the n th level of the m-dimensional qudit Cli ord hierarchy. If we can convert between logical qubits and qudits, then qudit Cli ord operators are qubit non-Cli ord operators. Conversion is achieved by qubit fusion and qudit fission using stabilizer circuits that consume a resource state. This resource is a fused qubit stabilizer state with a fault-tolerant state preparationmore » using stabilizer circuits.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moussa, Jonathan Edward

In this article, we consider four-dimensional qudits as qubit pairs and their qudit Pauli operators as qubit Cli ord operators. This introduces a nesting, C 2 1 C C 4 2 C C 2 3, where C m n is the n th level of the m-dimensional qudit Cli ord hierarchy. If we can convert between logical qubits and qudits, then qudit Cli ord operators are qubit non-Cli ord operators. Conversion is achieved by qubit fusion and qudit fission using stabilizer circuits that consume a resource state. This resource is a fused qubit stabilizer state with a fault-tolerant state preparationmore » using stabilizer circuits.« less

Stabilities and defect-mediated lithium-ion conduction in a ground state cubic Li 3 N structure

DOE PAGES

Nguyen, Manh Cuong; Hoang, Khang; Wang, Cai-Zhuang; ...

2016-01-07

A stable ground state structure with cubic symmetry of Li 3N (c-Li 3N) is found by ab initio initially symmetric random-generated crystal structure search method. Gibbs free energy, calculated within quasi-harmonic approximation, shows that c-Li 3N is the ground state structure for a wide range of temperature. The c-Li 3N structure has a negative thermal expansion coefficient at temperatures lower than room temperature, due mainly to two transverse acoustic phonon modes. This c-Li 3N phase is a semiconductor with an indirect band gap of 1.90 eV within hybrid density functional calculation. We also investigate the migration and energetics of nativemore » point defects in c-Li 3N, including lithium and nitrogen vacancies, interstitials, and anti-site defects. Lithium interstitials are found to have a very low migration barrier (~0.12 eV) and the lowest formation energy among all possible defects. Thus, the ionic conduction in c-Li 3N is expected to occur via an interstitial mechanism, in contrast to that in the well-known α-Li 3N phase which occurs via a vacancy mechanism.« less

PEGylated carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial.

PubMed

Misra, Hemant; Lickliter, Jason; Kazo, Friedericke; Abuchowski, Abraham

2014-08-01

PEGylated carboxyhemoglobin bovine (SANGUINATE) is a dual action carbon monoxide releasing (CO)/oxygen (O2 ) transfer agent for the treatment of hypoxia. Its components inhibit vasoconstriction, decrease extravasation, limit reactive oxygen species production, enhance blood rheology, and deliver oxygen to the tissues. Animal models of cerebral ischemia, peripheral ischemia, and myocardial ischemia demonstrated SANGUINATE's efficacy in reducing myocardial infarct size, limiting necrosis from cerebral ischemia, and promoting more rapid recovery from hind limb ischemia. In a Phase I trial, three cohorts of eight healthy volunteers received single ascending doses of 80, 120, or 160 mg/kg of SANGUINATE. Two volunteers within each cohort served as a saline control. There were no serious adverse events. Serum haptoglobin decreased, but did not appear to be dose related. The T1/2 was dose dependent and ranged from 7.9 to 13.8 h. In addition to the Phase I trial, SANGUINATE was used under an expanded access emergency Investigational New Drug. SANGUINATE was found to be safe and well tolerated in a Phase I clinical trial, and therefore it will advance into further clinical trials in patients. © 2014 The Authors. Artificial Organs published by Wiley Periodicals, Inc. on behalf of International Center for Artificial Organs and Transplantation (ICAOT).

Percutaneous implantation of a unibody endograft to treat non-aneurysmal aortoiliac disease.

PubMed

Cury, Marcus Vinícius Martins; Rodrigues, Thiago Osawa; Issa, Antônio Augusto Tadeu

2017-03-01

This case-series report describes the use of an Endologix AFX ® stent graft for the treatment of non-aneurysmal aortic disease. Over a period of 26 months, this device was successfully implanted in six patients with aortic bifurcation < 15 mm to treat critical limb ischemia secondary to dissection, ulcer, or coarctation.

Quality of life, binge eating and sexual function in participants treated for obesity with sustained release naltrexone/bupropion.

PubMed

Halseth, A; Shan, K; Gilder, K; Malone, M; Acevedo, L; Fujioka, K

2018-04-01

This multicenter, randomized, controlled, open-label trial examined weight-related quality of life, control over eating behaviour and sexual function after 26 weeks of treatment with either 32 mg naltrexone sustained release (SR)/360 mg bupropion SR plus a comprehensive lifestyle intervention program (NB + CLI, N = 153) or usual care (UC, N = 89), which included minimal lifestyle intervention. Impact of Weight on Quality of Life-Lite, Binge Eating Scale and Arizona Sexual Experiences Scale were assessed at baseline (BL) and weeks 16 and 26. NB + CLI and UC participants lost 9.46 and 0.94% respectively of initial body weight at week 26 (P < 0.0001). NB + CLI participants had greater improvements in Impact of Weight on Quality of Life-Lite total score than UC participants (P < 0.0001). In participants with moderate/severe Binge Eating Scale scores at BL, 91% of NB + CLI and 18% of UC participants experienced categorical improvements. In participants with Arizona Sexual Experiences Scale-defined sexual dysfunction at BL, 58% of NB + CLI and 19% of UC participants no longer met dysfunction criteria at week 26. The most frequent adverse events leading to discontinuation before week 26 in NB + CLI included nausea (10.5%); anxiety (3.3%); and headache, hypertension, insomnia and palpitations (1.3% each). Compared with UC, participants treated with NB + CLI experienced greater improvements in weight-related quality of life, control over eating behaviour, and sexual function.

Prevalence and individual risk factors associated with clinical lumbar instability in rice farmers with low back pain

PubMed Central

Puntumetakul, Rungthip; Yodchaisarn, Wantanee; Emasithi, Alongkot; Keawduangdee, Petcharat; Chatchawan, Uraiwan; Yamauchi, Junichiro

2015-01-01

Introduction Clinical lumbar instability (CLI) is one of the subgroups of chronic non-specific low back pain. Thai rice farmers often have poor sustained postures during a rice planting process and start their farming at an early age. However, individual associated factors of CLI are not known and have rarely been diagnosed in low back pain. This study aimed to determine the prevalence and individual associated factors of CLI in Thai rice farmers. Methods A cross-sectional survey was conducted among 323 Thai rice farmers in a rural area of Khon Kaen province, Thailand. Face-to-face interviews were conducted using the 13-item Delphi criteria questionnaire, after which an objective examination was performed using aberrant movement sign, painful catch sign, and prone instability test to obtain information. Individual factors such as sex, body mass index, waist-hip ratio, smoking, and number of years of farming experience, were recorded during the face-to-face interview. Results The prevalence of CLI in Thai rice farmers calculated by the method described in this study was 13% (age 44±10 years). Number of years of farming experience was found to be significantly correlated with the prevalence of CLI (adjusted odds ratio =2.02, 95% confidence interval =1.03–3.98, P<0.05). Conclusion This study provides prevalence of CLI in Thai rice farmers. Those with long-term farming experience of at least 30 years have a greater risk of CLI. PMID:25565778

Antibiofilm Activities of a Novel Chimeolysin against Streptococcus mutans under Physiological and Cariogenic Conditions

PubMed Central

Yang, Hang; Bi, Yongli; Shang, Xiaoran; Wang, Mengyue; Linden, Sara B.; Li, Yunpeng

2016-01-01

Streptococcus mutans often survives as a biofilm on the tooth surface and contributes to the development of dental caries. We investigated the efficacy of ClyR, an engineered chimeolysin, against S. mutans biofilms under physiological and cariogenic conditions. Susceptibility tests showed that ClyR was active against all clinical S. mutans isolates tested as well as S. mutans biofilms that displayed resistance to penicillin. The S. mutans biofilms that formed on hydroxyapatite discs under physiological sugar conditions and cariogenic conditions were reduced ∼2 logs and 3 logs after treatment with 100 μg/ml ClyR, respectively. In comparison, only a 1-log reduction was observed in the chlorhexidine gluconate (ChX)-treated group, and no killing effect was observed in the NaF-treated group. A mouse dental colonization model showed that repeated use of ClyR for 3 weeks (5 μg/day) reduced the number of colonized S. mutans cells in the dental plaques significantly (P < 0.05) and had no harmful effects on the mice. Furthermore, toxicity was not noted at concentrations exceeding those used for the in vitro and in vivo studies, and ClyR-specific antibodies could not be detected in mouse saliva after repeated use of ClyR in the oral cavity. Our data collectively demonstrate that ClyR is active against S. mutans biofilms both in vitro and in vivo, thus representing a preventative or therapeutic agent for use against dental caries. PMID:27736755

A pro-angiogenic degradable Mg-poly(lactic-co-glycolic acid) implant combined with rhbFGF in a rat limb ischemia model.

PubMed

Bao, Hanmei; Lv, Feng; Liu, Tianjun

2017-12-01

Site-specific controlled release of exogenous angiogenic growth factors, such as recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. Here, we have developed an implant composed of spiral magnesium (Mg) and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The encapsulated protein could release continually for 4weeks with well preserved bioactivity. We compared the angiogenic effect produced by Mg-PLGA-rhbFGF with that of a PLGA implant loaded with rhbFGF (PLGA-rhbFGF). The incorporation of Mg in the implant raised the microclimate pH in the polymer, which preserved the stability of rhbFGF. Mg-PLGA-rhbFGF exhibited advantages over PLGA-rhbFGF implant in terms of a cytocompatibility evaluation. An in vivo angiogenesis test further confirmed the efficacy of released rhbFGF. HE, CD31 and α-SMA staining revealed that the controlled release of rhbFGF from the Mg-PLGA-rhbFGF implant was superior in promoting angiogenesis compared with that of the PLGA-rhbFGF implant. Four weeks post-implantation, the capillary density of the Mg-PLGA-rhbFGF group was significantly higher than that of the PLGA-rhbFGF, control and the normal group (p<0.05, p<0.01 and p<0.01, respectively). Furthermore, the limb blood perfusion ratios of the Mg-PLGA-rhbFGF and PLGA-rhbFGF groups were dramatically increased, at 99.1±2.9% and 80.7±3.2%, respectively, whereas the ischemic limb did not recover in the control group. The biocompatibility of the implants was also evaluated. In conclusion, Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery. The results suggest potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia. Magnesium (Mg)-based implant has been already used in patients with critical limb ischemia. Site-specific controlled release of recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. We report here on a novel combination implant composed of spiral magnesium and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The preparation method does not involve any complex processes and results in a high encapsulation efficiency (approximately 100%). The degradation of metal Mg raise the microclimate pH in the PLGA polymer, which could well preserve the bioactivity of rhbFGF incorporated in the implant. Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery in rat limb ischemic model. This work marks the first report for controlled release of rhbFGF in combination with metal Mg, and suggests potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Impact of angiosome- and nonangiosome-targeted peroneal bypass on limb salvage and healing in patients with chronic limb-threatening ischemia.

PubMed

Ricco, Jean-Baptiste; Gargiulo, Mauro; Stella, Andrea; Abualhin, Mohammad; Gallitto, Enrico; Desvergnes, Mathieu; Belmonte, Romain; Schneider, Fabrice

2017-11-01

Direct (DIR) or indirect (IND) revascularization of pedal angiosomes in patients with chronic limb-threatening ischemia (CLTI) has an unclear impact on limb salvage and healing. The aim of this study was to evaluate the outcomes of DIR and IND revascularization in patients with a peroneal bypass and tissue loss. We conducted a retrospective study of a prospectively maintained database in two European university centers from 2004 to 2015. We extracted from this database all patients with CLTI and tissue loss who had received a bypass to the peroneal artery. All patients underwent angiography before bypass. Revascularization was considered DIR if the wound was in a peroneal angiosome. Wounds, ischemia, and infection were categorized according to the Wound, Ischemia, and foot Infection (WIfI) classification. Limb salvage and amputation-free survival were calculated using the Kaplan-Meier method. Cox regression was used to compare the role of patient characteristics, including diabetes, peroneal runoff, pedal arch angiosome, WIfI grade, chronic kidney disease, and diabetes, in amputation-free-survival. From January 2004 through October 2015, there were 120 peroneal bypasses performed in 120 patients with CLTI and foot tissue loss. Only 55 wounds (46%) could be ascribed to a peroneal angiosome. At 3 years, amputation-free survival in patients with DIR revascularization was 54.9% ± 7.3% compared with 56.5% ± 6.3% in patients with IND revascularization (P = .44), with no significant difference in wound healing. Amputation-free survival at 3 years in patients with two patent peroneal branches was 74.8% ± 6.9% compared with 45.0% ± 6.0% in patients with one patent peroneal branch (P = .003). Amputation-free survival at 3 years in patients with a patent pedal arch (Rutherford 0-1) was 73.0% ± 7.0% vs 45.7% ± 6.0% in patients with incomplete pedal arch (Rutherford 2-3; P = .0002). Amputation-free survival at 3 years in patients with grade 1 or grade 2 WIfI was 87.4% ± 8.3% compared with 48.4% ± 5.3% in patients with grade 3 or grade 4 WIfI (P = .001). Amputation-free survival at 3 years in patients with diabetes was 43.7% ± 6.2% compared with 73.1% ± 6.7% in patients without diabetes (P = .002). Wound healing at 6 months was not significantly improved by its location within or outside a peroneal angiosome. Cox regression analysis demonstrated that diabetes, patency of both peroneal branches, patency of pedal arch, and WIfI stage but not DIR angiosome revascularization were significant predictors of amputation-free survival. Our results suggest that in patients with CLTI and tissue loss receiving a peroneal bypass, patency of both peroneal branches and pedal arch was associated with a better healing rate and a better amputation-free survival rate irrespective of wound angiosome location. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Role of the plasma cascade systems in ischemia/reperfusion injury of bone.

PubMed

Zhang, Shengye; Wotzkow, Carlos; Bongoni, Anjan K; Shaw-Boden, Jane; Siegrist, Mark; Taddeo, Adriano; Blank, Fabian; Hofstetter, Willy; Rieben, Robert

2017-04-01

Ischemia/reperfusion (I/R) injury has been extensively studied in organs such as heart, brain, liver, kidney, and lung. As a vascularized organ, bone is known to be susceptible to I/R injury too, but the respective mechanisms are not well understood to date. We therefore hypothesized that, similar to other organs, plasma cascade-induced inflammation also plays a role in bone I/R injury. Reperfusion injury in rat tibia was induced by unilateral clamping of the femoral artery and additional use of a tourniquet, while keeping the femoral vein patent to prevent venous congestion. Rats were subjected to 4h ischemia and 24h reperfusion. Deposition of complement fragment C3b/c and fibrin as well as expression of tissue factor (TF), tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and E-selectin was detected by immunohistochemistry. In plasma, the levels of high mobility group box1 (HMGB1) were measured by ELISA. The total level of complement in serum was assessed by the CH50 test. Our results show that deposition of C3b/c was significantly increased with respect to healthy controls in cortical bone as well as in marrow of reperfused limbs. C3b/c deposition was also increased in cortical bone, but not in bone marrow, of contralateral limbs. Deposition of fibrin, as well as expression of PAI-1, was significantly increased in bone after ischemia and reperfusion, whereas expression of tPA was reduced. These differences were most prominent in vessels of bone, both in marrow and cortical bone, and both in reperfused and contralateral limbs. However, PAI-1, was only increased in vessels of reperfused cortical bone and there were no significant changes in expression of E-selectin. With respect to solid bone tissue, a significant increase of C3b/c and fibrin deposition was shown in osteocytes, and for fibrin also in the bone matrix, in both contralateral and reperfused cortical bone compared with normal healthy controls. A slight expression of TF was visible in osteocytes of the normal healthy control group, while TF was not present in the experimental groups. Moreover, CH50 values in serum decreased over time and HMGB1 was significantly increased in plasma of animals at the end of reperfusion. We conclude that ischemia and reperfusion of bone leads to activation of the complement and coagulation systems and a downregulation of the fibrinolytic cascade. In the acute phase, a vascular inflammation induced by activation of the plasma cascade systems also occurs in the bone. This is similar to I/R injury of other vascularized organs and tissues. Copyright © 2017 Elsevier Inc. All rights reserved.

Creating a Library of Climate Change Education Resources for Audiences in the Southeast United States

NASA Astrophysics Data System (ADS)

Carroll, J.; McNeal, K. S.; Williams, C. C.; Paz, J. O.; Cho, H. "; Nair, U. S.; Geroux, J.; Guthrie, C.; Wright, K.; Hill, J.

2011-12-01

The Climate Literacy Partnership in the Southeast (CLiPSE) is a part of the Climate Change Education Program supported by the National Science Foundation (http://CLiPSE-project.org). The established CLiPSE partnership is dedicated to improving climate literacy in the southeast and promoting scientifically accurate, formal educational resources for the K-12 classroom audience, as well as informal educational resources for audiences such as agriculture, education, leisure, and religious organizations, to name a few. The CLiPSE project has been successful in creating partnerships with the National Geographic Alliances, Departments of Education, and Mississippi Environmental Education Alliance, among others, to determine an effective strategic plan for reaching K-12 audiences. One goal in the strategic plan is to create a catalog of climate change education resources that are aligned to state standards in the SE. Eighty-seven resources from the Climate Literacy and Energy Awareness Network (http://cleanet.org) have been aligned with the state education standards for grades six through twelve in the southeast, beginning with science in Mississippi and expanding to include science and math in the remaining SE states. The criteria for aligning the existing resources includes: matching key terms, topics, and lesson activities with the content strands and essential skills included in the state science framework. By developing a searchable database containing climate resources already aligned with state standards, CLiPSE will have made these resources more appealing to educators in the SE, increasing the likelihood of resources being implemented in the classroom. The CLiPSE Climate Science Team has also created an inventory of scientifically sound, informal resources, which will be available for dispersion to appropriate audiences and communities. Cataloged resources, both formal and informal, grouped by a variety of means, to include audience, grade level, and resource origin (e.g. government agency, organization, museum, climate-related websites, etc.), will be made available to the public through the CLiPSE website, promoting accessibility of these resources to the various CLiPSE publics. The process of alignment and vetting will be discussed in this paper, along with the information and education "gaps" that exist for the specific CLiPSE audiences in the SE US.

Predictive ability of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system after first-time lower extremity revascularizations.

PubMed

Darling, Jeremy D; McCallum, John C; Soden, Peter A; Guzman, Raul J; Wyers, Mark C; Hamdan, Allen D; Verhagen, Hence J; Schermerhorn, Marc L

2017-03-01

The Society for Vascular Surgery (SVS) Wound, Ischemia and foot Infection (WIfI) classification system was proposed to predict 1-year amputation risk and potential benefit from revascularization. Our goal was to evaluate the predictive ability of this scale in a real-world selection of patients undergoing a first-time lower extremity revascularization for chronic limb-threatening ischemia (CLTI). From 2005 to 2014, 1336 limbs underwent a first-time lower extremity revascularization for CLTI, of which 992 had sufficient data to classify all three WIfI components (wound, ischemia, and foot infection). Limbs were stratified into the SVS WIfI clinical stages (from 1 to 4) for 1-year amputation risk estimation, a novel WIfI composite score from 0 to 9 (that weighs all WIfI variables equally), and a novel WIfI mean score from 0 to 3 (that can incorporate limbs missing any of the three WIfI components). Outcomes included major amputation; revascularization, major amputation, or stenosis (>3.5× step-up by duplex; RAS) events; and death. Predictors were identified using Cox regression models and Kaplan-Meier survival estimates. Of the 1336 first-time procedures performed, 992 limbs were classified in all three WIfI components (524 endovascular and 468 bypass; 26% rest pain and 74% tissue loss). Cox regression demonstrated that a one-unit increase in the WIfI clinical stage increases the risk of major amputation (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.7-3.2) and RAS events in all limbs (HR, 1.2; 95% CI, 1.1-1.3). Separate models of the entire cohort, a bypass-only cohort, and an endovascular-only cohort showed that a one-unit increase in the WIfI mean score is associated with an increase in the risk of major amputation (all three cohorts: HR, 5.3 [95% CI, 3.6-6.8], 4.1 [2.4-6.9], and 6.6 [3.8-11.6], respectively) and RAS events (all three cohorts: HR, 1.7 [95% CI, 1.4-2.0], 1.9 [1.4-2.6], and 1.4 [1.1-1.9], respectively). The novel WIfI composite and WIfI mean scores were the only consistent predictors of death among the three cohorts, with the WIfI mean score proving most strongly predictive in the entire cohort (HR, 1.4; 95% CI, 1.1-1.7), the bypass-only cohort (HR, 1.5; 95% CI, 1.1-1.9), and the endovascular-only cohort (HR, 1.4; 95% CI, 1.0-1.8). Although the individual WIfI wound component was able to predict mortality among all patients (HR, 1.1; 95% CI, 1.0-1.2) and bypass-only patients (HR, 1.2; 95% CI, 1.1-1.3), neither the additional individual WIfI components nor the WIfI clinical stage were able to significantly predict mortality among any cohort. This study supports the ability of the SVS WIfI classification system to predict major amputation; however, the novel WIfI mean and WIfI composite scores predict amputation, RAS events, and mortality more consistently than any other current WIfI scoring system. The WIfI mean score allows inclusion of all limbs, and both novel scoring systems are easier to conceptualize, give equal weight to each WIfI component, and may provide clinicians more effective comparisons in outcomes between patients. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Endovascular Management of Infected Femoral Artery Pseudoaneurysms in High-Risk Patients: A Case Series

DOE Office of Scientific and Technical Information (OSTI.GOV)

D’Oria, Mario, E-mail: mario.doria88@outlook.com; Sgorlon, Giada; Calvagna, Cristiano

We report our experience with the urgent treatment of two high-risk patients with infected femoral artery pseudoaneurysms (IFAPs) with the placement of a self-expandable covered stent (SECS). In both cases, there was no perioperative mortality and the aneurysm exclusion was successful without early or late stent thrombosis/stent fracture nor acute or chronic limb ischemia or limb loss. There was no recurrence of local or systemic infection during the follow-up period. Endovascular therapy represents a feasible treatment option for IFAPs in those patients for whom the risk of open surgical repair would be prohibitive, especially under urgent circumstances.

Eversion endarterectomy of the proximal superficial femoral artery: a source of inflow for distal bypass in case of hostile groin.

PubMed

Cavallaro, Antonio; Sterpetti, Antonio V; Dimarzo, Luca

2012-08-01

In selected patients, eversion endarterectomy of the proximal superficial femoral artery can represent a valid inflow for a distal bypass to avoid a "hostile" groin. Patency rates and limb salvage rates were retrospectively analysed for 21 consecutive patients who underwent distal bypass for severe lower limb ischemia and in whom the proximal superficial femoral artery was reopened with an eversion endarterectomy. In all patients, this technique was used to avoid a hostile groin. Five-year cumulative patency rates were 53% for femoropopliteal bypasses and 40% for femorotibial bypasses. Overall 5-y cumulative limb salvage was 72%. In case of hostile groin, eversion endarterectomy of the proximal superficial femoral artery is a valid solution to provide inflow for a distal bypass. Copyright © 2012 Elsevier Inc. All rights reserved.

Longitudinal study of arteriogenesis with swept source optical coherence tomography and hyperspectral imaging

NASA Astrophysics Data System (ADS)

Poole, Kristin M.; Patil, Chetan A.; Nelson, Christopher E.; McCormack, Devin R.; Madonna, Megan C.; Duvall, Craig L.; Skala, Melissa C.

2014-03-01

Peripheral arterial disease (PAD) is an atherosclerotic disease of the extremities that leads to high rates of myocardial infarction and stroke, increased mortality, and reduced quality of life. PAD is especially prevalent in diabetic patients, and is commonly modeled by hind limb ischemia in mice to study collateral vessel development and test novel therapies. Current techniques used to assess recovery cannot obtain quantitative, physiological data non-invasively. Here, we have applied hyperspectral imaging and swept source optical coherence tomography (OCT) to study longitudinal changes in blood oxygenation and vascular morphology, respectively, intravitally in the diabetic mouse hind limb ischemia model. Additionally, recommended ranges for controlling physiological variability in blood oxygenation with respect to respiration rate and body core temperature were determined from a control animal experiment. In the longitudinal study with diabetic mice, hyperspectral imaging data revealed the dynamics of blood oxygenation recovery distally in the ischemic footpad. In diabetic mice, there is an early increase in oxygenation that is not sustained in the long term. Quantitative analysis of vascular morphology obtained from Hessian-filtered speckle variance OCT volumes revealed temporal dynamics in vascular density, total vessel length, and vessel diameter distribution in the adductor muscle of the ischemic limb. The combination of hyperspectral imaging and speckle variance OCT enabled acquisition of novel functional and morphological endpoints from individual animals, and provides a more robust platform for future preclinical evaluations of novel therapies for PAD.

Polysaccharides and Oligosaccharides Produced on Malvar Wines Elaborated with Torulaspora delbrueckii CLI 918 and Saccharomyces cerevisiae CLI 889 Native Yeasts from D.O. "Vinos de Madrid".

PubMed

García, Margarita; Apolinar-Valiente, Rafael; Williams, Pascale; Esteve-Zarzoso, Braulio; Arroyo, Teresa; Crespo, Julia; Doco, Thierry

2017-08-09

Polysaccharides and oligosaccharides released into Malvar white wines elaborated through pure, mixed, and sequential cultures with Torulaspora delbrueckii CLI 918 and Saccharomyces cerevisiae CLI 889 native yeasts from D.O. "Vinos de Madrid" were studied. Both fractions from different white wines were separated by high-resolution size-exclusion chromatography. Glycosyl composition and wine polysaccharide linkages were determined by GC-EI-MS chromatography. Molar-mass distributions were determined by SEC-MALLS, and intrinsic viscosity was determined by differential viscometer. Yeast species and type of inoculation have a significant impact on wine carbohydrate composition and structure. Mannose residues from mannoproteins were significantly predominant in those cultures where T. delbrueckii was present in the fermentation process in comparison with when pure cultures of S. cerevisiae were present in the fermenation process. Galactose residues from polysaccharides rich in arabinose and galactose presented greater values in pure cultures of S. cerevisiae, indicating that S. cerevisiae released fewer mannoproteins than T. delbrueckii. Moreover, we reported structural differences between mannoproteins released by T. delbrueckii CLI 918 and those released by S. cerevisiae CLI 889. These findings help to provide important information about the polysaccharides and oligosaccharides released from the cell walls of Malvar grapes and the carbohydrates released from each yeast species.

Pressure chamber tests of eustachian tube function document lower efficiency in adults with colds when compared to without colds.

PubMed

Doyle, William J; Singla, Alok; Banks, Juliane; El-Wagaa, Jenna; Swarts, J Douglas

2014-07-01

Fractional gradient equilibrated (FGE) for ears with applied positive but not negative middle ear (ME)-ambient pressure gradients is highly sensitive to a cold-like illness (CLI). The sequential development of eustachian tube (ET) dysfunction, ME under-pressure, and otitis media (OM) characterizes many children during a CLI. If linked, OM burden would be lessened by interventions that promote/preserve good ET function during a CLI. Evaluating this requires a quantitative ET function test for MEs with an intact tympanic membrane responsive to a CLI. Pressure chamber testing of ET function was performed at +200 and -200 daPa in 3 groups of adults: group I, 21 subjects with an extant CLI and groups II and III, 14 and 57 adults, respectively, without a CLI. ME-chamber pressure gradient was recorded by tympanometry before and after the subject swallowed twice. ET functional efficiency was quantified as the FGE, which was then compared among groups using a Mann-Whitney U test. At chamber pressures of 200 daPa, the ME-chamber pressure gradient was negative, and FGE was low and not different among groups. At chamber pressures of -200 daPa that gradient was positive, and FGE was significantly higher in groups II and III when compared with group I.

Antibiofilm Activities of a Novel Chimeolysin against Streptococcus mutans under Physiological and Cariogenic Conditions.

PubMed

Yang, Hang; Bi, Yongli; Shang, Xiaoran; Wang, Mengyue; Linden, Sara B; Li, Yunpeng; Li, Yuhong; Nelson, Daniel C; Wei, Hongping

2016-12-01

Streptococcus mutans often survives as a biofilm on the tooth surface and contributes to the development of dental caries. We investigated the efficacy of ClyR, an engineered chimeolysin, against S. mutans biofilms under physiological and cariogenic conditions. Susceptibility tests showed that ClyR was active against all clinical S. mutans isolates tested as well as S. mutans biofilms that displayed resistance to penicillin. The S. mutans biofilms that formed on hydroxyapatite discs under physiological sugar conditions and cariogenic conditions were reduced ∼2 logs and 3 logs after treatment with 100 μg/ml ClyR, respectively. In comparison, only a 1-log reduction was observed in the chlorhexidine gluconate (ChX)-treated group, and no killing effect was observed in the NaF-treated group. A mouse dental colonization model showed that repeated use of ClyR for 3 weeks (5 μg/day) reduced the number of colonized S. mutans cells in the dental plaques significantly (P < 0.05) and had no harmful effects on the mice. Furthermore, toxicity was not noted at concentrations exceeding those used for the in vitro and in vivo studies, and ClyR-specific antibodies could not be detected in mouse saliva after repeated use of ClyR in the oral cavity. Our data collectively demonstrate that ClyR is active against S. mutans biofilms both in vitro and in vivo, thus representing a preventative or therapeutic agent for use against dental caries. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Experimental results of mesh fixation by a manual manipulator in a laparoscopic inguinal hernia repair model.

PubMed

Inaki, N; Waseda, M; Schurr, M O; Braun, M; Buess, G F

2007-02-01

Laparoscopic mesh fixation using a stapler can lead to complications such as nerve injury and bowel injury. However, mesh fixation by suturing with conventional laparoscopic instruments (CLI) is difficult because of limited degrees of freedom. A manual manipulator--Radius Surgical System (Radius)--whose tip can deflect and rotate, gives the surgeon two additional degrees of freedom. The aim of this study is to evaluate the introduction of Radius to mesh fixation in laparoscopic inguinal hernia repair. A model for inguinal hernia repair was prepared using animal organs in a trainer. Mesh fixation was performed using Radius, stapler, and CLI. Tensile strength during extraction of mesh toward the vertical direction, and execution time, were measured. The mean number of fixation points of Radius, stapler, and CLI was 9.3 +/- 1.5, 8.5 +/- 1.4, and 9.0 +/- 1.0, respectively. The mean tensile strength of fixation of mesh of Radius, stapler, and CLI was 140.7 +/- 48.9, 73.1 +/- 23.4, and 53.6 +/- 31.5 (N), respectively. The mean tensile strength per one fixation point by Radius, stapler, and CLI was 16.5 +/- 5.3, 8.7 +/- 2.8, and 6.3 +/- 3.6 (N), respectively. The mean execution time of Radius, stapler, and CLI was 479 +/- 108, 54 +/- 31, and 431 +/- 77 (sec), respectively. The mesh fixation by Radius was stronger than that by staples and CLI. Two additional degrees of freedom were useful in difficult angles. The introduction of Radius is feasible and facilitates the fixation of mesh with sutures in laparoscopic inguinal hernia repair.

Quality of life, binge eating and sexual function in participants treated for obesity with sustained release naltrexone/bupropion

PubMed Central

Shan, K.; Gilder, K.; Malone, M.; Acevedo, L.; Fujioka, K.

2018-01-01

Summary Objective This multicenter, randomized, controlled, open‐label trial examined weight‐related quality of life, control over eating behaviour and sexual function after 26 weeks of treatment with either 32 mg naltrexone sustained release (SR)/360 mg bupropion SR plus a comprehensive lifestyle intervention program (NB + CLI, N = 153) or usual care (UC, N = 89), which included minimal lifestyle intervention. Methods Impact of Weight on Quality of Life‐Lite, Binge Eating Scale and Arizona Sexual Experiences Scale were assessed at baseline (BL) and weeks 16 and 26. Results NB + CLI and UC participants lost 9.46 and 0.94% respectively of initial body weight at week 26 (P < 0.0001). NB + CLI participants had greater improvements in Impact of Weight on Quality of Life‐Lite total score than UC participants (P < 0.0001). In participants with moderate/severe Binge Eating Scale scores at BL, 91% of NB + CLI and 18% of UC participants experienced categorical improvements. In participants with Arizona Sexual Experiences Scale‐defined sexual dysfunction at BL, 58% of NB + CLI and 19% of UC participants no longer met dysfunction criteria at week 26. The most frequent adverse events leading to discontinuation before week 26 in NB + CLI included nausea (10.5%); anxiety (3.3%); and headache, hypertension, insomnia and palpitations (1.3% each). Conclusion Compared with UC, participants treated with NB + CLI experienced greater improvements in weight‐related quality of life, control over eating behaviour, and sexual function. PMID:29670752

Severe pain as a possible cause of dropped head syndrome that was attenuated after amputation of an ischemic lower limb.

PubMed

Maki, Satoshi; Koda, Masao; Furuya, Takeo; Takahashi, Kazuhisa; Yamazaki, Masashi

2016-03-02

Dropped head syndrome (DHS) is defined as weakness of the neck extensor muscles causing a correctable chin-on-the-chest deformity. Here we report the case of a patient with severe pain from lower leg ischemia showing DHS whose symptoms were attenuated by pain relief after amputation of the severely ischemic lower leg. To our knowledge this is the first report indicating that severe pain can cause DHS. A 64-year-old Asian woman was referred to our department with a 1-month history of DHS. She also suffered from severe right foot pain because of limb ischemia. She began to complain of DHS as her gangrenous foot pain worsened. She had neck pain and difficulty with forward gaze. We found no clinical or laboratory findings of neuromuscular disorder or isolated neck extensor myopathy. We amputated her leg below the knee because of progressive foot gangrene. Her severe foot pain resolved after the surgery and her DHS was attenuated. Severe pain can cause DHS. If a patient with DHS has severe pain in another part of the body, we recommend considering aggressive pain relief as a treatment option.

An en bloc approach to CT perfusion for the evaluation of limb ischemia.

PubMed

Barfett, Joe; Velauthapillai, Nivethan; Kloeters, Christian; Mikulis, David J; Jaskolka, Jeffrey D

2012-12-01

We examine volumetric CT perfusion in soft tissues of the entire foot with an en bloc technique to provide a meaningful measure of differentiation between mild and major vascular impairment. With Institutional Review Board approval, 22 healthy male subjects between the ages of 21 and 50 (mean 37) were enrolled. Volumetric computed tomography using an en bloc technique was conducted on 14 subjects for validation while unilateral vascular obstruction was simulated in the calves of the remaining 8 subjects. Perfusion estimates were made using in-house software and differences in perfusion estimates between feet were evaluated with Student's t-test at 95% confidence. Subjects with simulated major vascular obstruction (calf blood pressure cuff inflated to 200 mmHg) showed significantly higher ratios of perfusion estimates between the unobstructed and obstructed foot compared to subjects with simulated mild vascular obstruction (cuff inflated to 120 mmHg), mean 4.6, SD 2.6 vs. mean 1.3, SD 0.2; P = 0.05. CT perfusion using an en bloc technique shows promise for the future evaluation of patients with critical limb ischemia and particularly for re-characterization post medical, surgical or endovascular intervention.

Cathepsin L is required for endothelial progenitor cell-induced neovascularization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Urbich, Carmen; Heeschen, Christopher; Aicher, Alexandra

Infusion of endothelial progenitor cells (EPCs), but not of mature endothelial cells (ECs), promotes neovascularization after ischemia. We performed a gene expression profiling of EPCs and ECs to identify genes, which might be important for the neovascularization capacity of EPCs. Intriguingly, the protease cathepsin L (CathL) was highly expressed in EPCs as opposed to ECs and is essential for matrix degradation and invasion by EPCs in vitro. CathL deficient mice showed impaired functional recovery after hind limb ischemia supporting the concept for an important role of CathL in postnatal neovascularization. Infused CathL deficient progenitor cells failed to home to sitesmore » of ischemia and to augment neovascularization. In contrast, over expression of CathL in mature ECs significantly enhanced their invasive activity and induced their neovascularization capacity in vivo. Taken together, CathL plays a crucial role for the integration of circulating EPCs into the ischemic tissue and is required for neovascularization mediated by EPCs.« less

[Brain protection against cerebral ischemia].

PubMed

Kitagawa, Kazuo

2013-01-01

Previous clinical trials failed to show the benefit of several potentially protective drugs in acute ischemic stroke. However, there would be three main approaches for brain protection against stroke. The first is to develop a novel thrombolytic agent which is more efficient and safer than alteplase. Tenecteplase and desmoteplase are in progress as a new thrombolytic drug. The second strategy is to augment collateral circulation through leptomeningeal anastomosis. Administration of G-CSF could enhance arteriogenesis, but it takes several days to develop functional collateral. For this purpose, partial aortic balloon clumping or stimulation of pterygopalatine ganglion may be promising. The third one is to protect neurovascular unit against reperfusion injury. Brain hypothermia is the most effective strategy in experimental ischemia, and the clinical trial for hypothermia combined with thrombolysis therapy is in progress. Activation of endogenous protective response, as presented by ischemic tolerance, has focused on remote ischemic conditioning. Although the precise mechanisms of remote preconditioning remain unclear, intermittent limb ischemia is a safe approach. Remote ischemic conditioning is now investigated in acute patients with thrombolysis therapy.

Outcomes of tibial endovascular intervention in patients with poor pedal runoff.

PubMed

Baer-Bositis, Hallie E; Hicks, Taylor D; Haidar, Georges M; Sideman, Matthew J; Pounds, Lori L; Davies, Mark G

2018-06-01

Tibial interventions for critical limb ischemia are now commonplace. The aim of this study was to examine the impact of pedal runoff on patient-centered outcomes after tibial endovascular intervention. A database of patients undergoing lower extremity endovascular interventions at a single urban academic medical center between 2006 and 2016 was retrospectively queried. Patients with critical ischemia (Rutherford 5 and 6) were identified. Preintervention angiograms were reviewed in all cases to assess pedal runoff. Each dorsalis pedis, lateral plantar, and medial plantar artery was assigned a score according to the reporting standards of the Society for Vascular Surgery (0, no stenosis >20%; 1, 21%-49% stenosis; 2, 50%-99% stenosis; 2.5, half or less of the vessel length occluded; 3, more than half the vessel length occluded). A foot score (dorsalis pedis + medial plantar + lateral plantar + 1) was calculated for each foot (1-10). Two runoff score groups were identified: good vs poor, <7 and ≥7, respectively. Patient-oriented outcomes of clinical efficacy (absence of recurrent symptoms, maintenance of ambulation, and absence of major amputation), amputation-free survival (survival without major amputation), and freedom from major adverse limb events (above-ankle amputation of the index limb or major reintervention [new bypass graft, jump/interposition graft revision]) were evaluated. There were 1134 patients (56% male; average age, 59 years) who underwent tibial intervention for critical ischemia, with a mean of two vessels treated per patient and a mean pedal runoff score of 6 (47% had a runoff score ≥7). Overall major adverse cardiac events were equivalent at 30 days after the procedure in both groups. At 5 years, vessels with compromised runoff (score ≥7) had significantly lower ulcer healing (25% ± 3% vs 73% ± 4%, mean ± standard error of the mean [SEM]) and a lower 5-year limb salvage rate (45% ± 6% vs 69% ± 4%, mean ± SEM) compared with those with good runoff (score <7). Patients with poor pedal runoff (score ≥7) had significantly lower clinical efficacy (23% ± 8% vs 38% ± 4%, mean ± SEM), amputation-free survival (32% ± 6% vs 48% ± 5%, mean ± SEM), and freedom from major adverse limb events (23% ± 9% vs 41% ± 8%, mean ± SEM) at 5 years compared with patients with good runoff (score <7). Pedal runoff score can identify those patients who will not achieve ulcer healing and patient-centered outcomes after tibial intervention. Defining such subgroups will allow stratification of the patients and appropriate application of interventions. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease.

PubMed

Jones, W Schuyler; Baumgartner, Iris; Hiatt, William R; Heizer, Gretchen; Conte, Michael S; White, Christopher J; Berger, Jeffrey S; Held, Peter; Katona, Brian G; Mahaffey, Kenneth W; Norgren, Lars; Blomster, Juuso; Millegård, Marcus; Reist, Craig; Patel, Manesh R; Fowkes, F Gerry R

2017-01-17

In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown. The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were found for the primary efficacy end point (11.4% vs 11.3%; HR 1.01, 95% CI 0.88-1.15; P=0.90), all-cause mortality (9.2% vs 9.2%; HR 0.99, 95% CI 0.86-1.15; P=0.93), acute limb ischemia (2.5% vs 2.5%; HR 1.03, 95% CI 0.78-1.36; P=0.84), or major bleeding (1.9% vs 1.8%; HR 1.15, 95% CI 0.83-1.59; P=0.41). The median duration of follow-up was ≈30 months. After adjustment for baseline characteristics, patients enrolled based on previous revascularization for peripheral artery disease had higher rates of myocardial infarction and acute limb ischemia, with similar composite rates of cardiovascular death, myocardial infarction, and stroke when compared with patients enrolled based on the ankle-brachial index criterion. No significant differences were found between ticagrelor and clopidogrel for reduction of cardiovascular or acute limb events. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01732822. © 2016 American Heart Association, Inc.

Intracellular and extracellular expression of the major inducible 70kDa heat shock protein in experimental ischemia-reperfusion injury of the spinal cord.

PubMed

Awad, Hamdy; Suntres, Zacharias; Heijmans, John; Smeak, Daniel; Bergdall-Costell, Valerie; Christofi, Fievos L; Magro, Cynthia; Oglesbee, Michael

2008-08-01

Inflammatory responses exacerbate ischemia-reperfusion (IR) injury of spinal cord, although understanding of mediators is incomplete. The major inducible 70kDa heat shock protein (hsp70) is induced by ischemia and extracellular hsp70 (e-hsp70) can modulate inflammatory responses, but there is no published information regarding e-hsp70 levels in the cerebrospinal fluid (CSF) or serum as part of any neurological disease state save trauma. The present work addresses this deficiency by examining e-hsp70 in serum and CSF of dogs in an experimental model of spinal cord IR injury. IR injury of spinal cord caused hind limb paraplegia within 2-3 h that was correlated to lumbosacral poliomalacia with T cell infiltrates at 3 d post-ischemia. In this context, we showed a 5.2-fold elevation of e-hsp70 in CSF that was induced by ischemia and was sustained for the following 3 d observation interval. Plasma e-hsp70 levels were unaffected by IR injury, indicating e-hsp70 release from within the central nervous system. A putative source of this e-hsp70 was ependymal cells in the ischemic penumbra, based upon elevated i-hsp70 levels detected within these cells. Results warrant further investigation of e-hsp70's potential to modulate spinal cord IR injury.

Differential diagnosis of critical digital ischemia in systemic sclerosis: Report of five cases and review of the literature.

PubMed

Sharp, Charlotte A; Akram, Qasim; Hughes, Michael; Muir, Lindsay; Herrick, Ariane L

2016-10-01

Critical digital ischemia is a rare, but serious complication of systemic sclerosis (SSc) and is not always due solely to the non-inflammatory angiopathy that characterizes the SSc disease process. Our objective was to illustrate the range of presentations and causes of critical digital ischemia in patients with SSc in order to highlight how optimal management is dependent upon establishing the correct diagnosis. Five cases exemplifying differential diagnoses were identified and their case notes reviewed in order to extract clinically relevant data and images. A review of the literature was performed in PubMed in English. Causes of critical digital ischemia included typical micro-angiopathic changes and proximal (large vessel) disease. One case highlighted the difficulty of ascertaining whether an inflammatory cause is also present in SSc/SLE overlap syndrome. Two cases demonstrated embolic causes (thromboembolism due to atrial fibrillation and septic emboli). Critical digital ischemia in patients with SSc requires thorough investigation in order to avoid missing additional potentially modifiable causes including large vessel disease, inflammation, embolism, infection, and paraneoplastic syndromes. A firm evidence base for current medical and surgical interventions is lacking, highlighting the need for further research into the optimum management of this rare, but painful, debilitating, and limb-threatening complication of SSc. Copyright © 2016 Elsevier Inc. All rights reserved.

Parasitic Reactions in Nanosized Silicon Anodes for Lithium-Ion Batteries

DOE PAGES

Gao, Han; Xiao, Lisong; Plumel, Ingo; ...

2017-02-08

When designing nano-Si electrodes for lithium-ion batteries, the detrimental effect of the c-Li 15Si 4 phase formed upon full lithiation is often a concern. In this study, Si nanoparticles with controlled particle sizes and morphology were synthesized and parasitic reactions of the metastable c-Li 15Si 4 phase with the non-aqueous electrolyte was investigated. The use of smaller Si nanoparticles (~ 60 nm) and the addition of fluoroethylene carbonate additive played decisive roles in the parasitic reactions such that the c-Li 15Si 4 phase could disappear at the end of lithiation. This suppression of c-Li 15Si 4 improved cycle life ofmore » the nano-Si electrodes but with a little loss of specific capacity. Also the characteristic c-Li 15Si 4 peak in the dQ/dV plots can be used as an early-stage indicator to cell capacity fade during cycling. Lastly, our findings can contribute to the design guidelines of Si electrodes and allow us to quantify another factor to the performance of the Si electrodes.« less

Launching a permanent out-of-hour interventional radiology service: single-center experience from a German University Hospital.

PubMed

Goltz, J P; Janssen, H; Petritsch, B; Kickuth, R

2014-02-01

To evaluate the feasibility, frequency of use, types of intervention and labor costs of a formal round-the-clock interventional radiology on-call service. In 11/2011 a formal and permanent out-of-hour interventional radiology rota in addition to the general radiology out-of-hour rota (OOHR) was established. We retrospectively screened the interventional radiology database for procedures completed outside regular working hours, reviewed all interventions and manually selected cases in which the on-call interventionist was called in from home. We determined the type, frequency of use and costs (€/year and procedure) of this service between 1/2012 and 12/2012. The referring physicians' (sub-) specialties were evaluated. During the 12-month period, the on-call interventionists (n = 3) performed 92 procedures OOH. The procedures included angiography and hemorrhage control (n = 36, 39.1 %), angiography and intervention for acute limb ischemia (n = 25, 27.2 %), percutaneous biliary drainage (PTCD) (n = 10, 10.9 %), angiography for non-occlusive ischemia (n = 7, 7.6 %), and other (n = 14, 15.3 %). The total labor costs for the OOHR were € 42,312.21 (€ 32,982.60 lump sum for stand-by, €  9,329.61 for hours spent on procedures). The labor costs per procedure totaled € 459.92. The referring physicians' specialties were general/visceral (n = 25), vascular surgery (n = 24), internal medicine (n = 21), cardiac/thoracic vascular (n = 9), trauma surgery (n = 5), urology (n = 5), and anesthesiology (n = 3). A formal interventional OOHR is practicable in a university hospital setting. Most procedures were requested by general, vascular, and thoracic surgery as well as internal medicine with a focus on hemorrhage control, treatment of acute limb ischemia, and PTCD. The overall labor costs for the OOHR appear moderate. • In a university setting an OOHR for IR is feasible.• Labor costs per procedure appear moderate.• Hemorrhage control and treatment of limb ischemia were the most frequent procedures. Citation Format: • Goltz JP, Janssen H, Petritsch B et al. Launching a Permanent Out-of-Hour Interventional Radiology Service: Single-Center Experience from a German University Hospital. Fortschr Röntgenstr 2014; 186: 136 - 141. © Georg Thieme Verlag KG Stuttgart · New York.

Temporary arterial shunts to maintain limb perfusion after arterial injury: an animal study

NASA Technical Reports Server (NTRS)

Dawson, D. L.; Putnam, A. T.; Light, J. T.; Ihnat, D. M.; Kissinger, D. P.; Rasmussen, T. E.; Bradley, D. V. Jr

1999-01-01

BACKGROUND: Temporary shunt placement can quickly restore perfusion after extremity arterial injury. This study examined the adequacy of limb blood flow with shunt use, non-heparin-bonded shunt patency over prolonged periods, and the safety of this technique. METHODS: Common iliac arteries were divided and 4.0-mm Silastic Sundt shunts placed in 16 anesthetized pigs. Eight (group I) had shunts placed immediately; eight others (group II) were shunted after an hour of limb ischemia and hemorrhagic shock. Physiologic parameters and femoral artery blood flow in both hindlimbs were continuously monitored. Limb lactic acid generation, oxygen utilization, and hematologic and metabolic effects were serially evaluated for 24 hours. RESULTS: Shunts remained patent in 13 of 16 pigs. Shunts thrombosed in two group I animals because of technical errors, but functioned well after thrombectomy and repositioning. Patency could not be maintained in one animal that died from shock. Flow in group I shunted limbs was 57 (+/-11 SD) % of control. For group II animals in shock, shunted limb flow initially averaged 46 +/- 15% of control, but 4 hours after shunt placement, the mean limb blood flow was the same as in group I. Increased oxygen extraction compensated for the lower flow. Lactic acid production was not increased in comparison to control limbs. CONCLUSION: Shunts provided adequate flow in this model of extremity trauma. Correctly placed shunts stayed patent for 24 hours, without anticoagulation, if shunt placement followed resuscitation.

The role of FGF2 in migration and tubulogenesis of endothelial progenitor cells in relation to pro-angiogenic growth factor production.

PubMed

Litwin, Monika; Radwańska, Agata; Paprocka, Maria; Kieda, Claudine; Dobosz, Tadeusz; Witkiewicz, Wojciech; Baczyńska, Dagmara

2015-12-01

In recent years, special attention has been paid to finding new pro-angiogenic factors which could be used in gene therapy of vascular diseases such as critical limb ischaemia (CLI). Angiogenesis, the formation of new blood vessels, is a complex process dependent on different cytokines, matrix proteins, growth factors and other pro- or anti-angiogenic stimuli. Numerous lines of evidence suggest that key mediators of angiogenesis, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) together with fibroblast growth factor2 (FGF2) are involved in regulation of the normal and pathological process of angiogenesis. However, less information is available on the complex interactions between these and other angiogenic factors. The aim of this study was to characterise the effect of fibroblast growth factor2 on biological properties of human endothelial progenitor cells with respect to the expression level of other regulatory cytokines. Ectopic expression of FGF2 in EP cells stimulates their pro-angiogenic behaviour, leading to increased proliferation, migration and tube formation abilities. Moreover, we show that the expression profile of VEGF and other pro-angiogenic cytokines, such as HGF, MCP2, and interleukins, is affected differently by FGF2 in EPC. In conclusion, we provide evidence that FGF2 directly affects not only the biological properties of EP cells but also the expression pattern and secretion of numerous chemocytokines. Our results suggest that FGF2 could be applied in therapeutic approaches for CLI and other ischaemic diseases of the vascular system in vivo.

Predictive Ability of the SVS WIfI Classification System following First-time Lower Extremity Revascularizations

PubMed Central

Darling, Jeremy D.; McCallum, John C.; Soden, Peter A.; Guzman, Raul J.; Wyers, Mark C.; Hamdan, Allen D.; Verhagen, Hence J.; Schermerhorn, Marc L.

2017-01-01

OBJECTIVES The SVS WIfI (wound, ischemia, foot infection) classification system was proposed to predict 1-year amputation risk and potential benefit from revascularization. Our goal was to evaluate the predictive ability of this scale in a “real world” selection of patients undergoing a first time lower extremity revascularization for chronic limb threatening ischemia (CLTI). METHODS From 2005 to 2014, 1,336 limbs underwent a first time lower extremity revascularization for CLTI, of which 992 had sufficient data to classify all three WIfI components (wound, ischemia, and foot infection). Limbs were stratified into the SVS WIfI clinical stages (from 1 to 4) for 1-year amputation risk estimation, as well as a novel WIfI composite score from 0 to 9 (that weighs all WIfI variables equally) and a novel WIfI mean score from 0 to 3 (that can incorporate limbs missing any of the three WIfI components). Outcomes included major amputation, RAS events (revascularization, major amputation, or stenosis [>3.5× step-up by duplex]), and mortality. Predictors were identified using Cox regression models and Kaplan-Meier survival estimates. RESULTS Of the 1,336 first-time procedures performed, 992 limbs were classified in all three WIfI components (524 endovascular, 468 bypass; 26% rest pain, 74% tissue loss). Cox regression demonstrated that a one-unit increase in the WIfI clinical stage increases the risk of major amputation and RAS events in all limbs (Hazard Ratio [HR] 2.4; 95% Confidence Interval [CI] 1.7–3.2 and 1.2 [1.1–1.3], respectively). Separate models of the entire cohort, a bypass only cohort, and an endovascular only cohort showed that a one-unit increase in the WIfI mean score is associated with an increase in the risk of major amputation (all three cohorts; 5.3 [3.6–6.8], 4.1 [2.4–6.9], and 6.6 [3.8–11.6], respectively) and RAS events (all three cohorts; 1.7 [1.4–2.0], 1.9 [1.4–2.6], and 1.4 [1.1–1.9], respectively). The novel WIfI composite and WIfI mean scores were the only consistent predictors of mortality among the three cohorts, with the WIfI mean score proving most strongly predictive in the entire cohort (1.4 [1.1–1.7]), the bypass only cohort (1.5 [1.1–1.9]) and the endovascular only cohort (1.4 [1.0–1.8]). Although the individual WIfI wound component was able to predict mortality among all patients (1.1 [1.0–1.2]) and bypass only patients (1.2 [1.1–1.3]), no other individual WIfI component, nor the WIfI clinical stage, were able to significantly predict mortality among any cohort. CONCLUSION This study supports the ability of the SVS WIfI classification system to predict major amputation; however, the novel WIfI mean and WIfI composite scores predict amputation, RAS events, and mortality more consistently than any other current WIfI scoring system. The WIfI mean score allows inclusion of all limbs, and both novel scoring systems are easier to conceptualize, give equal weight to each WIfI component, and may provide clinicians more effective comparisons in outcomes between patients. PMID:28073665

Detection of microcirculatory impairment by transcutaneous oxymetry monitoring during hemodialysis: an observational study

PubMed Central

2014-01-01

Background Little is known about the effects of intermittent hemodialysis on microcirculatory perfusion. The aim of this study is to assess the effects of hemodialysis on microvascular perfusion using transcutaneous oxymetry (TCPO2). Methods In this observational study, hourly TCPO2 measurements were performed during hemodialysis sessions. Ankle brachial index (ABI) was carried out to classify patients according their vascular condition. Results 50 patients (mean age 70 ± 8 years old) were enrolled. Mean TCPO2 decreased significantly on average 23.9% between start and finish of hemodialysis. Severe ischemia (TCPO2 < 30 mmHg) and critical ischemia (TCPO2 < 10 mmHg) occurred during dialysis in 47.1% and 15.5% respectively. Critical ischemia occurred only in limbs with ABI < 0.9 (8.3%) or > 1.3 (28%). Patients with critical ischemia experienced a significantly larger decline in mean blood pressure (32.4 ± 26.1 mmHg vs 12.7 ± 10.7 mmHg; P = 0.007) and a more pronounced ultrafiltration (45.55 ± 16.9 ml/kg vs 35.17 ± 18.2 ml/kg; P = 0.04) compared to patients without ischemia. Clinical outcomes (death or vascular procedures) were five times more frequent in patients who had developed critical ischemia (55.7% vs 10.1% P = 0.01). The elevated age of patients, the low basal value of TCPO2, and the occurrence of critical ischemia were more frequently associated with clinical outcome (P = 0.03, P = 0.048, P = 0.01 respectively). Conclusions This study demonstrates that hemodialysis induces microcirculatory injury, dependent on blood pressure reduction, peripheral vascular state and ultrafiltration. The occurrence of critical ischemia is associated to pejorative patient outcome and therefore, TCPO2 seems to be useful to avoid potential distal tissue damage during hemodialysis. PMID:24400914

Novel Biomarkers of Arterial and Venous Ischemia in Microvascular Flaps

PubMed Central

Nguyen, Gerard K.; Monahan, John F. W.; Davis, Gabrielle B.; Lee, Yong Suk; Ragina, Neli P.; Wang, Charles; Zhou, Zhao Y.; Hong, Young Kwon; Spivak, Ryan M.; Wong, Alex K.

2013-01-01

The field of reconstructive microsurgery is experiencing tremendous growth, as evidenced by recent advances in face and hand transplantation, lower limb salvage after trauma, and breast reconstruction. Common to all of these procedures is the creation of a nutrient vascular supply by microsurgical anastomosis between a single artery and vein. Complications related to occluded arterial inflow and obstructed venous outflow are not uncommon, and can result in irreversible tissue injury, necrosis, and flap loss. At times, these complications are challenging to clinically determine. Since early intervention with return to the operating room to re-establish arterial inflow or venous outflow is key to flap salvage, the accurate diagnosis of early stage complications is essential. To date, there are no biochemical markers or serum assays that can predict these complications. In this study, we utilized a rat model of flap ischemia in order to identify the transcriptional signatures of venous congestion and arterial ischemia. We found that the critical ischemia time for the superficial inferior epigastric fasciocutaneus flap was four hours and therefore performed detailed analyses at this time point. Histolgical analysis confirmed significant differences between arterial and venous ischemia. The transcriptome of ischemic, congested, and control flap tissues was deciphered by performing Affymetrix microarray analysis and verified by qRT-PCR. Principal component analysis revealed that arterial ischemia and venous congestion were characterized by distinct transcriptomes. Arterial ischemia and venous congestion was characterized by 408 and 1536>2-fold differentially expressed genes, respectively. qRT-PCR was used to identify five candidate genes Prol1, Muc1, Fcnb, Il1b, and Vcsa1 to serve as biomarkers for flap failure in both arterial ischemia and venous congestion. Our data suggests that Prol1 and Vcsa1 may be specific indicators of venous congestion and allow clinicians to both diagnose and successfully treat microvascular complications before irreversible tissue damage and flap loss occurs. PMID:23977093

Experience with latrogenic pediatric vascular injuries. Incidence, etiology, management, and results.

PubMed Central

Flanigan, D P; Keifer, T J; Schuler, J J; Ryan, T J; Castronuovo, J J

1983-01-01

During a 32-month period, 79 extremities in 76 children (age 1 day-13 years, mean = 31 months) were evaluated with regard to iatrogenic vascular injuries. Prospectively, 42 children were studied pre- and post-cardiac catheterization. Ten of these children sustained vascular injuries (incidence = 24%). Thirty-four additional children were referred because of 35 iatrogenic vascular injuries as a result of transfemoral cardiac catheterization (n = 20), umbilical artery catheterization (n = 10), or recent surgery (n = 5). All 45 injuries were evaluated by lower extremity segmental Doppler pressure measurements in addition to routine physical examination at the time of injury and at frequent follow-up. An ankle/brachial pressure index (ABI) less than 0.9 was considered abnormal. Selected children (ABI less than 0.9 for greater than 30 days) underwent orthoroentgenograms to assess limb growth. The average ABI immediately following injury was 0.34 +/- 0.33. Thirty-four injuries were treated nonoperatively. Twelve injuries were excluded from further study due to death (n = 7) or being lost to follow-yp (n = 5). A return of ABI to normal was seen from 1 day to 2 years in 93% of children treated with heparin (n = 14) compared to 63% of children who were simply observed (n = 8) (p less than 0.10). The initial severity of ischemia did not correlate with the subsequent rate of improvement. Only patients with absent femoral pulses were selected for operative intervention, which consisted of aortic thrombectomy (n = 2), femorofemoral bypass (n = 2), femoral artery patch angioplasty (n = 1), or femoral artery thrombectomy (n = 7) with no mortality. Nine patients had immediate return of a normal ABI after surgery. A delayed return of ABI to normal occurred in the other two. Nine per cent of surgically treated children and 23% of nonsurgically treated children developed leg length discrepancies (0.5-3.0 cm) as a result of ischemia lasting greater than 30 days. Overall, 91% of the children in this series eventually regained normal circulation following injury and no child lost a limb. This study indicates that iatrogenic pediatric vascular injuries are common and can result in significant limb growth impairment. Immediate operative intervention is highly successful when the injury is proximal to the common femoral artery bifurcation and avoids the prolonged ischemia seen with nonoperative therapy. For more distal occlusions, heparin therapy provides better results than simple observation. Although therapeutic intervention for these injuries is generally successful, a limb length discrepancy rate of 14% mandates that indications for invasive vascular monitoring and diagnostic procedures be strict. Images Fig. 2. Fig. 7. PMID:6625714

Below-the-ankle Angioplasty and Stenting for Limb Salvage: Anatomical Considerations and Long-term Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Katsanos, Konstantinos, E-mail: katsanos@med.upatras.gr; Diamantopoulos, Athanasios; Spiliopoulos, Stavros

2013-08-01

PurposeTo report the long-term angiographic and clinical results in a series of below-the-ankle (BTA) angioplasty procedures and to present some biomechanical issues related to the unique anatomical geometry of the ankle.MethodsWe performed a retrospective analysis of BTA angioplasty procedures. Clinical end points included technical success, patient mortality, salvage of the treated foot, and repeat target lesion revascularization. Imaging end points included primary patency, binary restenosis of the target lesion at the 50 % threshold, and stent integrity (stent fracture, deformation, or collapse). Univariate subgroup analysis was performed.ResultsIn total, 40 limbs in 37 patients (age 73.5 {+-} 8.2 years) with criticalmore » limb ischemia were included and 42 inframalleolar lesions (4.2 {+-} 1.4 cm) were analyzed. Technical success was achieved in 95.2 % (40 of 42). Provisional stent placement was performed in 45.2 % (19 of 42). Two patients died, and two major amputations occurred up to 3 years. At 1 year, overall primary vessel patency was 50.4 {+-} 9.1 %, lesion binary restenosis rate was 64.1 {+-} 8.3 %, and repeat intervention-free survival was 93.6 {+-} 4.3 % according to life table analysis of all treated lesions. Pairwise subgroup analysis showed that BTA self-expanding stents were associated with significantly higher restenosis and poorer primary patency compared to plain balloon angioplasty or sirolimus-eluting balloon-expandable stents. Significant deformation and/or fracture of balloon-expandable stents placed BTA were identified in five of 11. Dynamic imaging showed that the dorsalis pedis artery is kinked during foot dorsiflexion, whereas the distal posterior tibial artery is kinked during plantar flexion of the foot.ConclusionBTA angioplasty for critical limb ischemia treatment is safe and feasible with satisfactory long-term results. BTA stent placement must be reserved for bailout indications.« less

Enriching the hydrogen storage capacity of carbon nanotube doped with polylithiated molecules

NASA Astrophysics Data System (ADS)

Panigrahi, P.; Naqvi, S. R.; Hankel, M.; Ahuja, R.; Hussain, T.

2018-06-01

In a quest to find optimum materials for efficient storage of clean energy, we have performed first principles calculations to study the structural and energy storage properties of one-dimensional carbon nanotubes (CNTs) functionalized with polylithiated molecules (PLMs). Van der Waals corrected calculations disclosed that various PLMs like CLi, CLi2, CLi3, OLi, OLi2, OLi3, bind strongly to CNTs even at high doping concentrations ensuring a uniform distribution of dopants without forming clusters. Bader charge analysis reveals that each Li in all the PLMs attains a partial positive charge and transform into Li+ cations. This situation allows multiple H2 molecules adsorbed with each Li+ through the polarization of incident H2 molecules via electrostatic and van der Waals type of interaction. With a maximum doping concentration, that is 3CLi2/3CLi3 and 3OLi2/3OLi3 a maximum of 36 H2 molecules could be adsorbed that corresponds to a reasonably high H2 storage capacity with the adsorption energies in the range of -0.33 to -0.15 eV/H2. This suits the ambient condition applications.

Glutathione adducts on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase Cys-674 regulate endothelial cell calcium stores and angiogenic function as well as promote ischemic blood flow recovery.

PubMed

Thompson, Melissa D; Mei, Yu; Weisbrod, Robert M; Silver, Marcy; Shukla, Praphulla C; Bolotina, Victoria M; Cohen, Richard A; Tong, Xiaoyong

2014-07-18

The sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) is key to Ca(2+) homeostasis and is redox-regulated by reversible glutathione (GSH) adducts on the cysteine (C) 674 thiol that stimulate Ca(2+) uptake activity and endothelial cell angiogenic responses in vitro. We found that mouse hind limb muscle ischemia induced S-glutathione adducts on SERCA in both whole muscle tissue and endothelial cells. To determine the role of S-glutathiolation, we used a SERCA 2 C674S heterozygote knock-in (SKI) mouse lacking half the key thiol. Following hind limb ischemia, SKI animals had decreased SERCA S-glutathione adducts and impaired blood flow recovery. We studied SKI microvascular endothelial cells in which total SERCA 2 expression was unchanged. Cultured SKI microvascular endothelial cells showed impaired migration and network formation compared with wild type (WT). Ca(2+) studies showed decreased nitric oxide (·NO)-induced (45)Ca(2+) uptake into the endoplasmic reticulum (ER) of SKI cells, while Fura-2 studies revealed lower Ca(2+) stores and decreased vascular endothelial growth factor (VEGF)- and ·NO-induced Ca(2+) influx. Adenoviral overexpression of calreticulin, an ER Ca(2+) binding protein, increased ionomycin-releasable stores, VEGF-induced Ca(2+) influx and endothelial cell migration. Taken together, these data indicate that the redox-sensitive Cys-674 thiol on SERCA 2 is required for normal endothelial cell Ca(2+) homeostasis and ischemia-induced angiogenic responses, revealing a novel redox control of angiogenesis via Ca(2+) stores. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Preclinical and clinical experience in vascular gene therapy: advantages over conservative/standard therapy.

PubMed

Nikol, S; Huehns, T Y

2001-04-01

No systemic pharmacological treatment has been shown to convincingly reduce the incidence of restenosis after angioplasty or increase the formation of collaterals in ischemic tissue in patients. The lack of success of many pharmaceutical agents in reducing restenosis rates or in inducing angiogenesis post-angioplasty and following stent implantation has encouraged the development of new technological treatment approaches. Gene therapy is a novel strategy with the potential to prevent some of the sequelae after arterial injury, particularly cell proliferation, and to induce growth of new vessels or remodeling of pre-existing vessel branches, which may help patients with critical ischemia. Gene therapy strategies have the advantage of minimizing systemic side effects and may have a long-term effect as the encoded protein is released. Most clinical trials investigating gene therapy for vascular disease have been uncontrolled phase I and IIa trials. Gene therapy into vessels with the genes for growth factors has been demonstrated to be feasible and efficient. Local drug delivery devices have been used in combination with gene therapy in several trials to maximize safety and efficiency. Data from experimental animal work indicates that gene therapy may modify intimal hyperplasia after arterial injury, but there are few clinical trials on restenosis in patients. Preliminary clinical results show only limited success in altering restenosis rates. In vitro and experimental in vivo investigations into gene therapy for angiogenesis demonstrate increased formation of collaterals and functional improvement of limb ischemia. There is some evidence of increased collateral formation and clinical improvement in patients with critical limb ischemia. Results of placebo-controlled and double-blind trials of gene therapy for vascular disease are awaited.

Wireless remote monitoring of myocardial ischemia using reconstructed 12-lead ECGs.

PubMed

Vukcevic, Vladan; Panescu, Dorin; Bojovic, Bosko; George, Samuel; Gussak, Ihor; Giga, Vojislav; Stankovic, Ivana

2010-01-01

CardioBip (CB) is a hand-held patient-activated device for recording and wireless transmission of reconstructed 12-lead ECG (12CB) based on patient specific matrices. It has 5 contact points: 3 precordial and 2 on the device top serving as limb leads when touched by index fingers. To determine whether CB could be used to monitor coronary disease (CAD) patients, we compared 12CB to simultaneous 12-lead ECGs (12L) in patients with CAD, pre-and post-exercise treadmill testing (ETT). The study goals were to assess: (1) whether 12CB can accurately reconstruct and wirelessly transmit 12-lead ECGs in CAD patients during ETT recovery; (2) whether 12CB can be used to evaluate ST segment changes in patients with exercise-induced ischemia.

Aortic intimal sarcoma masquerading as bilateral renal artery stenosis.

PubMed

Sethi, Supreet; Pothineni, Naga Krishna; Syal, Gaurav; Ali, Syed Mujtaba; Krause, Michelle W

2013-01-01

Aortic intimal sarcoma is a rare tumor with poor prognosis. The most common manifestations are thromboembolic phenomena and vascular obstruction. We present a case of aortic intimal sarcoma causing bilateral renal artery stenosis which manifested as resistant hypertension and acute kidney inury. Multiple attempts to stent the renal arteries were unsuccessful. Eventually the patient developed acute limb ischemia and oliguric kidney failure as complications of the primary tumor.

Marvels, mysteries, and misconceptions of vascular compensation to peripheral artery occlusion.

PubMed

Ziegler, Matthew A; Distasi, Matthew R; Bills, Randall G; Miller, Steven J; Alloosh, Mouhamad; Murphy, Michael P; Akingba, A George; Sturek, Michael; Dalsing, Michael C; Unthank, Joseph L

2010-01-01

Peripheral arterial disease is a major health problem and there is a significant need to develop therapies to prevent its progression to claudication and critical limb ischemia. Promising results in rodent models of arterial occlusion have generally failed to predict clinical success and led to questions of their relevance. While sub-optimal models may have contributed to the lack of progress, we suggest that advancement has also been hindered by misconceptions of the human capacity for compensation and the specific vessels which are of primary importance. We present and summarize new and existing data from humans, Ossabaw miniature pigs, and rodents which provide compelling evidence that natural compensation to occlusion of a major artery (i) may completely restore perfusion, (ii) occurs in specific pre-existing small arteries, rather than the distal vasculature, via mechanisms involving flow-mediated dilation and remodeling (iii) is impaired by cardiovascular risk factors which suppress the flow-mediated mechanisms and (iv) can be restored by reversal of endothelial dysfunction. We propose that restoration of the capacity for flow-mediated dilation and remodeling in small arteries represents a largely unexplored potential therapeutic opportunity to enhance compensation for major arterial occlusion and prevent the progression to critical limb ischemia in the peripheral circulation.

Marvels, Mysteries, and Misconceptions of Vascular Compensation to Peripheral Artery Occlusion

PubMed Central

ZIEGLER, MATTHEW A.; DISTASI, MATTHEW R.; BILLS, RANDALL G.; MILLER, STEVEN J.; ALLOOSH, MOUHAMAD; MURPHY, MICHAEL P.; AKINGBA, A. GEORGE; STUREK, MICHAEL; DALSING, MICHAEL C.; UNTHANK, JOSEPH L.

2010-01-01

Peripheral arterial disease is a major health problem and there is a significant need to develop therapies to prevent its progression to claudication and critical limb ischemia. Promising results in rodent models of arterial occlusion have generally failed to predict clinical success and led to questions of their relevance. While sub-optimal models may have contributed to the lack of progress, we suggest that advancement has also been hindered by misconceptions of the human capacity for compensation and the specific vessels which are of primary importance. We present and summarize new and existing data from humans, Ossabaw miniature pigs, and rodents which provide compelling evidence that natural compensation to occlusion of a major artery (i) may completely restore perfusion, (ii) occurs in specific pre-existing small arteries, rather than the distal vasculature, via mechanisms involving flow-mediated dilation and remodeling (iii) is impaired by cardiovascular risk factors which suppress the flow-mediated mechanisms and (iv) can be restored by reversal of endothelial dysfunction. We propose that restoration of the capacity for flow-mediated dilation and remodeling in small arteries represents a largely unexplored potential therapeutic opportunity to enhance compensation for major arterial occlusion and prevent the progression to critical limb ischemia in the peripheral circulation. PMID:20141596

Tibiopedal access for lower extremity arterial intervention: when to use and how to perform.

PubMed

Wiechmann, Bret N

2014-09-01

Tibiopedal artery access is being used with increasing frequency as an alternative access to facilitate procedural success in lower extremity arterial intervention. This technique is usually employed in the setting of critical limb ischemia and tibial artery intervention, but it may offer potential practical advantages for popliteal artery and even superficial femoral artery intervention in unique situations. As in all cases of lower extremity arterial intervention, consideration of access is important not only for initial approach to any obstructing lesion but also for exit strategy. The dorsalis pedis artery and posterior tibial artery can be readily accessed if necessary owing to their relatively superficial position in the foot or the ankle, yet their normal diameter and the presence of significant calcification (a common finding in patients with tibial occlusive disease and critical limb ischemia) can pose difficulties as well. In addition, the peroneal artery in the lower leg can be accessed percutaneously; however, its size and depth may present additional challenges. Meticulous attention to detail is paramount in avoiding complications in what may be the only distal vessel supplying the foot. This article describes common techniques in using tibiopedal artery access as a means of alternative access for successful infrainguinal intervention. Copyright © 2014 Elsevier Inc. All rights reserved.

Cerenkov Luminescence Imaging as a Modality to Evaluate Antibody-Based PET Radiotracers

PubMed Central

D’Souza, Jimson W.; Hensley, Harvey; Doss, Mohan; Beigarten, Charles; Torgov, Michael; Olafsen, Tove; Yu, Jian Q.

2017-01-01

Antibodies, and engineered antibody fragments, labeled with radioisotopes are being developed as radiotracers for the detection and phenotyping of diseases such as cancer. The development of antibody-based radiotracers requires extensive characterization of their in vitro and in vivo properties, including their ability to target tumors in an antigen-selective manner. In this study, we investigated the use of Cerenkov luminescence imaging (CLI) as compared with PET as a modality for evaluating the in vivo behavior of antibody-based radiotracers. Methods: The anti–prostate-specific membrane antigen (PSMA) huJ591 antibody (IgG; 150 kDa) and its minibody (Mb; 80 kDa) format were functionalized with the chelator 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and radiolabeled with the positron-emitting radionuclide 64Cu (half-life, 12.7 h). Immunoreactive preparations of the radiolabeled antibodies were injected into NCr nu/nu mice harboring PSMA-positive CWR22Rv1 and PSMA-negative PC-3 tumor xenografts. Tumor targeting was evaluated by both PET and CLI. Results: 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb retained the ability to bind cell surface PSMA, and both radiotracers exhibited selective uptake into PSMA-positive tumors. Under the experimental conditions used, PSMA-selective uptake of 64Cu-NODAGA-PSMA-IgG and 64Cu-NODAGA-PSMA-Mb was observed by CLI as early as 3 h after injection, with tumor-to-background ratios peaking at 24 (IgG) and 16 (Mb) h after injection. Targeting data generated by CLI correlated with that generated by PET and necropsy. Conclusion: CLI provided a rapid and simple assessment of the targeting specificity and pharmacokinetics of the antibody-based PET radiotracers that correlated well with the behavior observed by standard PET imaging. Moreover, CLI provided clear discrimination between uptake kinetics of an intact IgG and its small-molecular-weight derivative Mb. These data support the use of CLI for the evaluation of radiotracer performance. PMID:27539844

The chlorine budget of the present-day atmosphere - A modeling study

NASA Technical Reports Server (NTRS)

Weisenstein, Debra K.; Ko, Malcolm K. W.; Sze, Nien-Dak

1992-01-01

The contribution of source gases to the total amount of inorganic chlorine (ClY) is examined analytically with a time-dependent model employing 11 source gases. The source-gas emission data are described, and the modeling methodology is set forth with attention given to the data interpretation. The abundances and distributions are obtained for all 11 source gases with corresponding ClY production rates and mixing ratios. It is shown that the ClY production rate and the ClY mixing ratio for each source gas are spatially dependent, and the change in the relative contributions from 1950 to 1990 is given. Ozone changes in the past decade are characterized by losses in the polar and midlatitude lower stratosphere. The values for CFC-11, CCl4, and CH3CCl3 suggest that they are more evident in the lower stratosphere than is suggested by steady-state estimates based on surface concentrations.

EuCliD--a medical registry.

PubMed

Steil, H; Amato, C; Carioni, C; Kirchgessner, J; Marcelli, D; Mitteregger, A; Moscardo, V; Orlandini, G; Gatti, E

2004-01-01

The European Clinical Database EuCliD small star, filled has been developed as a tool for supervising selected quality indicators of about 200 European dialysis centers. Major efforts had to be made to comply with local and European laws regarding data security. EuCliD is a Lotus Notes based flat-file database currently containing medical data of more than 14,000 dialysis patients from 10 European countries. Another 15,000 patients from 150 centers in 4 South-American countries will be added soon. Data are entered either manually or by means of interfaces to existing local data managing systems. This information is transferred to a central Lotus Notes Server. Data evaluation was performed with statistical tools like SPSS. EuCliD is used as a part of the CQI (Continuous Quality Improvement) management system of Fresenius Medical Care (FMC) dialysis units. Each participating dialysis center receives (currently every half year) benchmarking reports at a regular interval. The benchmark for all quality parameters is the weighted mean of the corresponding data of all centers. An obvious impact of data sampling and data evaluation on the quality of the treatments could be observed within the first one and a half years of working with EuCliD. This also concerns important outcome predictors like Kt/V and hemoglobin concentration as the outcome itself expressed in hospitalization days and survival rates. With the help of EuCliD the user is able to sample clinical data, identify problems, search for solutions with the aim of improving the dialysis treatment quality and guarantee a high-class treatment quality for all patients.

Climate Literacy Partnership in the Southeast (CLiPSE): A Focus on Climate Change-related Dialogs with Faith-Based Groups as a form of Network Building in the Southeast United States - Lessons Learned

NASA Astrophysics Data System (ADS)

Carroll, F. J.; McNeal, K. S.; Hammerman, J.; Christiansen, J.

2013-05-01

The Climate Literacy Partnership in the Southeast (CLiPSE, http://CLiPSE-project.org), funded through the National Science Foundation Climate Change Education Partnership program, is dedicated to improving climate literacy in the Southeastern United States (SE US). By promoting science-based formal and informal educational resources, CLiPSE works through a diverse network of key partner organizations in the SE US to conduct effective public dialogues that address diverse audiences and support learning about climate, climate change, and its impact on human and environmental systems. The CLiPSE project successfully created partnerships with more than fifty key stakeholders, including agriculture, education, leisure, and religious organizations, along with culturally diverse communities. This presentation will explain the CLiPSE model for reaching key publics who hold traditional ideologies typically perceived as incompatible with climate change science. We will discuss the results of our interactions with the leaders of our partnering organizations, their knowledge, perceptions, needs, and input in crafting effective messages for their audiences, through addressing both learners' affective and cognitive domains. For the informal education sector, CLiPSE utilized several open discussion and learning forums aimed to promote critical thinking and civil conversation about climate change. Focusing on Faith-based audiences, a key demographic, in the Southeast US, CLiPSE also conducted an online, moderated, author-attended book study, discussing the thoughts and ideas contained in the work, "Green Like God," by Jonathan Merritt. We will share the questions we faced as we focused on and learned about faith-based audiences, such as: What are the barriers and opportunities?; How do we break out of the assumptions that we have to find the common ground?; How do the audiences understand the issues?; How do we understand the issues?; What common language can we find?; What happens when we bringing the multiple the multiple identities of faith and science together within ourselves and those we are trying to build relationships with? We will also share the lessons we learned while attempting to answer these questions, such as the role of trust and key influentials/leaders in talking with target audiences, the importance of face-to-face dialog and relationships in trust building.

Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels.

PubMed

Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

2016-08-01

Remote ischemic preconditioning is a well reported therapeutic strategy that induces cardioprotective effects but the underlying intracellular mechanisms have not been widely explored. The current study was designed to investigate the involvement of TRP and especially TRPV channels in remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 alternate cycles of inflation and deflation of 5 min each) was delivered using a blood pressure cuff tied on the hind limb of the anesthetized rat. Using Langendorff's system, the heart was perfused and subjected to 30-min ischemia and 120-min reperfusion. The myocardial injury was assessed by measuring infarct size, lactate dehydrogenase (LDH), creatine kinase (CK), LVDP, +dp/dtmax, -dp/dtmin, heart rate, and coronary flow rate. Gadolinium, TRP blocker, and ruthenium red, TRPV channel blocker, were employed as pharmacological tools. Remote hind limb preconditioning significantly reduced the infarct size, LDH release, CK release and improved coronary flow rate, hemodynamic parameters including LVDP, +dp/dtmax, -dp/dtmin, and heart rate. However, gadolinium (7.5 and 15 mg kg(-1)) and ruthenium red (4 and 8 mg kg(-1)) significantly attenuated the cardioprotective effects suggesting the involvement of TRP especially TRPV channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus possibly activates TRPV channels on the heart or sensory nerve fibers innervating the heart to induce cardioprotective effects. Alternatively, remote hind limb preconditioning stimulus may also activate the mechanosensitive TRP and especially TRPV channels on the sensory nerve fibers innervating the skeletal muscles to trigger cardioprotective neurogenic signaling cascade. The cardioprotective effects of remote hind limb preconditioning may be mediated via activation of mechanosensitive TRP and especially TRPV channels.

Canada's Composite Learning Index: A path towards learning communities

NASA Astrophysics Data System (ADS)

Cappon, Paul; Laughlin, Jarrett

2013-09-01

In the development of learning cities/communities, benchmarking progress is a key element. Not only does it permit cities/communities to assess their current strengths and weaknesses, it also engenders a dialogue within and between cities/communities on the means of enhancing learning conditions. Benchmarking thereby is a potentially motivational tool, energising further progress. In Canada, the Canadian Council on Learning created the world's first Composite Learning Index (CLI), the purpose of which is to measure the conditions of learning nationally, regionally and locally. Cities/communities in Canada have utilised the CLI Simulator, an online tool provided by the Canadian Council on Learning, to gauge the change in overall learning conditions which may be expected depending on which particular indicator is emphasised. In this way, the CLI has proved to be both a dynamic and a locally relevant tool for improvement, moreover a strong motivational factor in the development of learning cities/communities. After presenting the main features of the CLI, the authors of this paper sum up the lessons learned during its first 5 years (2006-2010) of existence, also with a view to its transferability to other regions. Indeed, the CLI model was already adopted in Europe by the German Bertelsmann foundation in 2010 and has the potential to be useful in many other countries as well.

A MODEL FOR TYPE 2 CORONAL LINE FOREST (CLiF) AGNs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Glidden, Ana; Rose, Marvin; Elvis, Martin

2016-06-10

We present a model for the classification of Coronal Line Forest Active Galactic Nuclei (CLiF AGNs). CLiF AGNs are of special interest due to their remarkably large number of emission lines, especially forbidden high-ionization lines (FHILs). Rose et al. suggest that their emission is dominated by reflection from the inner wall of the obscuring region rather than direct emission from the accretion disk. This makes CLiF AGNs laboratories to test AGN-torus models. Modeling an AGN as an accreting supermassive black hole surrounded by a cylinder of dust and gas, we show a relationship between the viewing angle and the revealedmore » area of the inner wall. From the revealed area, we can determine the amount of FHIL emission at various angles. We calculate the strength of [Fe vii] λ 6087 emission for a number of intermediate angles (30°, 40°, and 50°) and compare the results with the luminosity of the observed emission line from six known CLiF AGNs. We find that there is good agreement between our model and the observational results. The model also enables us to determine the relationship between the type 2:type 1 AGN fraction vs the ratio of torus height to radius, h / r .« less

Identification of Gambling Problems in Primary Care: Properties of the NODS-CLiP Screening Tool.

PubMed

Cowlishaw, Sean; McCambridge, Jim; Kessler, David

2018-06-25

There are several brief screening tools for gambling that possess promising psychometric properties, but have uncertain utility in generalist healthcare environments which prioritize prevention and brief interventions. This study describes an examination of the National Opinion Research Centre Diagnostic and Statistical Manual of Mental Disorders Screen for Gambling Problems (NODS-CLiP), in comparison with the Problem Gambling Severity Index (PGSI), when used to operationalize gambling problems across a spectrum of severity. Data were obtained from 1058 primary care attendees recruited from 11 practices in England who completed various measures including the NODS-CLiP and PGSI. The performance of the former was defined by estimates of sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs), when PGSI indicators of problem gambling (5+) and any gambling problems (1+), respectively, were reference standards. The NODS-CLiP demonstrated perfect sensitivity for problem gambling, along with high specificity and a NPV, but a low PPV. There was much lower sensitivity when the indicator of any gambling problems was the reference standard, with capture rates indicating only 20% of patients exhibiting low to moderate severity gambling problems (PGSI 1-4) were identified by the NODS-CLiP. The NODS-CLiP performs well when identifying severe cases of problem gambling, but lacks sensitivity for less severe problems and may be unsuitable for settings which prioritize prevention and brief interventions. There is a need for screening measures which are sensitive across the full spectrum of risk and severity, and can support initiatives for improving identification and responses to gambling problems in healthcare settings such as primary care.

Transgenic mouse lines for non-invasive ratiometric monitoring of intracellular chloride

PubMed Central

Batti, Laura; Mukhtarov, Marat; Audero, Enrica; Ivanov, Anton; Paolicelli, Rosa Chiara; Zurborg, Sandra; Gross, Cornelius; Bregestovski, Piotr; Heppenstall, Paul A.

2013-01-01

Chloride is the most abundant physiological anion and participates in a variety of cellular processes including trans-epithelial transport, cell volume regulation, and regulation of electrical excitability. The development of tools to monitor intracellular chloride concentration ([Cli]) is therefore important for the evaluation of cellular function in normal and pathological conditions. Recently, several Cl-sensitive genetically encoded probes have been described which allow for non-invasive monitoring of [Cli]. Here we describe two mouse lines expressing a CFP-YFP-based Cl probe called Cl-Sensor. First, we generated transgenic mice expressing Cl-Sensor under the control of the mouse Thy1 mini promoter. Cl-Sensor exhibited good expression from postnatal day two (P2) in neurons of the hippocampus and cortex, and its level increased strongly during development. Using simultaneous whole-cell monitoring of ionic currents and Cl-dependent fluorescence, we determined that the apparent EC50 for Cli was 46 mM, indicating that this line is appropriate for measuring neuronal [Cli] in postnatal mice. We also describe a transgenic mouse reporter line for Cre-dependent conditional expression of Cl-Sensor, which was targeted to the Rosa26 locus and by incorporating a strong exogenous promoter induced robust expression upon Cre-mediated recombination. We demonstrate high levels of tissue-specific expression in two different Cre-driver lines targeting cells of the myeloid lineage and peripheral sensory neurons. Using these mice the apparent EC50 for Cli was estimated to be 61 and 54 mM in macrophages and DRG, respectively. Our data suggest that these mouse lines will be useful models for ratiometric monitoring of Cli in specific cell types in vivo. PMID:23734096

The Incidence, Prevalence and Burden of OM in Unselected Children Aged 1 to 8 Years Followed by Weekly Otoscopy through the “Common Cold” Season

PubMed Central

Mandel, Ellen M.; Doyle, William J.; Winther, Birgit; Alper, Cuneyt M.

2008-01-01

Background There is a continuing interest in defining the incidence, prevalence and burden of otitis media (OM) in the individual and population for purposes of assigning “risk factors”. Often overlooked in past studies are the contributions of cold-like illnesses (CLIs) and sampling interval to those estimates. Objective Describe the incidence of symptomatic (AOM) and asymptomatic (OME) OM, the prevalence of OM, the contribution of CLI incidence, burden and other OM “risk factors” to the incidence and burden of OM, and the effect of sampling interval on those measures in children. Methods 148 children (74 male; 131 white, aged 1.0–8.6 years) were followed from November 1 to April 30 by weekly pneumatic otoscopy to diagnose OM presence/absence and by daily parental diary to assign CLI episodes. Data for previously identified OM “risk factors” were collected on 127. Results were summarized using standard measures of incidence, prevalence and burden, and multiple-regression techniques were used to identify OM “risk factors”. Results The basal OM prevalence was 20% with peaks in December and March and the temporal pattern was correlated with CLI prevalence. The incidence of OME (per 27232 child-days) was 317, AOM was 74 and CLI was 456. The seasonal pattern of AOM and OME incidences tracked and was correlated with that for CLIs. New OM episodes were usually of short duration (≤7 days in 40%, ≤4 weeks in 75–90%) and the usual OM burden was low (median=12%). OM and breastfeeding histories and CLI incidence/prevalence were significant predictors of OME and AOM incidence and OM burden. Longer sampling intervals were less efficient in capturing AOM and OME durations and incidences, but not OM burden. Conclusions These results demonstrate a high incidence and prevalence of OM, most OM episodes were of short duration and longer sampling intervals introduced biases into some parameter estimates. There was a significant relationship between OM and CLI incidence, prevalence and burden suggesting that CLI experience should be controlled for in assessing independent “risk factors” for AOM and OME. PMID:18272237

Creating a Partnering Community Aimed to Foster Climate Literacy in the Southeastern United States

NASA Astrophysics Data System (ADS)

Rutherford, D.; McNeal, K. S.; Smith, R.; Hare, D.; Nair, U. S.

2011-12-01

The Climate Literacy Partnership in the Southeast (CLiPSE) is a part of the Climate Change Education Program supported by the National Science Foundation (http://CLiPSE-project.org). The established CLiPSE partnership is dedicated to improving climate literacy in the southeast through crafting a shared vision and strategic plan among stakeholders that promotes scientific formal and informal educational resources, materials and programs; a diverse network of key partnering organizations throughout the Southeastern United States (SE US); and effective public dialogues that address diverse learners and audiences and supports learning of climate, climate change, and its relevance upon human and environmental systems. The CLiPSE project has been successful in creating partnerships with more than fifty key stakeholders that stem from a few key publics such as agriculture, education, leisure, religious organizations, and culturally diverse communities. These key publics in the SE US frequently consist of individuals that place great trust in local, private efforts, and CLiPSE has realized the importance of the role of the partnering organizations in providing information through a trusted source. A second unique characteristic of the SE US is the predominately conservative and Protestant citizenry in the region. Working with and through these communities enhances climate change education outreach to this citizenry. The CLiPSE project rests on solid climate science and learning science research in order to formulate an effective plan with desired learning outcomes of critical thinking and civil conversation through effective communication strategies. This paper will present the CLiPSE model in reaching the key publics that traditionally hold ideologies that are traditionally perceived as incompatible with climate change science. We will present the strategies utilized to bring together experts and researchers in climate science, learning science, and social science with practitioners and leaders of key stakeholder groups to formulate a shared climate change education plan in the SE US that is uniquely formatted for each target audience. We will also share what we have learned from interacting with the leaders of our partnering organizations in crafting effective messages for their audiences and addressing learners' affective and cognitive domains.

Technique and results of femoral bifurcation endarterectomy by eversion.

PubMed

Dufranc, Julie; Palcau, Laura; Heyndrickx, Maxime; Gouicem, Djelloul; Coffin, Olivier; Felisaz, Aurélien; Berger, Ludovic

2015-03-01

This study evaluated, in a contemporary prospective series, the safety and efficacy of femoral endarterectomy using the eversion technique and compared our results with results obtained in the literature for the standard endarterectomy with patch closure. Between 2010 and 2012, 121 patients (76% male; mean age, 68.7 years; diabetes, 28%; renal insufficiency, 20%) underwent 147 consecutive femoral bifurcation endarterectomies using the eversion technique, associating or not inflow or outflow concomitant revascularization. The indications were claudication in 89 procedures (60%) and critical limb ischemia in 58 (40%). Primary, primary assisted, and secondary patency of the femoral bifurcation, clinical improvement, limb salvage, and survival were assessed using Kaplan-Meier life-table analysis. Factors associated with those primary end-points were evaluated with univariate analysis. The technical success of eversion was of 93.2%. The 30-day mortality was 0%, and the complication rate was 8.2%; of which, half were local and benign. Median follow-up was 16 months (range, 1.6-31.2 months). Primary, primary assisted, and secondary patencies were, respectively, 93.2%, 97.2%, and 98.6% at 2 years. Primary, primary assisted, and secondary maintenance of clinical improvement were, respectively, 79.9%, 94.6%, and 98.6% at 2 years. The predictive factors for clinical degradation were clinical stage (Rutherford category 5 or 6, P = .024), platelet aggregation inhibitor treatment other than clopidogrel (P = .005), malnutrition (P = .025), and bad tibial runoff (P = .0016). A reintervention was necessary in 18.3% of limbs at 2 years: 2% involving femoral bifurcation, 6.1% inflow improvement, and 9.5% outflow improvement. The risk factors of reintervention were platelet aggregation inhibitor (other than clopidogrel, P = .049) and cancer (P = .011). Limb preservation at 2 years was 100% in the claudicant population. Limb salvage was 88.6% in the critical limb ischemia population, with a statistically higher rate for patients with malnutrition (P = .029), preoperative platelet count >450 ×10(9)/L (P = .0071), platelet aggregation inhibitor treatment other than clopidogrel (P = .022), preoperative deep femoral artery occlusion or stenosis >75% (P = .0064), and poor tibial runoff (P = .00042). Eversion femoral bifurcation endarterectomy is a safe, efficient, and reproducible technique for the treatment of atherosclerotic femoral lesions. Advantages are notable, especially the lack of need for prosthetic angioplasty, eliminating the risk of patch infection or pseudoaneurysms and permitting direct puncture if endovascular procedures are needed for assisted patency. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Magnetic Resonance Imaging Allows the Evaluation of Tissue Damage and Regeneration in a Mouse Model of Critical Limb Ischemia.

PubMed

Zaccagnini, Germana; Palmisano, Anna; Canu, Tamara; Maimone, Biagina; Lo Russo, Francesco M; Ambrogi, Federico; Gaetano, Carlo; De Cobelli, Francesco; Del Maschio, Alessandro; Esposito, Antonio; Martelli, Fabio

2015-01-01

Magnetic resonance imaging (MRI) provides non-invasive, repetitive measures in the same individual, allowing the study of a physio-pathological event over time. In this study, we tested the performance of 7 Tesla multi-parametric MRI to monitor the dynamic changes of mouse skeletal muscle injury and regeneration upon acute ischemia induced by femoral artery dissection. T2-mapping (T2 relaxation time), diffusion-tensor imaging (Fractional Anisotropy) and perfusion by Dynamic Contrast-Enhanced MRI (K-trans) were measured and imaging results were correlated with histological morphometric analysis in both Gastrocnemius and Tibialis anterior muscles. We found that tissue damage positively correlated with T2-relaxation time, while myofiber regeneration and capillary density positively correlated with Fractional Anisotropy. Interestingly, K-trans positively correlated with capillary density. Accordingly, repeated MRI measurements between day 1 and day 28 after surgery in ischemic muscles showed that: 1) T2-relaxation time rapidly increased upon ischemia and then gradually declined, returning almost to basal level in the last phases of the regeneration process; 2) Fractional Anisotropy dropped upon ischemic damage induction and then recovered along with muscle regeneration and neoangiogenesis; 3) K-trans reached a minimum upon ischemia, then progressively recovered. Overall, Gastrocnemius and Tibialis anterior muscles displayed similar patterns of MRI parameters dynamic, with more marked responses and less variability in Tibialis anterior. We conclude that MRI provides quantitative information about both tissue damage after ischemia and the subsequent vascular and muscle regeneration, accounting for the differences between subjects and, within the same individual, between different muscles.

Use of a Temporary Shunt as a Salvage Technique for Distal Extremity Amputations Requiring Repair by Vessel Grafting during Critical Ischemia

PubMed Central

Dadaci, Mehmet; Altuntas, Zeynep

2016-01-01

Background Although the use of temporary shunts in proximal extremity amputations has been reported, no study has described the use of temporary shunts in distal extremity amputations that require vein grafting. Moreover, the total volume of blood loss when temporary shunts are used has not been reported. The aim of this study was to investigate the applicability of a temporary shunt for distal extremity amputations requiring repair by vessel grafting with an ischemia time of >6 hours. This study also aimed to determine the total volume of blood loss when temporary shunts were used. Methods Patients who underwent distal major extremity replantation and/or revascularization with a vessel graft and who experienced ischemia for 6–8 hours between 2013 and 2014 were included in the study. A 6-Fr suction catheter was cut to 5 cm in length after the infusion of heparin, and secured with a 5-0 silk suture between the distal and the proximal ends of the artery. While bleeding continued, the bones were shortened and fixed. After the complete restoration of circulation, the arterial shunt created using the catheter was also repaired with a vein graft. Results Six patients were included in this study. The mean duration of ischemia was 7.25 hours. The mean duration of suction catheter use during limb revascularization was 7 minutes. The mean transfusion volume was 7.5 units. No losses of the extremity were observed. Conclusions This procedure should be considered in distal extremity amputations requiring repair by vessel grafting during critical ischemia. PMID:27896186

Early Outcomes following Endovascular, Open Surgical, and Hybrid Revascularization for Lower Extremity Acute Limb Ischemia.

PubMed

Davis, Frank M; Albright, Jeremy; Gallagher, Katherine A; Gurm, Hitinder S; Koenig, Gerald C; Schreiber, Theodore; Grossman, P Michael; Henke, Peter K

2018-03-05

Acute limb ischemia (ALI) of the lower extremity is a potentially devastating condition that requires urgent and definitive management. This challenging scenario is often treated with endovascular, open surgical, or hybrid revascularization (HyR) in an urgent basis, but the comparative effects of such therapies remain poorly defined. The purpose of this study was to compare the outcomes of endovascular, open surgical, and HyR for ALI in the contemporary era. A large statewide cardiovascular consortium of 45 hospitals was queried for patients between January 2012 and June 2015 who underwent an endovascular, open surgical, or HyR for ALI deemed at high risk of limb loss if not treated within 24 hr (Rutherford class IIA or IIB). A propensity score weighted analysis was performed controlling for demographics, medical history, and procedure type for patients. The primary outcomes were 30-day morbidity and mortality. A total of 1,480 patients underwent endovascular revascularization (ER; n = 818), open surgical revascularization (OSR; n = 195), or hybrid revascularization (HyR; n = 467) for ALI. The mean age was similar across revascularization technique with an increased predominance of male gender in open surgery cohort. Comorbidities for all groups were consistent with peripheral arterial disease. The most common endovascular procedures were angioplasty (93%) and thrombolysis (49.8%), whereas the most common surgical revascularization was femoral to popliteal bypass (32.8%), femoral to tibial bypass (28.2%), and thrombectomy (19.0%); ER as compared with OSR and HyR procedures was associated with less transfusion (OSR versus ER, odds ratio [OR] 2.7; HyR versus ER, OR 2.8; P < 0.001) and major amputation (OSR versus ER, OR 3.4; HyR versus ER, OR 4.0; P < 0.001) within 30 days of intervention. There was no difference in 30-day freedom from reintervention, myocardial infarction (MI), or mortality. Among patients requiring urgent revascularization for Rutherford grade IIA and IIB ischemia, ER has lower 30-day morbidity but similar mortality and rates of reintervention. Although long-term patency rates were not compared, ER may offer superior short-term outcomes compared with open surgery and hybrid revascularization. Copyright © 2018 Elsevier Inc. All rights reserved.

A Phase 1 Study of a Novel Bidirectional Perfusion Cannula in Patients Undergoing Femoral Cannulation for Cardiac Surgery.

PubMed

Marasco, Silvana F; Tutungi, Elli; Vallance, Shirley A; Udy, Andrew A; Negri, Justin C; Zimmet, Adam D; McGiffin, David C; Pellegrino, Vincent A; Moshinsky, Randall A

Leg ischemia is a serious complication of femoral artery cannulation. The primary aim of this study was to assess the safety and efficacy of a novel bidirectional femoral arterial cannula (Sorin Group USA, a wholly owned subsidiary of LivaNova PLC, Arvada, CO USA) that provides both antegrade and retrograde flow, in patients undergoing peripheral cannulation for cardiopulmonary bypass during cardiac surgery. Patients undergoing routine cardiac surgery requiring femoral artery cannulation for cardiopulmonary bypass were identified preoperatively. Informed written consent was obtained in all cases. Bidirectional cannula insertion used either a surgical cut-down and wire through needle approach or a percutaneous technique. Flow in the superficial femoral artery was assessed using Doppler ultrasound after commencement of cardiopulmonary bypass. Lower limb perfusion was assessed using reflectance near-infrared spectroscopy to measure regional oxygen saturations in the cannulated limb during cardiopulmonary bypass. Fifteen patients (median age = 61.3 years, range = 26-79 years, 10 males, 5 females) underwent femoral arterial cannulation using the novel bidirectional femoral cannula between August 2016 and May 2017. Fourteen cannulae were inserted directly into the femoral artery via a surgical cut-down and wire through needle technique. One bidirectional cannula was inserted using a percutaneous insertion technique. Indications included minimally invasive mitral and aortic valve surgery, thoracic aortic aneurysm repair, and redo cardiac surgery. The median duration of cardiopulmonary bypass was 129 minutes (range = 53-228 minutes). The cannula was inserted and positioned without difficulty in 14 of 15 patients. Incorrect sizing and arterial spasm prevented correct cannula positioning in one patient. Antegrade flow in the superficial femoral artery was observed on Doppler ultrasound in 12 of 12 patients in which this was performed. Continuous stable distal perfusion was demonstrated in the cannulated limb in 14 of 15 patients. No procedural complications occurred in the immediate or convalescent postoperative period. This study demonstrates that in patients undergoing femoral arterial cannulation for cardiopulmonary bypass during cardiac surgery, the use of a novel bidirectional cannula is safe and easy to insert and provides stable distal perfusion of the cannulated limb. Use of the device should largely obviate the need to insert a separate downstream perfusion cannula or use other techniques to protect against lower limb ischemia. Further research on a larger scale and in different patient populations is now warranted.

Endovascular treatment of atherosclerotic popliteal artery disease based on dynamic angiography findings.

PubMed

Cui, Chaoyi; Huang, Xintian; Liu, Xiaobing; Li, Weimin; Lu, Xinwu; Lu, Min; Jiang, Mier; Yin, Minyi

2017-01-01

To evaluate efficacy, safety, and midterm patency of endovascular treatment of obstructive popliteal artery (PA) disease. A retrospective evaluation of patients with atherosclerotic PA disease who underwent percutaneous transluminal balloon angioplasty and provisional stent, based on both conventional and dynamic angiographies, was conducted from June 2011 to June 2014. Forty-three patients were included in the study, and most patients had limited surgical revascularization options. Demographic characteristics, angiographic findings, interventional data, complications, vessel patency, limb salvage rates, and survival rates were analyzed. The median lesion length was 5 cm with 72.1% having total occlusions. The second popliteal segment (P2) was involved most frequently (60.5%, n = 26). Critical limb ischemia was present in 69.8%. The technical success rate was 92.9% (42/43 limbs), with 29 cases requiring adjunctive nitinol stents after balloon angioplasty (47.6% based on conventional angiography, 21.4% based on dynamic angiography, and 4.8% additional stents based on dynamic angiography). Complications included thromboembolism (2.3%), perforation (2.3%), pseudoaneurysm (2.3%), and myocardial infarction (2.3%). Stent fracture was present in three cases (7.1%) during the mean follow-up period of 18.3 months. The baseline ankle-brachial index significantly improved after the intervention, from 0.49 ± 0.11 to 0.92 ± 0.14 (P < .01). The Rutherford-Becker class decreased from 3.95 ± 0.76 to 1.76 ± 0.95 (P < .01) at 12 months. The 1-year primary, primary-assisted, and secondary patency rates were 75.2% ± 6.8%, 82.4% ± 6.0%, and 89.9% ± 4.8%, respectively. The limb salvage and amputation-free survival rates at 12 months were 91.6% and 87.0%, respectively. Balloon angioplasty with a provisional stent based on dynamic angiography is a feasible, safe, and effective therapy for patients with obstructive PA disease. Although the occurrence of stent fracture is still inevitable, patients with critical limb ischemia who have limited surgical options may get more benefits from the endovascular treatment of PA obstructive diseases. Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Language Control Abilities of Late Bilinguals

ERIC Educational Resources Information Center

Festman, Julia

2012-01-01

Although all bilinguals encounter cross-language interference (CLI), some bilinguals are more susceptible to interference than others. Here, we report on language performance of late bilinguals (Russian/German) on two bilingual tasks (interview, verbal fluency), their language use and switching habits. The only between-group difference was CLI:…

Measuring achievement goal motivation, mindsets and cognitive load: validation of three instruments' scores.

PubMed

Cook, David A; Castillo, Richmond M; Gas, Becca; Artino, Anthony R

2017-10-01

Measurement of motivation and cognitive load has potential value in health professions education. Our objective was to evaluate the validity of scores from Dweck's Implicit Theories of Intelligence Scale (ITIS), Elliot's Achievement Goal Questionnaire-Revised (AGQ-R) and Leppink's cognitive load index (CLI). This was a validity study evaluating internal structure using reliability and factor analysis, and relationships with other variables using the multitrait-multimethod matrix. Two hundred and thirty-two secondary school students participated in a medical simulation-based training activity at an academic medical center. Pre-activity ITIS (implicit theory [mindset] domains: incremental, entity) and AGQ-R (achievement goal domains: mastery-approach, mastery-avoidance, performance-approach, performance-avoidance), post-activity CLI (cognitive load domains: intrinsic, extrinsic, germane) and task persistence (self-directed repetitions on a laparoscopic surgery task) were measured. Internal consistency reliability (Cronbach's alpha) was > 0.70 for all domain scores except AGQ-R performance-avoidance (alpha 0.68) and CLI extrinsic load (alpha 0.64). Confirmatory factor analysis of ITIS and CLI scores demonstrated acceptable model fit. Confirmatory factor analysis of AGQ-R scores demonstrated borderline fit, and exploratory factor analysis suggested a three-domain model for achievement goals (mastery-approach, performance and avoidance). Correlations among scores from conceptually-related domains generally aligned with expectations, as follows: ITIS incremental and entity, r = -0.52; AGQ-R mastery-avoidance and performance-avoidance, r = 0.71; mastery-approach and performance-approach, r = 0.55; performance-approach and performance-avoidance, r = 0.43; mastery-approach and mastery-avoidance, r = 0.36; CLI germane and extrinsic, r = -0.35; ITIS incremental and AGQ-R mastery-approach, r = 0.34; ITIS incremental and CLI germane, r = 0.44; AGQ-R mastery-approach and CLI germane, r = 0.48 (all p < 0.001). We found no correlation between the number of task repetitions (i.e. persistence) and mastery-approach scores, r = -0.01. ITIS and CLI scores had appropriate internal structures and relationships with other variables. AGQ-R scores fit a three-factor (not four-factor) model that collapsed avoidance into one domain, although relationships of other variables with the original four domain scores generally aligned with expectations. Mastery goals are positively correlated with germane cognitive load. © 2017 John Wiley & Sons Ltd and The Association for the Study of Medical Education.

Pit Bull attack causing limb threatening vascular trauma -A case series.

PubMed

Harnarayan, Patrick; Islam, Shariful; Ramsingh, Christi; Naraynsingh, Vijay

2018-01-01

Non-fatal human dog bites are commonplace amongst animal attacks on human beings and these present with mainly skin and soft tissue injuries. However, they can also present with life threatening head and neck injuries, massive soft tissue trauma, as well as combined orthopedic and vascular extremity injuries where a high possibility of limb loss exists. We present two adult dog bite victims with multiple bites inflicted by large canines identified as Pit-Bull Terriers. They were presented with deep lacerations to the axillary area resulting in limb ischemia and loss of upper limb pulses. The right axillary artery was crushed in both patients whilst the axillary vein was lacerated in one. The vessels were repaired; the wounds debrided and both limbs were salvaged. Canine attacks by Pit Bull Terriers and Rottweiler's can occur at any age and in any anatomical area of the body particularly the limbs. Injuries involving the extremities presenting with no pulses or pulsatile bleeding demand an urgent exploration as any undue delay is intolerable especially if there are bony injuries like fractures or fracture/dislocation. All patients with complex neurovascular injuries should be managed by a multidisciplinary team for an optimal outcome. Attacks by Pit Bull Terriers are more likely to cause severe morbidity than other breeds of dogs. Immediate surgical exploration is required to prevent catastrophic outcomes, especially limb loss. Stronger animal control laws, public education and responsible dog ownership may reduce deaths from these canines. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Yeast Monitoring of Wine Mixed or Sequential Fermentations Made by Native Strains from D.O. "Vinos de Madrid" Using Real-Time Quantitative PCR.

PubMed

García, Margarita; Esteve-Zarzoso, Braulio; Crespo, Julia; Cabellos, Juan M; Arroyo, Teresa

2017-01-01

There is an increasing trend toward understanding the impact of non- Saccharomyces yeasts on the winemaking process. Although Saccharomyces cerevisiae is the predominant species at the end of fermentation, it has been recognized that the presence of non- Saccharomyces species during alcoholic fermentation can produce an improvement in the quality and complexity of the final wines. A previous work was developed for selecting the best combinations between S. cerevisiae and five non- Saccharomyces ( Torulaspora delbrueckii, Schizosaccharomyces pombe, Candida stellata, Metschnikowia pulcherrima , and Lachancea thermotolorans ) native yeast strains from D.O. "Vinos de Madrid" at the laboratory scale. The best inoculation strategies between S. cerevisiae and non- Saccharomyces strains were chosen to analyze, by real-time quantitative PCR (qPCR) combined with the use of specific primers, the dynamics of inoculated populations throughout the fermentation process at the pilot scale using the Malvar white grape variety. The efficiency of the qPCR system was verified independently of the samples matrix, founding the inoculated yeast species throughout alcoholic fermentation. Finally, we can validate the positive effect of selected co-cultures in the Malvar wine quality, highlighting the sequential cultures of T. delbrueckii CLI 918/ S. cerevisiae CLI 889 and C. stellata CLI 920/ S. cerevisiae CLI 889 and, mixed and sequential cultures of L. thermotolerans 9-6C combined with S. cerevisiae CLI 889.

Method‐of‐use study of naltrexone sustained release (SR)/bupropion SR on body weight in individuals with obesity

PubMed Central

Shan, Kevin; Walsh, Brandon; Gilder, Kye; Fujioka, Ken

2016-01-01

Objective This study assessed the effects of 32 mg naltrexone sustained release (SR)/360 mg bupropion SR (NB) on body weight in adults with obesity, with comprehensive lifestyle intervention (CLI), for 78 weeks. Methods In this phase 3b, randomized, open‐label, controlled study, subjects received NB + CLI or usual care (standard diet/exercise advice) for 26 weeks. NB subjects not achieving 5% weight loss at week 16 were discontinued, as indicated by product labeling. After week 26, usual care subjects began NB + CLI. Assessments continued through week 78. The primary end point was percent change in weight from baseline to week 26 in the per protocol population. Other end points included percentage of subjects achieving ≥5%, ≥10%, and ≥15% weight loss, percent change in weight at week 78, and adverse events (AEs) necessitating study medication discontinuation. Results NB + CLI subjects lost significantly more weight than usual care subjects at week 26 (8.52% difference; P < 0.0001). Weight loss persisted through 78 weeks. In total, 20.7% of subjects discontinued medication for AEs, including 7.0% for nausea. Conclusions Treatment with NB, used as indicated by prescribing information and with CLI, significantly improved weight loss over usual care alone. NB‐facilitated weight loss was sustained for 78 weeks and was deemed safe and well tolerated. PMID:28026920

A Structured Review of Antithrombotic Therapy in Peripheral Artery Disease With a Focus on Revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative.

PubMed

Hess, Connie N; Norgren, Lars; Ansel, Gary M; Capell, Warren H; Fletcher, John P; Fowkes, F Gerry R; Gottsäter, Anders; Hitos, Kerry; Jaff, Michael R; Nordanstig, Joakim; Hiatt, William R

2017-06-20

Peripheral artery disease affects >200 million people worldwide and is associated with significant limb and cardiovascular morbidity and mortality. Limb revascularization is recommended to improve function and quality of life for symptomatic patients with peripheral artery disease with intermittent claudication who have not responded to medical treatment. For patients with critical limb ischemia, the goals of revascularization are to relieve pain, help wound healing, and prevent limb loss. The baseline risk of cardiovascular and limb-related events demonstrated among patients with stable peripheral artery disease is elevated after revascularization and related to atherothrombosis and restenosis. Both of these processes involve platelet activation and the coagulation cascade, forming the basis for the use of antiplatelet and anticoagulant therapies to optimize procedural success and reduce postprocedural cardiovascular risk. Unfortunately, few high-quality, randomized data to support use of these therapies after peripheral artery disease revascularization exist, and much of the rationale for the use of antiplatelet agents after endovascular peripheral revascularization is extrapolated from percutaneous coronary intervention literature. Consequently, guideline recommendations for antithrombotic therapy after lower limb revascularization are inconsistent and not always evidence-based. In this context, the purpose of this structured review is to assess the available randomized data for antithrombotic therapy after peripheral arterial revascularization, with a focus on clinical trial design issues that may affect interpretation of study results, and highlight areas that require further investigation. © 2017 American Heart Association, Inc.

Adjunctive Therapy to Improve Functional Recovery after Limb Ischemia Reperfusion Injury

DTIC Science & Technology

2017-10-01

end-point for the operative procedure that reads as follows: “If an animal is observed on preparation for surgery to have an elevated exhaled end...protocol, e.g. the agent is effective even when administered after the leg has become ischemic. Given that small animal studies have been performed and...in a large animal model that better simulates the way the human body responds to treatment of this important injury process. 15. SUBJECT TERMS

Risk factors associated with self-reported symptoms of digital ischemia in elite male volleyball players in the Netherlands.

PubMed

van de Pol, D; Kuijer, P P F M; Langenhorst, T; Maas, M

2014-08-01

One in every four elite male volleyball players in the Netherlands reported blue or pale digits in the dominant hand. Little is known about risk factors. To assess whether personal-, sports-, and work-related risk factors are associated with these symptoms in these volleyball players, a survey was performed among elite male volleyball players in the Dutch national top league and in the Dutch beach volleyball team. The questionnaire assessed the presence of symptoms and risk factors. Binary logistic regression was performed to calculate odds ratios (ORs). A total of 99 of the 107 athletes participated - a response rate of 93%. Two sports-related risk factors were associated with symptoms of blue or pale digits: 18-30 years playing volleyball [OR = 6.70; 95% confidence interval (CI) 1.12-29.54] and often/always performing weight training to increase dominant limb strength (OR = 2.70; 95% CI 1.05-6.92). No significant other sports-, personal-, or work-related risk factors were found. Playing volleyball for more than 17 years and often/always performing weight training to increase dominant limb strength were independently associated with an increased risk on ischemia-related complaints of the dominant hand in elite male volleyball players. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Unilateral iliofemoral occlusive disease: long-term results of the semi-closed endarterectomy with the ring-stripper.

PubMed

van den Dungen, J J; Boontje, A H; Kropveld, A

1991-11-01

Nowadays, fewer endarterectomies are performed for treatment of occlusive arterial disease; more often a bypass procedure is done. This study investigates whether the results of the semiclosed endarterectomy for unilateral iliofemoral occlusive disease indeed indicate a wider use of bypass procedures for such short obstructions. Ninety-four patients with an obstructed external iliac and common femoral artery, but with patent ipsilateral common iliac and contralateral iliac arteries, underwent 101 operations. Seven of these patients were operated on at a later stage for occlusive disease on the contralateral side. Ninety-three endarterectomies were performed, and an iliofemoral bypass graft was inserted eight times because an endarterectomy was not feasible. Sixty-two operations were performed for disabling claudication, and 39 operations were performed for limb-threatening ischemia. Eighty-five percent of the patients who underwent an endarterectomy for disabling claudication became asymptomatic. Eighty percent of the patients who underwent an endarterectomy for limb-threatening ischemia became asymptomatic or improved to claudication. After endarterectomy no deaths, false aneurysms, or infections occurred. The patency rates at 1, 5, and 10 years were 94%, 83%, and 65%, respectively. We conclude that the semiclosed endarterectomy with the ringstripper of a unilateral obstruction of one external iliac and common femoral artery can be performed with a low morbidity and without deaths and gives good long-term results.

47 CFR 76.1804 - Aeronautical frequencies: leakage monitoring (CLI).

Code of Federal Regulations, 2010 CFR

2010-10-01

... through 76.616 and § 76.1803; (d) Carrier frequency, tolerance, and type of modulation of all carriers in... 47 Telecommunication 4 2010-10-01 2010-10-01 false Aeronautical frequencies: leakage monitoring... Aeronautical frequencies: leakage monitoring (CLI). An MVPD shall notify the Commission before transmitting any...

Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease.

PubMed

Hiatt, William R; Fowkes, F Gerry R; Heizer, Gretchen; Berger, Jeffrey S; Baumgartner, Iris; Held, Peter; Katona, Brian G; Mahaffey, Kenneth W; Norgren, Lars; Jones, W Schuyler; Blomster, Juuso; Millegård, Marcus; Reist, Craig; Patel, Manesh R

2017-01-05

Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease. In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months. The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49). In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).

Attenuation of Skeletal Muscle and Renal Injury to the Lower Limb following Ischemia-Reperfusion Using mPTP Inhibitor NIM-811

PubMed Central

Garbaisz, David; Turoczi, Zsolt; Aranyi, Peter; Fulop, Andras; Rosero, Oliver; Hermesz, Edit; Ferencz, Agnes; Lotz, Gabor; Harsanyi, Laszlo; Szijarto, Attila

2014-01-01

Introduction Operation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. NIM-811 (N-metyl-4-isoleucine-cyclosporine) is a mitochondria specific drug, which can prevent ischemic-reperfusion (IR) injury, by inhibiting mitochondrial permeability transition pores (mPTP). Objectives Our aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811. Materials and methods Wistar rats underwent 180 minutes of bilateral lower limb ischemia and 240 minutes of reperfusion. Four animal groups were formed called Sham (receiving vehicle and sham surgery), NIM-Sham (receiving NIM-811 and sham surgery), IR (receiving vehicle and surgery), and NIM-IR (receiving NIM-811 and surgery). Serum, urine and histological samples were taken at the end of reperfusion. NADH-tetrazolium staining, muscle Wet/Dry (W/D) ratio calculations, laser Doppler-flowmetry (LDF) and mean arterial pressure (MAP) monitoring were performed. Renal peroxynitrite concentration, serum TNF-α and IL-6 levels were measured. Results Less significant histopathological changes were observable in the NIM-IR group as compared with the IR group. Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p<0.001; CK: p<0.001; K+: p = 0.017). Muscle mitochondrial viability proved to be significantly higher (p = 0.001) and renal function parameters were significantly better (creatinine: p = 0.016; FENa: p<0.001) in the NIM-IR group in comparison to the IR group. Serum TNF-α and IL-6 levels were significantly lower (TNF-α: p = 0.003, IL-6: p = 0.040) as well as W/D ratio and peroxynitrite concentration were significantly lower (p = 0.014; p<0.001) in the NIM-IR group than in the IR group. Conclusion NIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury. PMID:24968303

Attenuation of skeletal muscle and renal injury to the lower limb following ischemia-reperfusion using mPTP inhibitor NIM-811.

PubMed

Garbaisz, David; Turoczi, Zsolt; Aranyi, Peter; Fulop, Andras; Rosero, Oliver; Hermesz, Edit; Ferencz, Agnes; Lotz, Gabor; Harsanyi, Laszlo; Szijarto, Attila

2014-01-01

Operation on the infrarenal aorta and large arteries of the lower extremities may cause rhabdomyolysis of the skeletal muscle, which in turn may induce remote kidney injury. NIM-811 (N-metyl-4-isoleucine-cyclosporine) is a mitochondria specific drug, which can prevent ischemic-reperfusion (IR) injury, by inhibiting mitochondrial permeability transition pores (mPTP). Our aim was to reduce damages in the skeletal muscle and the kidney after IR of the lower limb with NIM-811. Wistar rats underwent 180 minutes of bilateral lower limb ischemia and 240 minutes of reperfusion. Four animal groups were formed called Sham (receiving vehicle and sham surgery), NIM-Sham (receiving NIM-811 and sham surgery), IR (receiving vehicle and surgery), and NIM-IR (receiving NIM-811 and surgery). Serum, urine and histological samples were taken at the end of reperfusion. NADH-tetrazolium staining, muscle Wet/Dry (W/D) ratio calculations, laser Doppler-flowmetry (LDF) and mean arterial pressure (MAP) monitoring were performed. Renal peroxynitrite concentration, serum TNF-α and IL-6 levels were measured. Less significant histopathological changes were observable in the NIM-IR group as compared with the IR group. Serum K+ and necroenzyme levels were significantly lower in the NIM-IR group than in the IR group (LDH: p<0.001; CK: p<0.001; K+: p = 0.017). Muscle mitochondrial viability proved to be significantly higher (p = 0.001) and renal function parameters were significantly better (creatinine: p = 0.016; FENa: p<0.001) in the NIM-IR group in comparison to the IR group. Serum TNF-α and IL-6 levels were significantly lower (TNF-α: p = 0.003, IL-6: p = 0.040) as well as W/D ratio and peroxynitrite concentration were significantly lower (p = 0.014; p<0.001) in the NIM-IR group than in the IR group. NIM-811 could have the potential of reducing rhabdomyolysis and impairment of the kidney after lower limb IR injury.

Cerenkov and radioluminescence imaging of brain tumor specimens during neurosurgery

NASA Astrophysics Data System (ADS)

Spinelli, Antonello Enrico; Schiariti, Marco P.; Grana, Chiara M.; Ferrari, Mahila; Cremonesi, Marta; Boschi, Federico

2016-05-01

We presented the first example of Cerenkov luminescence imaging (CLI) and radioluminescence imaging (RLI) of human tumor specimens. A patient with a brain meningioma localized in the left parietal region was injected with 166 MBq of Y90-DOTATOC the day before neurosurgery. The specimens of the tumor removed during surgery were imaged using both CLI and RLI using an optical imager prototype developed in our laboratory. The system is based on a cooled electron multiplied charge coupled device coupled with an f/0.95 17-mm C-mount lens. We showed for the first time the possibility of obtaining CLI and RLI images of fresh human brain tumor specimens removed during neurosurgery.

Therapeutic neovascularization by nanotechnology-mediated cell-selective delivery of pitavastatin into the vascular endothelium.

PubMed

Kubo, Mitsuki; Egashira, Kensuke; Inoue, Takahiro; Koga, Jun-ichiro; Oda, Shinichiro; Chen, Ling; Nakano, Kaku; Matoba, Tetsuya; Kawashima, Yoshiaki; Hara, Kaori; Tsujimoto, Hiroyuki; Sueishi, Katsuo; Tominaga, Ryuji; Sunagawa, Kenji

2009-06-01

Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization. In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice. NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia.

Ensuring Lessons Teach the Curriculum with a Lesson Plan Resource

ERIC Educational Resources Information Center

Craft, Heddi; Bland, Paul D.

2004-01-01

The Curriculum Leadership Institute (CLI) and classroom teachers working in conjunction with Emporia State University in Emporia, Kansas, developed the Lesson Plan Resource system. The CLI is a not-for-profit school consulting and publishing firm, also based in Emporia, Kansas, whose curriculum development model is used in over 1,000 schools in…

Cost Improvement Analysis

DTIC Science & Technology

1986-06-01

Cc) Ul y Cli U;ra ISO or.) . ............ t cc fl .9 it it ý I oli CC) I it cli L3 I HIM .......... 114 t4l t.r IM...Burroughz Cost AFIT/LSQ AV785-6280 Curve Programs Prof. Jeff Daneman Z-100 Cost Curve ASD/ACCR AV785- 8583 Programs Capt Arthur Mills * *- PROGRAMS CONCEPT

Content-Language Integrated Second Language Instruction: Curriculum and the CCUEI Context

ERIC Educational Resources Information Center

Trube, Mary Barbara

2012-01-01

This paper examines the content-language integrated (CLI) second language (L2) education offered by the CCUEI Research Collaborative in China. It explores how CCUEI-developed curriculum reflects the theoretical foundations of an immersion experiment and how the research-based theoretical foundations of CLI L2 have been applied in practice. It…

DETECTION OF TWO ISOMERIC BINDING CONFIGURATIONS IN A PROTEIN-APTAMER COMPLEX WITH A BIOLOGICAL NANOPORE

PubMed Central

Van Meervelt, Veerle; Soskine, Misha; Maglia, Giovanni

2015-01-01

Protein-DNA interactions play critical roles in biological systems, and they often involve complex mechanisms and dynamics that are not easily measured by ensemble experiments. Recently, we have shown that folded proteins can be internalised inside ClyA nanopores and studied by ionic current recordings at the single-molecule level. Here, we use ClyA nanopores to sample the interaction between the G-quadruplex fold of the thrombin binding aptamer (TBA) and human thrombin (HT). Surprisingly, the internalisation of the HT:TBA complex inside the nanopore induced two types of current blockades with distinguished residual current and lifetime. Using single nucleobase substitutions to TBA we showed that these two types of blockades originate from TBA binding to thrombin with two isomeric orientations. Voltage dependencies and the use of ClyA nanopores with two different diameters allowed assessing the effect of the applied potential and confinement, and revealed that the two binding configurations of TBA to HT display different lifetimes. These results show that the ClyA nanopores might provide a new approach to probe conformational heterogeneity in protein:DNA interactions. PMID:25493908

Review of biomedical Čerenkov luminescence imaging applications

PubMed Central

Tanha, Kaveh; Pashazadeh, Ali Mahmoud; Pogue, Brian W

2015-01-01

Čerenkov radiation is a fascinating optical signal, which has been exploited for unique diagnostic biological sensing and imaging, with significantly expanded use just in the last half decade. Čerenkov Luminescence Imaging (CLI) has desirable capabilities for niche applications, using specially designed measurement systems that report on radiation distributions, radiotracer and nanoparticle concentrations, and are directly applied to procedures such as medicine assessment, endoscopy, surgery, quality assurance and dosimetry. When compared to the other imaging tools such as PET and SPECT, CLI can have the key advantage of lower cost, higher throughput and lower imaging time. CLI can also provide imaging and dosimetry information from both radioisotopes and linear accelerator irradiation. The relatively short range of optical photon transport in tissue means that direct Čerenkov luminescence imaging is restricted to small animals or near surface human use. Use of Čerenkov-excitation for additional molecular probes, is now emerging as a key tool for biosensing or radiosensitization. This review evaluates these new improvements in CLI for both medical value and biological insight. PMID:26309766

Yeast Monitoring of Wine Mixed or Sequential Fermentations Made by Native Strains from D.O. “Vinos de Madrid” Using Real-Time Quantitative PCR

PubMed Central

García, Margarita; Esteve-Zarzoso, Braulio; Crespo, Julia; Cabellos, Juan M.; Arroyo, Teresa

2017-01-01

There is an increasing trend toward understanding the impact of non-Saccharomyces yeasts on the winemaking process. Although Saccharomyces cerevisiae is the predominant species at the end of fermentation, it has been recognized that the presence of non-Saccharomyces species during alcoholic fermentation can produce an improvement in the quality and complexity of the final wines. A previous work was developed for selecting the best combinations between S. cerevisiae and five non-Saccharomyces (Torulaspora delbrueckii, Schizosaccharomyces pombe, Candida stellata, Metschnikowia pulcherrima, and Lachancea thermotolorans) native yeast strains from D.O. “Vinos de Madrid” at the laboratory scale. The best inoculation strategies between S. cerevisiae and non-Saccharomyces strains were chosen to analyze, by real-time quantitative PCR (qPCR) combined with the use of specific primers, the dynamics of inoculated populations throughout the fermentation process at the pilot scale using the Malvar white grape variety. The efficiency of the qPCR system was verified independently of the samples matrix, founding the inoculated yeast species throughout alcoholic fermentation. Finally, we can validate the positive effect of selected co-cultures in the Malvar wine quality, highlighting the sequential cultures of T. delbrueckii CLI 918/S. cerevisiae CLI 889 and C. stellata CLI 920/S. cerevisiae CLI 889 and, mixed and sequential cultures of L. thermotolerans 9-6C combined with S. cerevisiae CLI 889. PMID:29326669

Dynamic [Cl-]i measurement with chloride sensing quantum dots nanosensor in epithelial cells

NASA Astrophysics Data System (ADS)

Wang, Yuchi; Mao, Hua; Wong, Lid B.

2010-02-01

We have synthesized a chloride sensing quantum dots (QD) nanosensor, Cl-QD, for the dynamic measurements of chloride ion concentration in the millimolar range, a sensitivity that is applicable to most physiological intracellular chloride ion concentration ([Cl-]i) measurements in epithelial cells. The Cl-QD is synthesized by conjugating an anion receptor, 1-(2-mercapto-ethyl)-3-phenyl-thiourea (MEPTU) to a water soluble CdSe/ZnS QD at an emission wavelength of 620 nm. Upon binding of chloride ions to the Cl-QD, a photo-induced electron transfer mechanism caused the fluorescence of the QD to quench. This resulted in an inversely proportional relationship between the chloride ion concentration and the fluorescence intensity of the Cl-QD. We have utilized this Cl-QD to measure [Cl-]i in T84 and CF-PAC cultured cells, with either the C1C-2 or CFTR chloride channels being manipulated by pharmacological chloride channel activators and inhibitors. Activations of C1C-2 and CFTR chloride channels in T84 by the respective lubiprostone and genistein caused predictive increases in the fluorescence of the Cl-QD, i.e., a decrease of [Cl-]i. Conversely, glibenclamide, a chloride channel inhibitor, applied to the CF-PAC cells caused a predictable decrease in the fluorescence of Cl-QD due to the increase of [Cl-]i. These are the first data in using QD-based chloride ion sensors for dynamic measurements of intracellular chloride ion concentrations in epithelial cells.

H₂S protecting against lung injury following limb ischemia-reperfusion by alleviating inflammation and water transport abnormality in rats.

PubMed

Qi, Qi Ying Chun; Chen, Wen; Li, Xiao Ling; Wang, Yu Wei; Xie, Xiao Hua

2014-06-01

To investigate the effect of H₂S on lower limb ischemia-reperfusion (LIR) induced lung injury and explore the underlying mechanism. Wistar rats were randomly divided into control group, IR group, IR+ Sodium Hydrosulphide (NaHS) group and IR+ DL-propargylglycine (PPG) group. IR group as lung injury model induced by LIR were given 4 h reperfusion following 4 h ischemia of bilateral hindlimbs with rubber bands. NaHS (0.78 mg/kg) as exogenous H₂S donor and PPG (60 mg/kg) which can suppress endogenous H₂S production were administrated before LIR, respectively. The lungs were removed for histologic analysis, the determination of wet-to-dry weight ratios and the measurement of mRNA and protein levels of aquaporin-1 (AQP₁), aquaporin-5 (AQP₅) as indexes of water transport abnormality, and mRNA and protein levels of Toll-like receptor 4 (TLR₄), myeloid differentiation primary-response gene 88 (MyD88) and p-NF-κB as indexes of inflammation. LIR induced lung injury was accompanied with upregulation of TLR₄-Myd88-NF-κB pathway and downregulation of AQP1/AQP₅. NaHS pre-treatment reduced lung injury with increasing AQP₁/AQP₅ expression and inhibition of TLR₄-Myd88-NF-κB pathway, but PPG adjusted AQP₁/AQP₅ and TLR4 pathway to the opposite side and exacerbated lung injury. Endogenous H₂S, TLR₄-Myd88-NF-κB pathway and AQP₁/AQP₅ were involved in LIR induced lung injury. Increased H₂S would alleviate lung injury and the effect is at least partially depend on the adjustment of TLR₄-Myd88-NF-κB pathway and AQP₁/AQP₅ expression to reduce inflammatory reaction and lessen pulmonary edema. Copyright © 2014 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Type 2 diabetes impairs the ability of skeletal muscle pericytes to augment postischemic neovascularization in db/db mice.

PubMed

Hayes, Katherine L; Messina, Louis M; Schwartz, Lawrence M; Yan, Jinglian; Burnside, Amy S; Witkowski, Sarah

2018-05-01

Peripheral artery disease is an atherosclerotic occlusive disease that causes limb ischemia and has few effective noninterventional treatments. Stem cell therapy is promising, but concomitant diabetes may limit its effectiveness. We evaluated the therapeutic potential of skeletal muscle pericytes to augment postischemic neovascularization in wild-type and type 2 diabetic (T2DM) mice. Wild-type C57BL/6J and leptin receptor spontaneous mutation db/db T2DM mice underwent unilateral femoral artery excision to induce limb ischemia. Twenty-four hours after ischemia induction, CD45 - CD34 - CD146 + skeletal muscle pericytes or vehicle controls were transplanted into ischemic hindlimb muscles. At postoperative day 28, pericyte transplantation augmented blood flow recovery in wild-type mice (79.3 ± 5% vs. 61.9 ± 5%; P = 0.04), but not in T2DM mice (48.6% vs. 46.3 ± 5%; P = 0.51). Pericyte transplantation augmented collateral artery enlargement in wild-type (26.7 ± 2 μm vs. 22.3 ± 1 μm, P = 0.03), but not T2DM mice (20.4 ± 1.4 μm vs. 18.5 ± 1.2 μm, P = 0.14). Pericyte incorporation into collateral arteries was higher in wild-type than in T2DM mice ( P = 0.002). Unexpectedly, pericytes differentiated into Schwann cells in vivo. In vitro, Insulin increased Nox2 expression and decreased tubular formation capacity in human pericytes. These insulin-induced effects were reversed by N-acetylcysteine antioxidant treatment. In conclusion, T2DM impairs the ability of pericytes to augment neovascularization via decreased collateral artery enlargement and impaired engraftment into collateral arteries, potentially via hyperinsulinemia-induced oxidant stress. While pericytes show promise as a unique form of stem cell therapy to increase postischemic neovascularization, characterizing the molecular mechanisms by which T2DM impairs their function is essential to achieve their therapeutic potential.

Fatigue-related firing of distal muscle nociceptors reduces voluntary activation of proximal muscles of the same limb.

PubMed

Kennedy, David S; McNeil, Chris J; Gandevia, Simon C; Taylor, Janet L

2014-02-15

With fatiguing exercise, firing of group III/IV muscle afferents reduces voluntary activation and force of the exercised muscles. These afferents can also act across agonist/antagonist pairs, reducing voluntary activation and force in nonfatigued muscles. We hypothesized that maintained firing of group III/IV muscle afferents after a fatiguing adductor pollicis (AP) contraction would decrease voluntary activation and force of AP and ipsilateral elbow flexors. In two experiments (n = 10) we examined voluntary activation of AP and elbow flexors by measuring changes in superimposed twitches evoked by ulnar nerve stimulation and transcranial magnetic stimulation of the motor cortex, respectively. Inflation of a sphygmomanometer cuff after a 2-min AP maximal voluntary contraction (MVC) blocked circulation of the hand for 2 min and maintained firing of group III/IV muscle afferents. After a 2-min AP MVC, maximal AP voluntary activation was lower with than without ischemia (56.2 ± 17.7% vs. 76.3 ± 14.6%; mean ± SD; P < 0.05) as was force (40.3 ± 12.8% vs. 57.1 ± 13.8% peak MVC; P < 0.05). Likewise, after a 2-min AP MVC, elbow flexion voluntary activation was lower with than without ischemia (88.3 ± 7.5% vs. 93.6 ± 3.9%; P < 0.05) as was torque (80.2 ± 4.6% vs. 86.6 ± 1.0% peak MVC; P < 0.05). Pain during ischemia was reported as Moderate to Very Strong. Postfatigue firing of group III/IV muscle afferents from the hand decreased voluntary drive and force of AP. Moreover, this effect decreased voluntary drive and torque of proximal unfatigued muscles, the elbow flexors. Fatigue-sensitive group III/IV muscle nociceptors act to limit voluntary drive not only to fatigued muscles but also to unfatigued muscles within the same limb.

Influence of sildenafil and donepezil administration on the serum redox balance in experimentally induced lower limb critical ischemia.

PubMed

Constantinescu, Mihaela Ioana; Constantinescu, Dan Petru; Andercou, Aurel; Mironiuc, Ion Aurel

2013-01-01

Chronic lower limb ischemia (CLLI) leads to endothelial cell dysfunctions and endothelial lesions. The use of substances that release nitric oxide and activate endothelial nitric oxide synthase has proved to be useful in increasing angiogenesis and arteriogenesis under critical ischemia conditions. To investigate the therapeutic effect of Sildenafil and Donepezil with a vasodilating action in experimentally induced CLLI and on serum redox homeostasis. The research was performed in 3 groups of rats (n=10 animals/group) with experimentally induced CLLI: group I - control group; group II - animals treated postoperatively with a therapeutic dose of sildenafil, and group III - animals treated postoperatively with a therapeutic dose of donepezil. Oxidative stress (OS) indicators (malondialdehyde - MDA, protein carbonyls - PC), antioxidant (AO) defense indicators (reduced glutathione - GSH and oxidized glutathione - GSSH), and ceruloplasmin (CP) were determined on days 7, 14, 21 and 30. Statistical processing was performed using the Excel application (Microsoft Office 2007), with the StatsDirect v.2.7.2 software. Changes in OS were evidenced in all groups on account of a decrease in MDA and PC. The greatest OS decrease in all groups was on day 30. AO defence changes were represented by decreased levels of GSH and GSSG in all groups, at the studied moments. Intracellular AO defense in the cytosol, nucleus and mitochondria was similar in all groups, (decreased GSH, GSSG and GSH/GSSG ratio). We found increased extracellular levels of GSH, GSSG, and CP and increased extracellular GSH/GSSG ratio at level compared to values on day 7. 1) The administration of sildenafil (group II) and donepezil (group III) has favorable effects on reducing OS in experimentally induced CLLI. 2) Sildenafil and Donepezil administration stimulates extracellular AO defense on account of CP. 3) Sildenafil and Donepezil administration influences intracellular redox homeostasis on account of the GSH/GSSG couple, the major redox buffer in the body.

Structural and electrochemical properties of the doped spinels Li 1.05M 0.02Mn 1.98O 3.98N 0.02 (M = Ga 3+, Al 3+, or Co 3+; N = S 2- or F -) for use as cathode material in lithium batteries

NASA Astrophysics Data System (ADS)

Amaral, Fábio A.; Bocchi, Nerilso; Brocenschi, Ricardo F.; Biaggio, Sonia R.; Rocha-Filho, Romeu C.

The doped and milled spinels Li 1.05M 0.02Mn 1.98O 3.98N 0.02 (M = Ga 3+, Al 3+ or Co 3+; N = S 2- or F -) are studied aiming at obtaining an improved charge/discharge cycling performance. These spinels are prepared by a solid-state reaction among the precursors ɛ-MnO 2, LiOH, and the respective oxide/salt of the doping ions at 750 °C for 72 h and milled for 30 min. The obtained spinels are characterized by XRD, SEM, and determinations of the average manganese valence n. In the charge and discharge tests, the doped spinels present outstanding initial values of the specific discharge capacity C (117-126 mA h g -1), decreasing in the following order: C(Li 1.05Al 0.02Mn 1.98S 3.02O 3.98) > C(Li 1.05Al 0.02Mn 1.98F 3.02O 3.98) > C(Li 1.05Ga 0.02Mn 1.98S 3.02O 3.98) > C(Li 1.05Ga 0.02Mn 1.98F 3.02O 3.98) > C(Li 1.05Co 0.02Mn 1.98S 3.02O 3.98) > C(Li 1.05Co 0.02Mn 1.98F 3.02O 3.98). The doped spinel Li 1.05Ga 0.02Mn 1.98S 3.02O 3.98 presents an excellent electrochemical performance, with a low capacity loss even after 300 charge and discharge cycles (from 120 to 115 mA h g -1 or 4%).

Cerenkov luminescence imaging of medical isotopes

PubMed Central

Ruggiero, Alessandro; Holland, Jason P.; Lewis, Jason S.; Grimm, Jan

2011-01-01

The development of novel multimodality imaging agents and techniques represents the current frontier of research in the field of medical imaging science. However, the combination of nuclear tomography with optical techniques has yet to be established. Here, we report the use of the inherent optical emissions from the decay of radiopharmaceuticals for Cerenkov luminescence imaging (CLI) of tumors in vivo and correlate the results with those obtained from concordant immuno-PET studies. Methods In vitro phantom studies were used to validate the visible light emission observed from a range of radionuclides including the positron emitters 18F, 64Cu, 89Zr, and 124I; β-emitter 131I; and α-particle emitter 225Ac for potential use in CLI. The novel radiolabeled monoclonal antibody 89Zr-desferrioxamine B-[DFO-J591 for immuno-PET of prostate-specific membrane antigen (PSMA) expression was used to coregister and correlate the CLI signal observed with the immuno-PET images and biodistribution studies. Results Phantom studies confirmed that Cerenkov radiation can be observed from a range of positron-,β-, and α-emitting radionuclides using standard optical imaging devices. The change in light emission intensity versus time was concordant with radionuclide decay and was also found to correlate linearly with both the activity concentration and the measured PET signal (percentage injected dose per gram). In vivo studies conducted in male severe combined immune deficient mice bearing PSMA-positive, subcutaneous LNCaP tumors demonstrated that tumor-specific uptake of 89Zr-DFO-J591 could be visualized by both immuno-PET and CLI. Optical and immuno-PET signal intensities were found to increase over time from 24 to 96 h, and biodistribution studies were found to correlate well with both imaging modalities. Conclusion These studies represent the first, to our knowledge, quantitative assessment of CLI for measuring radiotracer uptake in vivo. Many radionuclides common to both nuclear tomographic imaging and radiotherapy have the potential to be used in CLI. The value of CLI lies in its ability to image radionuclides that do not emit either positrons or γ-rays and are, thus, unsuitable for use with current nuclear imaging modalities. Optical imaging of Cerenkov radiation emission shows excellent promise as a potential new imaging modality for the rapid, high-throughput screening of radiopharmaceuticals PMID:20554722

Effect of Buyang Huanwu decoction on amino acid content in cerebrospinal fluid of rats during ischemic/reperfusion injury.

PubMed

Wang, Lisheng; Huang, Yuwei; Wu, Junhong; Lv, Gengbin; Zhou, Liling; Jia, Jie

2013-12-01

The inhibitory effect of Buyang Huanwu decoction (BYHWD) on ischemic injury has been proven, but it is not clear how amino acid levels in cerebrospinal fluid (CSF) are associated with BYHWD treatment, nor the mechanism by which BYHWD protects the brain from ischemia/reperfusion injury. We investigated the effect of BYHWD on the amino acid content of CSF in rats during ischemia-reperfusion injury. Ischemia was imposed by right middle cerebral artery occlusion (MCAO). CSF was continuously collected from the striatum via brain microdialysis before and after ischemia/reperfusion. We used on-line derivatization combined with high-performance liquid chromatography with fluorescence detection (HPLC-FD) to determine levels of glutamate (Glu), aspartate (Asp), glycine (Gly), taurine (Tau), and γ-aminobutyric acid (GABA) in CSF. The MCAO model displayed an infarct lesion in the ipsilateral hemisphere and nerve injuries, as the left upper limb was unable to extend and turn leftward. Significant increases in excitatory and inhibitory amino acids were observed in the CSF of the ischemic rats relative to the sham-operated group (P<0.01). Treatment with BYHWD reduced the areas of cerebral infarction and improved the neurological behavior scores of rats after MCAO. BYHWD treatment was also associated with a significant decrease in excitatory amino acids and increase in inhibitory amino acids in the CSF. Only the higher dose of BYHWD (20mg/kg) affected all these levels significantly. Attenuated excitatory toxicity and reduced areas of cerebral infarction associated with BYHWD treatment might be due to a protective mechanism induced by BYHWD against ischemia/reperfusion injury. Copyright © 2013 Elsevier B.V. All rights reserved.

Pathogenesis of the limb manifestations and exercise limitations in peripheral artery disease.

PubMed

Hiatt, William R; Armstrong, Ehrin J; Larson, Christopher J; Brass, Eric P

2015-04-24

Patients with peripheral artery disease have a marked reduction in exercise performance and daily ambulatory activity irrespective of their limb symptoms of classic or atypical claudication. This review will evaluate the multiple pathophysiologic mechanisms underlying the exercise impairment in peripheral artery disease based on an evaluation of the current literature and research performed by the authors. Peripheral artery disease results in atherosclerotic obstructions in the major conduit arteries supplying the lower extremities. This arterial disease process impairs the supply of oxygen and metabolic substrates needed to match the metabolic demand generated by active skeletal muscle during walking exercise. However, the hemodynamic impairment associated with the occlusive disease process does not fully account for the reduced exercise impairment, indicating that additional pathophysiologic mechanisms contribute to the limb manifestations. These mechanisms include a cascade of pathophysiological responses during exercise-induced ischemia and reperfusion at rest that are associated with endothelial dysfunction, oxidant stress, inflammation, and muscle metabolic abnormalities that provide opportunities for targeted therapeutic interventions to address the complex pathophysiology of the exercise impairment in peripheral artery disease. © 2015 American Heart Association, Inc.

"Ich Brauche Mix-Cough": Cross-Linguistic Influence Involving German, English and Farsi

ERIC Educational Resources Information Center

Kazzazi, Kerstin

2011-01-01

This paper deals with cross-linguistic influence (CLI) in early trilingualism involving the languages German, English and Farsi. The data come from the case study of the author's two children growing up in a trilingual family within a monolingual German-speaking environment. Specific types of CLI from the non-dominant language Farsi on German and…

Dual AAV therapy ameliorates exercise-induced muscle injury and functional ischemia in murine models of Duchenne muscular dystrophy.

PubMed

Zhang, Yadong; Yue, Yongping; Li, Liang; Hakim, Chady H; Zhang, Keqing; Thomas, Gail D; Duan, Dongsheng

2013-09-15

Neuronal nitric oxide synthase (nNOS) membrane delocalization contributes to the pathogenesis of Duchenne muscular dystrophy (DMD) by promoting functional muscle ischemia and exacerbating muscle injury during exercise. We have previously shown that supra-physiological expression of nNOS-binding mini-dystrophin restores normal blood flow regulation and prevents functional ischemia in transgenic mdx mice, a DMD model. A critical next issue is whether systemic dual adeno-associated virus (AAV) gene therapy can restore nNOS-binding mini-dystrophin expression and mitigate muscle activity-related functional ischemia and injury. Here, we performed systemic gene transfer in mdx and mdx4cv mice using a pair of dual AAV vectors that expressed a 6 kb nNOS-binding mini-dystrophin gene. Vectors were packaged in tyrosine mutant AAV-9 and co-injected (5 × 10(12) viral genome particles/vector/mouse) via the tail vein to 1-month-old dystrophin-null mice. Four months later, we observed 30-50% mini-dystrophin positive myofibers in limb muscles. Treatment ameliorated histopathology, increased muscle force and protected against eccentric contraction-induced injury. Importantly, dual AAV therapy successfully prevented chronic exercise-induced muscle force drop. Doppler hemodynamic assay further showed that therapy attenuated adrenergic vasoconstriction in contracting muscle. Our results suggest that partial transduction can still ameliorate nNOS delocalization-associated functional deficiency. Further evaluation of nNOS binding mini-dystrophin dual AAV vectors is warranted in dystrophic dogs and eventually in human patients.

A new management for limb graft occlusion after endovascular aneurysm repair adding a vollmar ring stripper: the unclogging technique.

PubMed

Ronsivalle, Salvatore; Faresin, Francesca; Franz, Francesca; Pedon, Luigi; Rettore, Carlo; Zonta, Loretta; Olivieri, Armando

2013-11-01

Lower extremity ischemia for limb thrombosis is a well-known adverse event after endovascular abdominal aortic aneurysm repair (EVAR), ranging from 2.6-7.4%. We report our experience in the management of graft limb occlusion that occurred in patients who underwent EVAR in our institution. In cases in which balloon catheter thrombectomy is not useful or is risky, it is important to take into consideration the use of a Vollmar ring stripper (Aesculap, San Jose, CA) to avoid dislodging or disrupting the sealing zones. This technique has taken from thromboendarterectomy the principle of detaching plaque from adventitia and transformed it in a less traumatic way for dissecting thromboses from endografts. Between September 1999 and December 2011, 608 patients underwent EVAR in our institution. In cases of severe claudication or critical ischemia, we tried to remove the thrombus using mild Fogarty balloon traction; in cases of progressive and old stratification, we added the Vollmar ring stripper. After recanalization, if there was a stenosis, an angioplasty was performed and in most patients an adequately size Cheatham platinum stent was positioned. If the endovascular approach failed, bypass procedures were considered. In 608 patients over a mean follow-up time of 72 months, there were 23 cases of limb thrombosis. Fifteen of the 23 limb occlusions were identified within 6 months after aneurysm repair. The mean time to occlusion was 8.2 ± 4.3 months (range: 20 days-25 months). Presenting symptoms were mild to moderate claudication (Rutherford classification I) in 3 patients (13%), medium severe claudication (Rutherford classification IIA) in 18 patients (78.3%), and paresthesia and rest pain (Rutherford classification IIB) in 2 patients (8.7%; 1 of those patients had a loss of motor function). Four (17.4%) were stable during follow-up, and in 1 of these cases we tried thrombolysis without thrombosis resolution. In 13 (56.5%) cases, we performed balloon catheter thrombectomy with a LeMaitre over the wire embolectomy catheter (LeMaitre Vascular, Burlington, MA). In 8 of 13 (61.5%) patients with certain thrombosis characteristics, we decided to add to the balloon catheter a Vollmar ring stripper for mechanical catheter thrombectomy. In all 13 thrombectomy cases, blood flow was restored through the limb with the endograft itself. There were no episodes of graft dislocation, disruption of the sealing zones, or recurrences. In 5 (21.7%) cases, a femorofemoral crossover was performed, and in 1 (4.3%) case, an axillofemoral bypass was performed. During the follow-up period, 2 of the 5 femorofemoral crossovers closed after 6 and 8 months, respectively. This unclogging technique, alone or associated with Vollmar ring stripper, proves to be simple, safe, and effective in the treatment of graft limb occlusion. Additional research will help confirm the role of Vollmar ring stripper. Copyright © 2013 Elsevier Inc. All rights reserved.

EuCliD (European Clinical Database): a database comparing different realities.

PubMed

Marcelli, D; Kirchgessner, J; Amato, C; Steil, H; Mitteregger, A; Moscardò, V; Carioni, C; Orlandini, G; Gatti, E

2001-01-01

Quality and variability of dialysis practice are generally gaining more and more importance. Fresenius Medical Care (FMC), as provider of dialysis, has the duty to continuously monitor and guarantee the quality of care delivered to patients treated in its European dialysis units. Accordingly, a new clinical database called EuCliD has been developed. It is a multilingual and fully codified database, using as far as possible international standard coding tables. EuCliD collects and handles sensitive medical patient data, fully assuring confidentiality. The Infrastructure: a Domino server is installed in each country connected to EuCliD. All the centres belonging to a country are connected via modem to the country server. All the Domino Servers are connected via Wide Area Network to the Head Quarter Server in Bad Homburg (Germany). Inside each country server only anonymous data related to that particular country are available. The only place where all the anonymous data are available is the Head Quarter Server. The data collection is strongly supported in each country by "key-persons" with solid relationships to their respective national dialysis units. The quality of the data in EuCliD is ensured at different levels. At the end of January 2001, more than 11,000 patients treated in 135 centres located in 7 countries are already included in the system. FMC has put the patient care at the centre of its activities for many years and now is able to provide transparency to the community (Authorities, Nephrologists, Patients.....) thus demonstrating the quality of the service.

Adenovirus-mediated E2-EPF UCP Gene Transfer Prevents Autoamputation in a Mouse Model of Hindlimb Ischemia

PubMed Central

Lim, Jung Hwa; Shin, Hyo Jung; Park, Kyeong-Su; Lee, Chan Hee; Jung, Cho-Rok; Im, Dong-Soo

2012-01-01

E2-EPF ubiquitin carrier protein (UCP) stabilizes hypoxia-inducible factor-1α (HIF-1α) inducing ischemic vascular responses. Here, we investigated the effect of UCP gene transfer on therapeutic angiogenesis. Adenovirus-encoded UCP (Ad-F-UCP) increased the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) in cells and mice. Conditioned media from UCP-overexpressing cells promoted proliferation, tubule formation, and invasion of human umbilical-vascular-endothelial cells (HUVECs), and vascularization in chorioallantoic membrane (CAM) assay. Ad-F-UCP increased the vessel density in the Martigel plug assay, and generated copious vessel-like structures in the explanted muscle. The UCP effect on angiogenesis was dependent on VEGF and FGF-2. In mouse hindlimb ischemia model (N = 30/group), autoamputation (limb loss) occurred in 87% and 68% of the mice with saline and Ad encoding β-galactosidase (Ad-LacZ), respectively, whereas only 23% of the mice injected with Ad-F-UCP showed autoamputation after 21 days of treatment. Ad-F-UCP increased protein levels of HIF-1α, platelet-endothelial cell adhesion molecule-1 (PECAM-1), smooth muscle cell actin (SMA) in the ischemic muscle, and augmented blood vessels doubly positive for PECAM-1 and SMA. Consequently, UCP gene transfer prevented muscle degeneration and autoamputation of ischemic limb. The results suggest that E2-EPF UCP may be a target for therapeutic angiogenesis. PMID:22294149

Adenovirus-mediated E2-EPF UCP gene transfer prevents autoamputation in a mouse model of hindlimb ischemia.

PubMed

Lim, Jung Hwa; Shin, Hyo Jung; Park, Kyeong-Su; Lee, Chan Hee; Jung, Cho-Rok; Im, Dong-Soo

2012-04-01

E2-EPF ubiquitin carrier protein (UCP) stabilizes hypoxia-inducible factor-1α (HIF-1α) inducing ischemic vascular responses. Here, we investigated the effect of UCP gene transfer on therapeutic angiogenesis. Adenovirus-encoded UCP (Ad-F-UCP) increased the expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) in cells and mice. Conditioned media from UCP-overexpressing cells promoted proliferation, tubule formation, and invasion of human umbilical-vascular-endothelial cells (HUVECs), and vascularization in chorioallantoic membrane (CAM) assay. Ad-F-UCP increased the vessel density in the Martigel plug assay, and generated copious vessel-like structures in the explanted muscle. The UCP effect on angiogenesis was dependent on VEGF and FGF-2. In mouse hindlimb ischemia model (N = 30/group), autoamputation (limb loss) occurred in 87% and 68% of the mice with saline and Ad encoding β-galactosidase (Ad-LacZ), respectively, whereas only 23% of the mice injected with Ad-F-UCP showed autoamputation after 21 days of treatment. Ad-F-UCP increased protein levels of HIF-1α, platelet-endothelial cell adhesion molecule-1 (PECAM-1), smooth muscle cell actin (SMA) in the ischemic muscle, and augmented blood vessels doubly positive for PECAM-1 and SMA. Consequently, UCP gene transfer prevented muscle degeneration and autoamputation of ischemic limb. The results suggest that E2-EPF UCP may be a target for therapeutic angiogenesis.

Paclitaxel-Coated Balloons: Review of a Promising Interventional Approach to Preventing Restenosis in Femoropopliteal Arteries

PubMed Central

Teleb, Mohamed; Wardi, Miraie; Gosavi, Sucheta; Said, Sarmad; Mukherjee, Debabrata

2015-01-01

Peripheral arterial disease (PAD), a major cause of morbidity and mortality worldwide, is characterized by intermittent claudication and is associated with chronic diseases such as diabetes and hypertension. The goal of treatment is to address the underlying cause and to modify risk factors. Although medical management is the first-line treatment of PAD, some individuals may have severe symptoms and require revascularization with percutaneous transluminal angioplasty with or without stent placement or surgery. Interventional approaches may, however, be associated with high prevalence of restenosis and subsequent complications such as critical limb ischemia and amputation. Drug-eluting balloons (DEBs) are a new interventional technology with the primary goal of preventing restenosis. We review the clinical trials and studies that assessed the efficacy and safety profile of DEB and will focus on the restenosis rate in femoropopliteal arteries including target lesion revascularization (TLR) and late lumen lesion (LLL) using different modalities of intervention such as stents and DEB. Average data collected from the trials reported included restenosis rate of 25%, 0.3 mm LLL, and 14% reduction in TLR with DEB versus uncoated balloons. Below the knee (BTK) only intervention studies were excluded from this review as endovascular approach is usually reserved for critical limb ischemia for BTK disease. Interventional approach to treat PAD with DEB appears to be a promising technology. Additional larger studies are needed to further define safety, efficacy, and longer term outcome with this novel technology. PMID:27231422

The influence of patients' nutritional status on the prevalence, course and treatment outcomes of lower limb ischemia: an overview of current evidence.

PubMed

Spychalska-Zwolińska, Marta; Zwoliński, Tomasz; Anaszewicz, Marzena; Budzyński, Jacek

2018-04-01

The association of lower limb ischemia (LLI) with disturbances in nutritional status, in respect to over- or undernutrition, is still uncertain. The aim of this study was to present the current state of knowledge on this issue. Systematic review of papers published between 2006 and 2018. The literature shows inconclusive evidence regarding the impact of nutritional status on the risk, course, prognosis and outcomes of conservative and invasive treatment of LLI. The majority of publications available demonstrate greater LLI prevalence in overweight and obese patients, a worse prognosis both in malnourished and severely obese patients, poorer outcomes of invasive treatment in underweight patients, and better results for endovascular and surgical treatment in patients with overweight and class I obesity, although without such a relationship for conservative therapy. Possible explanations linking nutritional status and LLI seem to be: the endocrine, paracrine, and autocrine activity of adipose tissue, a decrease in physical activity, and the effect of diet-dependent comorbidities, e.g. diabetes mellitus, hypertension and dyslipidemia. There is a growing body of evidence concerning an association between LLI and patients' nutritional status. A so-called "obesity paradox" or "BMI paradox" seems to exist among patients with LLI and mainly concerns outcomes of endovascular and surgical treatment. However, further studies are needed to evaluate the clinical importance of body composition, the distribution and endocrine activity of adipose tissue, and the effect of weight reduction and/or nutritional support in the LLI patient group.

ROS-Responsive Microspheres for On Demand Antioxidant Therapy in a Model of Diabetic Peripheral Arterial Disease

PubMed Central

Poole, KM; Nelson, CE; Joshi, RV; Martin, JR; Gupta, MK; Haws, SC; Kavanaugh, TE; Skala, MC; Duvall, CL

2014-01-01

A new microparticle-based delivery system was synthesized from reactive oxygen species (ROS)-responsive poly(propylene sulfide) (PPS) and tested for “on demand” antioxidant therapy. PPS is hydrophobic but undergoes a phase change to become hydrophilic upon oxidation and thus provides a useful platform for ROS-demanded drug release. This platform was tested for delivery of the promising anti-inflammatory and antioxidant therapeutic molecule curcumin, which is currently limited in use in its free form due to poor pharmacokinetic properties. PPS microspheres efficiently encapsulated curcumin through oil-in-water emulsion and provided sustained, on demand release that was modulated in vitro by hydrogen peroxide concentration. The cytocompatible, curcumin-loaded microspheres preferentially targeted and scavenged intracellular ROS in activated macrophages, reduced in vitro cell death in the presence of cytotoxic levels of ROS, and decreased tissue-level ROS in vivo in the diabetic mouse hind limb ischemia model of peripheral arterial disease. Interestingly, due to the ROS scavenging behavior of PPS, the blank microparticles also showed inherent therapeutic properties that were synergistic with the effects of curcumin in these assays. Functionally, local delivery of curcumin-PPS microspheres accelerated recovery from hind limb ischemia in diabetic mice, as demonstrated using non-invasive imaging techniques. This work demonstrates the potential for PPS microspheres as a generalizable vehicle for ROS-demanded drug release and establishes the utility of this platform for improving local curcumin bioavailability for treatment of chronic inflammatory diseases. PMID:25522975

Estrogen-dependent efficacy of limb ischemic preconditioning in female rats.

PubMed

Pócs, Levente; Janovszky, Ágnes; Garab, Dénes; Terhes, Gabriella; Ocsovszki, Imre; Kaszaki, József; Boros, Mihály; Piffkó, József; Szabó, Andrea

2018-01-01

Our aim was to examine the effects of ischemic preconditioning (IPC) on the local periosteal and systemic inflammatory consequences of hindlimb ischemia-reperfusion (IR) in Sprague-Dawley rats with chronic estrogen deficiency (13 weeks after ovariectomy, OVX) in the presence and absence of chronic 17beta-estradiol supplementation (E2, 20 µg kg -1 , 5 days/week for 5 weeks); sham-operated (non-OVX) animals served as controls. As assessed by intravital fluorescence microscopy, rolling and the firm adhesion of polymorphonuclear neutrophil leukocytes (PMNs) gave similar results in the Sham + IR and OVX + IR groups in the tibial periosteal microcirculation during the 3-h reperfusion period after a 60-min tourniquet ischemia. Postischemic increases in periosteal PMN adhesion and PMN-derived adhesion molecule CD11b expressions, however, were significantly reduced by IPC (two cycles of 10'/10') in Sham animals, but not in OVX animals; neither plasma free radical levels (as measured by chemiluminescence), nor TNF-alpha release was affected by IPC. E2 supplementation in OVX animals restored the IPC-related microcirculatory integrity and PMN-derived CD11b levels, and TNF-alpha and free radical levels were reduced by IPC only with E2. An enhanced estrogen receptor beta expression could also be demonstrated after E2 in the periosteum. Overall, the beneficial periosteal microcirculatory effects of limb IPC are lost in chronic estrogen deficiency, but they can be restored by E2 supplementation. This suggests that the presence of endogenous estrogen is a necessary facilitating factor of the anti-inflammatory protection provided by limb IPC in females. The IPC-independent effects of E2 on inflammatory reactions should also be taken into account in this model. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:97-105, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

miR172 down-regulates the translation of cleistogamy 1 in barley

USDA-ARS?s Scientific Manuscript database

Floret opening in barley is induced by the swelling of the lodicule, a trait under the control of the cleistogamy1 (cly1) gene. The product of cly1 is a member of the APETALA2 (AP2) transcription factor family, which inhibits lodicule development. A sequence polymorphism at the miR172 target site wi...

Innovations in Nuclear Imaging Instrumentation: Cerenkov Imaging.

PubMed

Tamura, Ryo; Pratt, Edwin C; Grimm, Jan

2018-07-01

Cerenkov luminescence (CL) is blue glow light produced by charged subatomic particles travelling faster than the phase velocity of light in a dielectric medium such as water or tissue. CL was first discovered in 1934, but for biomedical research it was recognized only in 2009 after advances in optical camera sensors brought the required high sensitivity. Recently, applications of CL from clinical radionuclides have been rapidly expanding to include not only preclinical and clinical biomedical imaging but also an approach to therapy. Cerenkov Luminescence Imaging (CLI) utilizes CL generated from clinically relevant radionuclides alongside optical imaging instrumentation. CLI is advantageous over traditional nuclear imaging methods in terms of infrastructure cost, resolution, and imaging time. Furthermore, CLI is a truly multimodal imaging method where the same agent can be detected by two independent modalities, with optical (CL) imaging and with positron emission tomography (PET) imaging. CL has been combined with small molecules, biomolecules and nanoparticles to improve diagnosis and therapy in cancer research. Here, we cover the fundamental breakthroughs and recent advances in reagents and instrumentation methods for CLI as well as therapeutic application of CL. Copyright © 2018 Elsevier Inc. All rights reserved.

Endovascular Treatment of Supra-Aortic Extracranial Stenoses in Patients with Vertebrobasilar Insufficiency Symptoms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zaytsev, A.Y., E-mail: cir-auz@mail.ru; Stoyda, A.Y.; Smirnov, V.E.

2006-10-15

Purpose. Stenoses and thromboses of vessels feeding the vertebrobasilar territory can evoke serious disturbances including ischemic stroke. We present our experience of endovascular interventions for patients with signs of vertebrobasilar insufficiency (VBI) resulted from subclavian, vertebral and brachiocephalic arterial stenoses. Methods. Twenty-one patients (10 men) aged from 35 to 84 years (mean 64.3 years) with symptoms compatible with VBI underwent balloon angioplasty and stenting of subclavian (SA), innominate (IA) and vertebral (VA) arteries. Procedures were done by radiologists experienced in systematic stenting of the lesions. VBI was manifested by persistent signs in 15 patients, and by transitory ischemic attacks inmore » the posterior circulatory territory in 4 (19%). Two patients (10%) experienced ischemic strokes (in the vertebrobasilar circulation in both cases). In 3 patients (14%) VBI was accompanied by upper limb vascular insufficiency symptoms. All cases were resistant to medical treatment. A neurologist assessed complaints, initial VBI signs and their alteration after intervention in all patients. Outcomes were measured with the 5-point scale suggested by Malek et al.: (1) excellent result (asymptomatic, no neurologic deficits and no symptoms of vertebrobasilar ischemia); (2) good (no neurologic deficits, at most one transient episode of vertebrobasilar ischemia over a period of 3 months after treatment); (3) fair (minimal neurologic deficit and at most one transient episode per month of vertebrobasilar ischemia); (4) poor (no improvement compared with neurologic status before treatment and/or persistent symptoms of vertebrobasilar ischemia); (5) death (regardless of cause). Endovascular treatment was performed for SA stenosis in 15 patients, for SA occlusion in 2, for IA stenosis in 2, and for VA stenosis in 2. There were 15 cases of atherosclerosis, 2 of aortoarteritis, 4 of proximal SA kinking. SA and IA stenoses ranged from 60% to 100% (mean 74.5%), VA stenoses were 90% in both cases. Results. Initial technical success was achieved in 96% of cases. There were no postprocedural complications or deaths. During 6-36 months (mean 21.3 months) of follow-up all patients showed improvement in VBI symptoms or upper limb ischemia. Within 36 months after the procedure outcomes were estimated as excellent and good in 13 patients (76%) and poor in 2 (12%), the last being attributed to atherosclerosis progression in other vascular areas. Restenosis in the stented area has developed in 1 patient (6%). Conclusions. Balloon angioplasty and stenting of extracranial vertebrobasilar arterial stenoses appeared to be effective in endovascular treatment of medically resistant VBI. Further investigations are required to clarify the role of subclavian artery kinking in VBI development and indications for various methods of its correction.« less

Iliac Artery Stent Placement Relieves Claudication in Patients with Iliac and Superficial Femoral Artery Lesions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ichihashi, Shigeo, E-mail: shigeoichihashi@yahoo.co.jp; Higashiura, Wataru; Itoh, Hirofumi

Purpose. To evaluate the efficacy of iliac artery stent placement for relief of claudication in patients with both iliac and superficial femoral artery (SFA) lesions. Methods. Stent placement for only iliac artery occlusive disease was performed in 94 limbs (74 patients) with both iliac and SFA occlusive disease on the same limb. All procedures were performed because intermittent claudication did not improve after continuation of antiplatelet medication therapy and home-based exercise for 3 months. Rutherford classification was 2 in 20 limbs and 3 in 74 limbs. Patients with critical limb ischemia were excluded. Median duration of follow-up was 40 months.more » Primary patency rates of the iliac stent, clinical improvement rates, and risk factors for requiring additional SFA procedures were evaluated. Results. Primary patency rates of the iliac stent at 1, 3, 5, and 7 years were 97, 93, 79, and 79 %, respectively. The initial clinical improvement rate was 87 %. Continued clinical improvement rates at 1, 3, 5, and 7 years were 87, 81, 69, and 66 %, respectively. SFA Trans-Atlantic Inter-Society Consensus (TASC) II C/D lesion was a significant risk factor for requiring additional SFA procedures. Conclusion. Intermittent claudication was relieved by iliac stent placement in most patients with both iliac and SFA lesions. Thus, the indications for treatment of the SFA intended for claudicants should be evaluated after treatment of the iliac lesion.« less

Severe limb ischemia syndrome.

PubMed

Suchý, T

1991-01-01

In the course of the study of the syndrome of severe limb ischemia (SLI) in a representative clinical material of 300 patients and a number of experimental studies, we arrived to the proposal of this optimal methodical procedure for acute vascular closures of traumatic and non-traumatic origin in the limbs: a) In every injury and sudden pain with a change of the function of the limb, it is necessary to think of the SLI syndrome and to search targetedly for it. b) In injuries connected with bleeding our first-rate task is the control of this bleeding. For a temporary arrest of the bleeding it is necessary to prefer more physiological methods sparing collateral circulation to the still most used tourniquet. For this purpose a new device for temporary hemostasis called Hemostop has proved itself, designed by the author and attested both experimentally and clinically, protected as a Czechoslovak patent. From surgical measures have acquitted themselves from this viewpoint the insertion of vascular clamp, ligature of the vessel or its temporary cannulation. c) To set the diagnosis of SLI, it usually suffices a careful anamnesis and clinical examination, advantageous is the investigation by ultrasound. The angiography because of time consumption should be used only in indicated cases. d) The time factor--"race against the time"--has to be always borne on our mind. It is necessary to achieve the recovery of blood circulation in the limb up to 6 or at the latest up to 10 hours from the onset of injury or closure. e) For shortening of the period of tissue hypoxia it is of advantage to use the temporary cannulation of injured vessels. This should be used always, whenever because of any reasons, it is not possible to execute the final reconstructive operation up to 10 hours since the injury, e. g. in polytraumatism, transport difficulties and the like. f) In isolated vascular injuries without bleeding (about 45%) and in all non-traumatic SLI the patients must be efficiently heparinized (i. v. administration, at best by infusion) to prevent the growth of the distal thrombus. g) Final vascular reconstruction should be performed only by erudited surgeons, always with thromboctomy and in protected coagulum. Optimal reconstructive performance should be chosen: for embolism the thromboembolectomy, for acute thrombosis usually the bypassing the afflicted vascular portion by the graft, in injuries appears as the optimal reconstructive measure the anastomosis end to end. At the simultaneous or isolated lesion of the stem vein, we must always try to reconstruct it.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparsion between Intravenous Delivered Human Fetal Bone Marrow Mesenchymal Stromal Cells and Mononuclear Cells in the Treatment of Rat Cerebral Infarct.

PubMed

Huang, Ai-Hua; Zhang, Ping-Ping; Zhang, Bin; Ma, Bu-Qing; Guan, Yun-Qian; Zhou, Yi-Dan

2016-10-10

Objective To compare the effecacy of human mesenchymal stromal cell (hMSC) with human mononuclear cell (hMNC) in treating rat cerebral infarct.Methods The SD rat models of cerebral infarct were established by distal middle cerebral artery occlusion (dMCAO). Rats were divided into four groups: sham,ischemia vehicle,MSC,and MNC transplantation groups. For the transplantation group,1×10 6 hMSCs or hMNCs were intravascularly transplanted into the tail vein 1 hour after the ischemia onset. The ischemia vehicle group received dMCAO surgery and intravascular saline injection 1,3,5,and 7 days after the ischemia onset,and then behavioral tests were performed. At 48 h after the ischemia onset,the abundance of Iba- 1,the symbol of activated microglia,was evaluated in the peri-ischemia striatum area; meanwhile,the neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in ipsilateral peri-ischemia striatum area were also measured. Results The relative infarct volume in ischemia vehicle group,hMSC group,and hMNC transplantation group were (37.85±4.40)%,(33.41±3.82)%,and (30.23±3.63)%,respectively. The infarct volumes of MSC group (t=2.100,P=0.034) and MNC group (t=2.109,P=0.0009) were significantly smaller than that of ischemia vehicle group,and that of MNC group was significantly smaller than that of MSC group (t=1.743,P=0.043). One day after transplantation,the score of ischemia vehicle group in limb placing test was (4.32±0.71)%,which was significantly lower than that in sham group (9.73±0.36)% (t=2.178,P=8.61×10 -11 ). The scores of MSC and MNC group,which were (5.09±0.62)% (t=2.1009,P=0.024) and (5.90±0.68)% (t=2.1008,P=0.0001),respectively,were significantly higher than that of ischemia vehicle group; also,the score of MNC group was significantly higher than that of MSC group(t=2.1009,P=0.0165). The contralateral forelimb scores of MSC and MNC groups in beam walking test were (5.56±0.86)% (t=2.120,P=0.020) and (5.13±0.95)% (t=2.131,P=0.003),were both significantly lower than that of ischemia vehicle group [(6.47±0.61)%]. Three days after the transplantation,the limb placing test score of MNC group [(6.91±1.10)%] was significantly higher than that of ischemia vehicle group (5.80±0.82)% (t=2.110,P=0.027). The score of MSC group [(6.30±0.77)%] showed no statistic difference with that of ischemia vehicle group(t=2.101,P=0.199).The contralateral forelimb scores of MNC group in beam walking test [(4.34±0.58)%] was significantly lower than that of ischemia vehicle group [(5.31±0.65)%] (t=2.100,P=0.006) and MSC group [(4.92±0.53)%] (t=2.100,P=0.041); there was no statistic difference between MSC group and ischemia vehicle group (t=2.109,P=0.139). The relative abundance of Iba- 1 in sham,ischemia vehicle,MSC,and MNC groups was 1.00+0.00,1.72±0.21,1.23±0.08,and 1.48±0.06,respectively. The Iba-1 relative abundance of ischemia vehicle group was significantly higher than that of sham group (t=2.262,P=2.9×10 -6 ). The Iba-1 relative abundances of both MSC (t=2.178,P=3.91×10 -5 )and MNC (t=2.200,P=0.007)groups were significantly lower than that of ischemia vehicle group. It was also significantly lower in MNC group than in MSC group also (t=2.120,P=7.09×10 -6 ). Three days after transplantation,the BDNF and GDNF levels of MSC group,which were (531.127±73.176)pg/mg (t=2.109,P=0.003)and(127.780±16.733)pg/mg(t=2.100,P=2.76×10 -5 ),respectively,were significantly higher than those of ischemia vehicle group,which were (401.988±89.006)pg/mg and (86.278±14.832) pg/mg,respectively. The BDNF and GDNF levels of MNC group,which were (627.429±65.646)pg/mg (t=2.144,P=0.017) and (153.117±20.443)pg/mg (t=2.109,P=0.010),respectively,were all significantly higher than that of MSC group. At day 7,the BDNF and GDNF levels of MSC group,which were (504.776±83.282)pg/mg (t=2.101,P=0.005) and (81.641±11.019)pg/mg (t=2.100,P=0.002),respectively,were significantly higher than those of ischemia vehicle group,which were (389.257±70.440)pg/mg and (64.322±9.855) pg/mg,respectively. The BDNF and GDNF levels of MNC group,which were (589.068±63.323)pg/mg (t=2.100,P=0.027) and (102.161±19.932)pg/mg (t=2.144,P=0.017),respectively,were all significantly higher than that of MSC group. Conclusions Both hMSC and hMNC are beneficial to the ischemia-damaged brain when they are intravascularly transplanted within 1 h after the onset of ischemia. The anti-inflammation ability and secretion of neurotrophic factors are the underlying mechanisms of the therapeutic effects. MNC is more effective than MSC in reducing infarct area and improving behaviors,which might be explained by the fact that MNC induces more GDNF and BDNF in brain than MSC.

Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo.

PubMed

Mena, Hebe Agustina; Zubiry, Paula Romina; Dizier, Blandine; Schattner, Mirta; Boisson-Vidal, Catherine; Negrotto, Soledad

2018-05-02

We have previously demonstrated that acidic preconditioning of human endothelial colony-forming cells (ECFC) increased proliferation, migration, and tubulogenesis in vitro, and increased their regenerative potential in a murine model of hind limb ischemia without baseline disease. We now analyze whether this strategy is also effective under adverse conditions for vasculogenesis, such as the presence of ischemia-related toxic molecules or diabetes, one of the main target diseases for cell therapy due to their well-known healing impairments. Cord blood-derived CD34 + cells were seeded in endothelial growth culture medium (EGM2) and ECFC colonies were obtained after 14-21 days. ECFC were exposed at pH 6.6 (preconditioned) or pH 7.4 (nonpreconditioned) for 6 h, and then pH was restored at 7.4. A model of type 2 diabetes induced by a high-fat and high-sucrose diet was developed in nude mice and hind limb ischemia was induced in these animals by femoral artery ligation. A P value < 0.05 was considered statistically significant (by one-way analysis of variance). We found that acidic preconditioning increased ECFC adhesion and the release of pro-angiogenic molecules, and protected ECFC from the cytotoxic effects of monosodium urate crystals, histones, and tumor necrosis factor (TNF)α, which induced necrosis, pyroptosis, and apoptosis, respectively. Noncytotoxic concentrations of high glucose, TNFα, or their combination reduced ECFC proliferation, stromal cell-derived factor (SDF)1-driven migration, and tubule formation on a basement membrane matrix, whereas almost no inhibition was observed in preconditioned ECFC. In type 2 diabetic mice, intravenous administration of preconditioned ECFC significantly induced blood flow recovery at the ischemic limb as measured by Doppler, compared with the phosphate-buffered saline (PBS) and nonpreconditioned ECFC groups. Moreover, the histologic analysis of gastrocnemius muscles showed an increased vascular density and reduced signs of inflammation in the animals receiving preconditioned ECFC. Acidic preconditioning improved ECFC survival and angiogenic activity in the presence of proinflammatory and damage signals present in the ischemic milieu, even under high glucose conditions, and increased their therapeutic potential for postischemia tissue regeneration in a murine model of type 2 diabetes. Collectively, our data suggest that acidic preconditioning of ECFC is a simple and inexpensive strategy to improve the effectiveness of cell transplantation in diabetes, where tissue repair is highly compromised.

Korean Guidelines for Interventional Recanalization of Lower Extremity Arteries

PubMed Central

Bae, Jae Ik; Jeon, Yong Sun; Kim, Chang Won; Jae, Hwan Jun; Park, Kwang Bo; Cho, Young Kwon; Kim, Man Deuk

2015-01-01

Peripheral arterial occlusive disease caused by atherosclerosis can present with intermittent claudication or critical limb ischemia. Proper diagnosis and management is warranted to improve symptoms and salvage limbs. With the introduction of new techniques and dedicated materials, endovascular recanalization is widely performed for the treatment of peripheral arterial occlusive disease because it is less invasive than surgery. However, there are various opinions regarding the appropriate indications and procedure methods for interventional recanalization according to operator and institution in Korea. Therefore, we intend to provide evidence based guidelines for interventional recanalization by multidisciplinary consensus. These guidelines are the result of a close collaboration between physicians from many different areas of expertise including interventional radiology, interventional cardiology, and vascular surgery. The goal of these guidelines is to ensure better treatment, to serve as a guide to the clinician, and consequently, to contribute to public health care. PMID:26175569

Long Non-Coding RNA Malat1 Regulates Angiogenesis in Hindlimb Ischemia.

PubMed

Zhang, Xuejing; Tang, Xuelian; Hamblin, Milton H; Yin, Ke-Jie

2018-06-11

Angiogenesis is a complex process that depends on the delicate regulation of gene expression. Dysregulation of transcription during angiogenesis often leads to various human diseases. Emerging evidence has recently begun to show that long non-coding RNAs (lncRNAs) may mediate angiogenesis in both physiological and pathological conditions; concurrently, underlying molecular mechanisms are largely unexplored. Previously, our lab identified metastasis associates lung adenocarcinoma transcript 1 ( Malat1 ) as an oxygen-glucose deprivation (OGD)-responsive endothelial lncRNA. Here we reported that genetic deficiency of Malat1 leads to reduced blood vessel formation and local blood flow perfusion in mouse hind limbs at one to four weeks after hindlimb ischemia. Malat1 and vascular endothelial growth factor receptor 2 ( VEGFR2 ) levels were found to be increased in both cultured mouse primary skeletal muscle microvascular endothelial cells (SMMECs) after 16 h OGD followed by 24 h reperfusion and in mouse gastrocnemius muscle that underwent hindlimb ischemia followed by 28 days of reperfusion. Moreover, Malat1 silencing by locked nucleic acid (LNA)-GapmeRs significantly reduced tube formation, cell migration, and cell proliferation in SMMEC cultures. Mechanistically, RNA subcellular isolation and RNA-immunoprecipitation experiments demonstrate that Malat1 directly targets VEGFR2 to facilitate angiogenesis. The results suggest that Malat1 regulates cell-autonomous angiogenesis through direct regulation of VEGFR2.

Regeneration of dental pulp by stem cells.

PubMed

Nakashima, M; Iohara, K

2011-07-01

Angiogenesis/vasculogenesis and neurogenesis are essential for pulp regeneration. Two subfractions of side-population (SP) cells, CD31(-)/CD146(-) SP cells and CD105(+) cells with angiogenic and neurogenic potential, were isolated by flow cytometry from canine dental pulp. In an experimental model of mouse hindlimb ischemia, transplantation of these cell populations resulted in an increase in blood flow, including high-density capillary formation. In a model of rat cerebral ischemia, stem cell transplantations enhanced neuronal regeneration and recovery from motor disability. Autologous transplantation of the CD31(-)/CD146(-) SP cells into an in vivo model of amputated pulp resulted in complete regeneration of pulp tissue with vascular and neuronal processes within 14 days. The transplanted cells expressed pro-angiogenic factors, implying trophic action on endothelial cells. Autologous transplantation of CD31(-)/CD146(-) SP cells or CD105(+) cells with stromal-cell-derived factor-1 (SDF-1) into root canals after whole pulp removal of mature teeth resulted in complete regeneration of pulp replete with nerves and vasculature by day 14, followed by dentin formation along the dentinal wall by day 35. Therefore, the potential utility of fractionated SP cells and CD105(+) cells in angiogenesis and neurogenesis was demonstrated by treatment of limb and cerebral ischemia following pulpotomy and pulpectomy.

Multilingual Acquisition of Vowels in L1 Polish, L2 Danish and L3 English

ERIC Educational Resources Information Center

Sypianska, Jolanta

2016-01-01

The aim of this paper is to determine whether all languages in the linguistic repertoire of a multilingual speaker manifest cross-linguistic influence (CLI) and establish the directions of CLI on the basis of chosen vowels from the linguistic repertoire of two groups: the Bilingual group (L1 Polish/L2 Danish) and the Multilingual group (L1…

The temporal profile of the reaction of microglia, astrocytes, and macrophages in the delayed onset paraplegia after transient spinal cord ischemia in rabbits.

PubMed

Matsumoto, Satoshi; Matsumoto, Mishiya; Yamashita, Atsuo; Ohtake, Kazunobu; Ishida, Kazuyoshi; Morimoto, Yasuhiro; Sakabe, Takefumi

2003-06-01

In the present study, we sought to elucidate the temporal profile of the reaction of microglia, astrocytes, and macrophages in the progression of delayed onset motor dysfunction after spinal cord ischemia (15 min) in rabbits. At 2, 4, 8, 12, 24, and 48 h after reperfusion (9 animals in each), hind limb motor function was assessed, and the lumbar spinal cord was histologically examined. Delayed motor dysfunction was observed in most animals at 48 h after ischemia, which could be predicted by a poor recovery of segmental spinal cord evoked potentials at 15 min of reperfusion. In the gray matter of the lumbar spinal cord, both microglia and astrocytes were activated early (2 h) after reperfusion. Microglia were diffusely activated and engulfed motor neurons irrespective of the recovery of segmental spinal cord evoked potentials. In contrast, early astrocytic activation was confined to the area where neurons started to show degeneration. Macrophages were first detected at 8 h after reperfusion and mainly surrounded the infarction area later. Although the precise roles of the activation of microglia, astrocytes, and macrophages are to be further determined, the results indicate that understanding functional changes of astrocytes may be important in the mechanism of delayed onset motor dysfunction including paraplegia. Microglia and macrophages play a role in removing tissue debris after transient spinal cord ischemia. Disturbance of astrocytic defense mechanism, breakdown of the blood-spinal cord barrier, or both seemed to be involved in the development of delayed motor dysfunction.

Fluoro-Jade and TUNEL staining as useful tools to identify ischemic brain damage following moderate extradural compression of sensorimotor cortex.

PubMed

Kundrotiene, Jurgita; Wägner, Anna; Liljequist, Sture

2004-01-01

Cerebral ischemia was produced by moderate compression for 30 min of a specific brain area in the sensorimotor cortex of Sprague-Dawley rats. On day 1, that is 24 h after the transient sensorimotor compression, ischemia-exposed animals displayed a marked focal neurological deficit documented as impaired beam walking performance. This functional disturbance was mainly due to contralateral fore- and hind-limb paresis. As assessed by daily beam walking tests it was shown that there was a spontaneous recovery of motor functions over a period of five to seven days after the ischemic event. Using histopathological analysis (Nissl staining) we have previously reported that the present experimental paradigm does not produce pannecrosis (tissue cavitation) despite the highly reproducible focal neurological deficit. We now show how staining with fluorescent markers for neuronal death, that is Fluoro-Jade and TUNEL, respectively, identifies regional patterns of selective neuronal death. These observations add further support to the working hypothesis that the brain damage caused by cortical compression-induced ischemia consists of scattered, degenerating neurons in specific brain regions. Postsurgical administration of the AMPA receptor specific antagonist, LY326325 (30 mg/kg; i.p., 70 min after compression), not only improved beam walking performance on day 1 to 3, respectively but also significantly reduced the number of Fluoro-Jade stained neurons on day 5. These results suggest that enhanced AMPA/glutamate receptor activity is at least partially responsible for the ischemia-produced brain damage detected by the fluorescent marker Fluoro-Jade.

Usefulness of the low profile "True 8" intra-aortic balloon pumping catheter for preventing limb lschemia.

PubMed

Kuki, S; Taniguchi, K; Masai, T; Yoshida, K; Yamamoto, K; Matsuda, H

2001-01-01

The most important limitation in the use of an intra-aortic balloon pumping (IABP) is the risk of vascular complications. Recently, an IABP catheter with an 8.0 French shaft and low profile that may decrease the risk of vascular morbidity has been developed. We evaluated the in vitro balloon performance and the prevention of limb ischemia in clinical use. An 8.0 French IABP catheter was compared with a standard 9.5 French catheter. Inflation time (IT), deflation time (DT), and changes in volume (V) generated by the balloon were measured during the pumping cycle in an experimental model. The inflation velocity (V/IT) and deflation velocity (V/DT) were calculated as parameters of balloon performance. At 120 bpm the V/IT and V/DT were 0.34 ml/msec and 0.28 ml/msec with the 8.0 French, and 0.33 ml/msec and 0.24 ml/msec with the 9.5 French catheter. Twelve patients with coronary artery disease, ranging in age from 41 to 87 years (mean, 66 years), who underwent IABP support, were divided into group 1 (8.0 French, n = 4) and group 2 (9.5 French, n = 8). Ankle-arm pressure index (API), lactate extraction ratio (LER) in the limb with IABP insertion, and cardiac index (CI) were measured at 1, 12, and 24 hours postoperatively. There were no major vascular complications and no counterpulsation related morbidity. There was no significant difference between the two groups with regard to age, duration of IABP support, and incidence of peripheral vascular disease and diabetes. The percentage of women patients was significantly higher in group 1 (100% vs. 25%), whereas body surface area was significantly smaller (1.45 +/- 0.14 vs. 1.68 +/- 0.12 m2). The API in group 1 were slightly higher than those in group 2 throughout the observed period (not significant). The LER and Cl showed no significant differences between the two groups. These results suggest that the 8.0 French IABP catheter with a low profile has an acceptable in vitro performance, and its clinical application may be effective in preventing limb ischemia in a high-risk subset of patients such as women and smaller patients.

H2O2-responsive molecularly engineered polymer nanoparticles as ischemia/reperfusion-targeted nanotherapeutic agents

NASA Astrophysics Data System (ADS)

Lee, Dongwon; Bae, Soochan; Hong, Donghyun; Lim, Hyungsuk; Yoon, Joo Heung; Hwang, On; Park, Seunggyu; Ke, Qingen; Khang, Gilson; Kang, Peter M.

2013-07-01

The main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury is the overproduction of reactive oxygen species (ROS). Hydrogen peroxide (H2O2), the most abundant form of ROS produced during I/R, causes inflammation, apoptosis and subsequent tissue damages. Here, we report H2O2-responsive antioxidant nanoparticles formulated from copolyoxalate containing vanillyl alcohol (VA) (PVAX) as a novel I/R-targeted nanotherapeutic agent. PVAX was designed to incorporate VA and H2O2-responsive peroxalate ester linkages covalently in its backbone. PVAX nanoparticles therefore degrade and release VA, which is able to reduce the generation of ROS, and exert anti-inflammatory and anti-apoptotic activity. In hind-limb I/R and liver I/R models in mice, PVAX nanoparticles specifically reacted with overproduced H2O2 and exerted highly potent anti-inflammatory and anti-apoptotic activities that reduced cellular damages. Therefore, PVAX nanoparticles have tremendous potential as nanotherapeutic agents for I/R injury and H2O2-associated diseases.

The usefulness of Duplex Doppler ultrasound in the angiological and dermatological diagnosis of patients with blue toe syndrome.

PubMed

Pawlaczyk, Katarzyna; Gabriel, Marcin; Strzelecka-Węklar, Daria A; Krasiński, Zbigniew; Stanisic, Michal; Gabriel, Zofia; Dzieciuchowicz, Łukasz; Adamski, Zygmunt

2017-10-01

Peripheral microembolism is one of the most frequent causes of acute limb ischemia. In order to effectively prevent relapses it is essential to localize and eliminate the source of embolism. To evaluate the role of Duplex Doppler ultrasound examination in identifying the causes of blue toe syndrome (BTS). The group of 165 patients with clinical symptoms of BTS on their upper limbs ( n = 16) and lower limbs ( n = 149) was investigated. They all underwent Duplex Doppler ultrasound of the major arteries of the extremities, where ischemic changes occurred. Morphological and functional changes which might be potential sources of microembolism were identified in 146 patients. These changes included significant short-length stenoses or unstable atherosclerotic plaque ( n = 73), true aneurysms ( n = 42) and pseudoaneurysms ( n = 17). In 11 cases, pathology of vascular prostheses in the form of anastomotic aneurysms, infection and residual thrombi after fibrinolysis was detected. In all cases, Duplex diagnosis was confirmed by other imaging and intraoperative tests. Duplex Doppler ultrasound of the arteries in the affected limb with a full length view should be the first-line examination in diagnosing patients with BTS. In the absence of hemodynamic blood flow disturbances in the major arteries in patients with symptoms of BTS, it is advisable to start haematological tests to identify/exclude congenital or acquired thrombophilia.

Globus File Transfer Services | High-Performance Computing | NREL

Science.gov Websites

Account To get a Globus account, sign up on the Globus account website. To get access to the NREL endpoint continue. Use the Globus credentials you used to register your Globus.org account. Go to the Transfer Files Globus.org account to allow ssh CLI access To use the CLI you must have a Globus account with ssh access

Interaction of chloride and bicarbonate transport across the basolateral membrane of rabbit proximal straight tubule. Evidence for sodium coupled chloride/bicarbonate exchange.

PubMed Central

Sasaki, S; Yoshiyama, N

1988-01-01

The existence of chloride/bicarbonate exchange across the basolateral membrane and its physiologic significance were examined in rabbit proximal tubules. S2 segments of the proximal straight tubule were perfused in vitro and changes in intracellular pH (pHi) and chloride activity (aCli) were monitored by double-barreled microelectrodes. Total peritubular chloride replacement with gluconate increased pHi by 0.8, and this change was inhibited by a pretreatment with an anion transport inhibitor, SITS. Peritubular bicarbonate reduction increased aCli, and most of this increase was lost when ambient sodium was totally removed. The reduction rates of pHi induced by a peritubular bicarbonate reduction or sodium removal were attenuated by 20% by withdrawal of ambient chloride. SITS application to the bath in the control condition quickly increased pHi, but did not change aCli. However, the aCli slightly decreased in response to SITS when the basolateral bicarbonate efflux was increased by reducing peritubular bicarbonate concentration. It is concluded that sodium coupled chloride/bicarbonate exchange is present in parallel with sodium-bicarbonate cotransport in the basolateral membrane of the rabbit proximal tubule, and it contributes to the basolateral bicarbonate and chloride transport. PMID:2450891

Constraining wintertime sources of inorganic chlorine over the northeast United States

NASA Astrophysics Data System (ADS)

Haskins, J.; Jaegle, L.; Shah, V.; Lopez-Hilfiker, F.; Lee, B. H.; Campuzano Jost, P.; Schroder, J. C.; Day, D. A.; Fiddler, M. N.; Holloway, J. S.; Sullivan, A.; Veres, P. R.; Weber, R. J.; Dibb, J. E.; Brown, S. S.; Jimenez, J. L.; Thornton, J. A.

2017-12-01

Wintertime multiphase chlorine chemistry is thought to play a significant role in the regional distribution of oxidants, the lifetime of VOCs, and the transport of NOx downwind of urban sources. However, the sources and chemistry of reactive chlorine remain highly uncertain. During the WINTER 2015 aircraft campaign, the inorganic chlorine budget was dominated by HCl (g) and total particulate chloride, accounting for greater than 85% of the total chlorine budget within the boundary layer. The total concentration of inorganic chlorine compounds found over marine regions was 1014 pptv and 609 pptv over continental regions with variability found to be driven by changes in meteorological conditions, particle liquid water content, particle pH, and proximity to large anthropogenic sources. However, displacement of particle chloride was often not a large enough source to fully explain the concentrations of gas phase Cly compounds. We use the GEOS-Chem global chemical transport model to simulate the emissions, gas-particle partitioning, and downwind transport and deposition of Cly during winter. Simulated concentrations of HCl, particle chloride, and other dominant Cly compounds are compared to measurements made during the WINTER aircraft campaign. The relative roles of Cly sources from sea-salt aerosol and anthropogenic sources such as power plants, biomass burning and road salt are explored.

Endovascular interventions for TASC II D femoropopliteal lesions.

PubMed

Baril, Donald T; Chaer, Rabih A; Rhee, Robert Y; Makaroun, Michel S; Marone, Luke K

2010-06-01

Advances in endovascular techniques have provided new options in the treatment of complex infrainguinal occlusive lesions. The purpose of this study was to evaluate outcomes of endovascular interventions on TransAtlantic InterSociety (TASC) II D femoropopliteal occlusive disease. All patients undergoing endovascular interventions for femoropopliteal occlusive disease between July 2004 and July 2009 were reviewed. Patient demographics, pre- and postprocedure ankle-brachial indices (ABI) and anatomic factors were analyzed. Outcomes evaluated included primary patency, assisted-patency, secondary patency, predictors of restenosis, and wound healing. Five hundred eighty-five limbs were treated during the period reviewed. The study group included 79 TASC D limbs in 74 patients (mean age 76.5 +/- 11.9 years, male sex: 53%). Fifty-six limbs (71%) underwent treatment for critical limb ischemia, including 42 (53%) with tissue loss. Eleven patients (15%) had previous failed bypasses. Preoperative ABIs were unobtainable for 23 patients, while the remaining 56 had a mean baseline ABI of 0.54 +/- 0.28. There was one periprocedural mortality. Five patients (6.3%) had periprocedural complications. Mean increase in ABI postprocedure was 0.49 +/- 0.35. Follow-up was available for 74 limbs at a mean of 10.7 months (range, 1-35). There were 18 mortalities (24.3%) during the follow-up period. No patient required a major amputation during this follow-up period. Twenty-one limbs (26.6%) experienced restenosis and nine limbs (11.4%) experienced occlusion. Twenty-nine limbs underwent reintervention during the follow-up time, including nine which underwent multiple reinterventions. Primary, assisted-primary, and secondary patency rates at 12 and 24 months were 52.2%, 88.4%, 92.6% and 27.5%, 74.2%, and 88.9%, respectively. Predictors of restenosis/occlusion included hypercholesterolemia, the presence of a popliteal artery stent, and patients who were current or former smokers. Endovascular interventions for TASC II D lesions can be safely performed with excellent hemodynamic improvement and limb salvage rates. Restenosis is not uncommon in this population, which mandates strict follow-up. Further follow-up is necessary to determine the long-term efficacy of these interventions. Copyright (c) 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

Radial extracorporeal shock wave therapy improves cerebral blood flow and neurological function in a rat model of cerebral ischemia.

PubMed

Kang, Nan; Zhang, Jing; Yu, Xiaotong; Ma, Yuewen

2017-01-01

We performed middle cerebral artery occlusion (MCAO) in rats to investigate the effect and some of the underlying mechanisms of radial extracorporeal shock wave therapy (rESWT) in cerebral ischemia rats. We measured neurological function and cerebral blood flow (CBF) using a full-field laser perfusion imager and brain infarct volume on days 3, 12, and 30. Immunofluorescence, western blot, and real-time polymerase chain reaction (PCR) techniques were used to detect the expression of vascular endothelial growth factor (VEGF), neuron-specific enolase (NSE), nestin, Wnt3a, and β-catenin in the ischemic hemisphere. The dose of rESWT used on the head revealed remarkable advantages over sham rESWT, as demonstrated by improved neurological function scores, increased CBF, and reduced brain infarct volume. Furthermore, applying rESWT to the head and limbs enhanced short-term neurological function. Our results confirmed that rESWT can induce VEGF expression over an extended period with a profound effect, which may be the primary reason for CBF recovery. High NSE and nestin expression levels suggest that rESWT enhanced the number of neurons and neural stem cells (NSCs). Wnt3a and β-catenin expression were up-regulated in the ischemic hemisphere, indicating that rESWT promoted NSC proliferation and differentiation via the Wnt/β-catenin pathway. Overall, our findings suggest that an appropriate rESWT dose delivered to the head of rats helps restore neurological function and CBF, and additional application of rESWT to the limbs is more effective than treating the head alone.

Second Language Attainment and First Language Attrition: The Case of VOT in Immersed Dutch-German Late Bilinguals

ERIC Educational Resources Information Center

Stoehr, Antje; Benders, Titia; van Hell, Janet G.; Fikkert, Paula

2017-01-01

Speech of late bilinguals has frequently been described in terms of cross-linguistic influence (CLI) from the native language (L1) to the second language (L2), but CLI from the L2 to the L1 has received relatively little attention. This article addresses L2 attainment and L1 attrition in voicing systems through measures of voice onset time (VOT)…

Quantitative assessment of Cerenkov luminescence for radioguided brain tumor resection surgery

NASA Astrophysics Data System (ADS)

Klein, Justin S.; Mitchell, Gregory S.; Cherry, Simon R.

2017-05-01

Cerenkov luminescence imaging (CLI) is a developing imaging modality that detects radiolabeled molecules via visible light emitted during the radioactive decay process. We used a Monte Carlo based computer simulation to quantitatively investigate CLI compared to direct detection of the ionizing radiation itself as an intraoperative imaging tool for assessment of brain tumor margins. Our brain tumor model consisted of a 1 mm spherical tumor remnant embedded up to 5 mm in depth below the surface of normal brain tissue. Tumor to background contrast ranging from 2:1 to 10:1 were considered. We quantified all decay signals (e±, gamma photon, Cerenkov photons) reaching the brain volume surface. CLI proved to be the most sensitive method for detecting the tumor volume in both imaging and non-imaging strategies as assessed by contrast-to-noise ratio and by receiver operating characteristic output of a channelized Hotelling observer.

Clopidogrel Responsiveness in Patients Undergoing Peripheral Angioplasty

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pastromas, Georgios, E-mail: geopastromas@gmail.com; Spiliopoulos, Stavros, E-mail: stavspiliop@upatras.gr; Katsanos, Konstantinos, E-mail: katsanos@med.upatras.gr

2013-12-15

Purpose: To investigate the incidence and clinical significance of platelet responsiveness in patients receiving clopidogrel after peripheral angioplasty procedures. Materials and Methods: This prospective study included patients receiving antiplatelet therapy with clopidogrel 75 mg after infrainguinal angioplasty or stenting and who presented to our department during routine follow-up. Clopidogrel responsiveness was tested using the VerifyNow P2Y12 Assay. Patients with residual platelet reactivity units (PRU) {>=} 235 were considered as nonresponders (NR group NR), whereas patients with PRU < 235 were considered as normal (responders [group R]). Primary end points were incidence of resistance to clopidogrel and target limb reintervention (TLR)-freemore » survival, whereas secondary end points included limb salvage rates and the identification of any independent predictors influencing clinical outcomes. Results: In total, 113 consecutive patients (mean age 69 {+-} 8 years) with 139 limbs were enrolled. After clopidogrel responsiveness analysis, 61 patients (53.9 %) with 73 limbs (52.5 %) were assigned to group R and 52 patients (46.1 %) with 66 limbs (47.5 %) to group NR. Mean follow-up interval was 27.7 {+-} 22.9 months (range 3-95). Diabetes mellitus, critical limb ischemia, and renal disease were associated with clopidogrel resistance (Fisher's exact test; p < 0.05). According to Kaplan-Meier analysis, TLR-free survival was significantly superior in group R compared with group NR (20.7 vs. 1.9 %, respectively, at 7-year follow-up; p = 0.001), whereas resistance to clopidogrel was identified as the only independent predictor of decreased TLR-free survival (hazard rate 0.536, 95 % confidence interval 0.31-0.90; p = 0.01). Cumulative TLR rate was significantly increased in group NR compared with group R (71.2 % [52 of 73] vs. 31.8 % [21 of 66], respectively; p < 0.001). Limb salvage was similar in both groups. Conclusion: Clopidogrel resistance was related with significantly more repeat interventions after peripheral angioplasty procedures.« less

A novel platelet lysate hydrogel for endothelial cell and mesenchymal stem cell-directed neovascularization.

PubMed

Robinson, Scott T; Douglas, Alison M; Chadid, Tatiana; Kuo, Katie; Rajabalan, Ajai; Li, Haiyan; Copland, Ian B; Barker, Thomas H; Galipeau, Jacques; Brewster, Luke P

2016-05-01

Mesenchymal stem cells (MSC) hold promise in promoting vascular regeneration of ischemic tissue in conditions like critical limb ischemia of the leg. However, this approach has been limited in part by poor cell retention and survival after delivery. New biomaterials offer an opportunity to localize cells to the desired tissue after delivery, but also to improve cell survival after delivery. Here we characterize the mechanical and microstructural properties of a novel hydrogel composed of pooled human platelet lysate (PL) and test its ability to promote MSC angiogenic activity using clinically relevant in vitro and in vivo models. This PL hydrogel had comparable storage and loss modulus and behaved as a viscoelastic solid similar to fibrin hydrogels despite having 1/4-1/10th the fibrin content of standard fibrin gels. Additionally, PL hydrogels enabled sustained release of endogenous PDGF-BB for up to 20days and were resistant to protease degradation. PL hydrogel stimulated pro-angiogenic activity by promoting human MSC growth and invasion in a 3D environment, and enhancing endothelial cell sprouting alone and in co-culture with MSCs. When delivered in vivo, the combination of PL and human MSCs improved local tissue perfusion after 8days compared to controls when assessed with laser Doppler perfusion imaging in a murine model of hind limb ischemia. These results support the use of a PL hydrogel as a scaffold for MSC delivery to promote vascular regeneration. Innovative strategies for improved retention and viability of mesenchymal stem cells (MSCs) are needed for cellular therapies. Human platelet lysate is a potent serum supplement that improves the expansion of MSCs. Here we characterize our novel PL hydrogel's desirable structural and biologic properties for human MSCs and endothelial cells. PL hydrogel can localize cells for retention in the desired tissue, improves cell viability, and augments MSCs' angiogenic activity. As a result of these unique traits, PL hydrogel is ideally suited to serve as a cell delivery vehicle for MSCs injected into ischemic tissues to promote vascular regeneration, as demonstrated here in a murine model of hindlimb ischemia. Published by Elsevier Ltd.

Plasma viscosity increase with progression of peripheral arterial atherosclerotic disease.

PubMed

Poredos, P; Zizek, B

1996-03-01

Increased blood and plasma viscosity has been described in patients with coronary and peripheral arterial disease. However, the relation of viscosity to the extent of arterial wall deterioration--the most important determinant of clinical manifestation and prognosis of the disease--is not well known. Therefore, the authors studied plasma viscosity as one of the major determinants of blood viscosity in patients with different stages of arterial disease of lower limbs (according to Fontaine) and its relation to the presence of some risk factors of atherosclerosis. The study encompassed four groups of subjects: 19 healthy volunteers (group A), 18 patients with intermittent claudication up to 200 m (stage II; group B), 15 patients with critical ischemia of lower limbs (stage III and IV; group C), and 16 patients with recanalization procedures on peripheral arteries. Venous blood samples were collected from an antecubital vein without stasis for the determination of plasma viscosity (with a rotational capillary microviscometer, PAAR), fibrinogen, total cholesterol, alpha-2-macroglobulin, and glucose concentrations. In patients with recanalization procedure local plasma viscosity was also determined from blood samples taken from a vein on the dorsum of the foot. Plasma viscosity was most significantly elevated in the patients with critical ischemia (1.78 mPa.sec) and was significantly higher than in the claudicants (1.68 mPa.sec), and the claudicants also had significantly higher viscosity than the controls (1.58 mPa.sec). In patients in whom a recanalization procedure was performed, no differences in systemic and local plasma viscosity were detected, neither before nor after recanalization of the diseased artery. In all groups plasma viscosity was correlated with fibrinogen concentration (r=0.70, P < 0.01) and total cholesterol concentration (r=0.24, P < 0.05), but in group C (critical ischemia) plasma viscosity was most closely linked to the concentration of alpha-2-macroglobulin (r=0.78, P < 0.01). These results indicate that in patients with peripheral arterial disease plasma viscosity increases with the progression of the atherosclerotic process and is correlated with the clinical stages of the disease.

Effect of Mailuoning injection on 8-iso-prostaglandin F2 alpha and superoxide dismutase in rabbits with extremity ischemia-reperfusion injury.

PubMed

Wang, Dai-Jun; Tian, Hua

2014-12-01

To date, there are no effective treatments for extremity ischemia-reperfusion (IR) injury. The objective of the present study was to explore the protective effect of Mailuoning on IR injury by investigating the plasma levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF2α) and the activity of superoxide dismutase (SOD) in rabbits. The experimental models of posterior limb IR injury were established in thirty rabbits that were divided into three groups: the sham, IR, and IR + Mailuoning groups. At the end of ischemia, Mailuoning was injected intravenously into the rabbits in the IR + Mailuoning group, and normal saline solution was administered to the rabbits in the sham and IR groups. Venous blood samples were collected to measure the levels of 8-iso-PGF2α and the activity of SOD in the plasma at the following time points: at the onset of ischemia, the end of ischemia, and 2, 4, 8, 12, and 24 h after reperfusion. The skeletal muscles were harvested to examine the ultrastructure. The levels of 8-iso-PGF2α increased significantly and SOD activity decreased in the IR group at every time point after reperfusion (P <0.01 or P <0.05). In contrast, the levels of 8-iso-PGF2α and SOD activity were not significantly different after reperfusion in the IR + Mailuoning group (P >0.05) but were significantly different compared with the IR group (P <0.01). Using electron microscopy, the skeletal muscle injury was shown to be milder in the IR+ Mailuoning group after reperfusion compared with the IR group. The Mailuoning is capable of decreasing the excessive production of 8-iso-PGF2α and protecting SOD activity, thereby exhibiting a protective effect on extremity IR injury. Copyright © 2014 Elsevier Inc. All rights reserved.

Tetrahydrobiopterin, l-Arginine and Vitamin C Act Synergistically to Decrease Oxidant Stress and Increase Nitric Oxide That Increases Blood Flow Recovery after Hindlimb Ischemia in the Rat

PubMed Central

Yan, Jinglian; Tie, Guodong; Messina, Louis M

2012-01-01

Nitric oxide (NO) derived from endothelial nitric oxide synthase (eNOS) is a potent vasodilator and signaling molecule that plays essential roles in neovascularization. During limb ischemia, decreased NO bioavailability occurs secondary to increased oxidant stress, decreased l-arginine and tetrahydrobiopterin. This study tested the hypothesis that dietary cosupplementation with tetrahydrobiopterin (BH4), l-arginine and vitamin C acts synergistically to decrease oxidant stress, increase NO and thereby increase blood flow recovery after hindlimb ischemia. Rats were fed normal chow, chow supplemented with BH4 or l-arginine (alone or in combination) or chow supplemented with BH4 + l-arginine + vitamin C for 1 wk before induction of hindlimb ischemia. In the is-chemic hindlimb, cosupplementation with BH4 + l-arginine resulted in greater eNOS and phospho-eNOS (P-eNOS) expression, Ca2+-dependent NOS activity and NO concentration in the ischemic calf region (gastrocnemius), as well as greater NO concentration in the region of collateral arteries (gracilis). Rats receiving cosupplementation of BH4 + l-arginine led to greater recovery of foot perfusion and greater collateral enlargement than did rats receiving either agent separately. The addition of vitamin C to the BH4 + l-arginine regimen further increased these dependent variables. In addition, rats given all three supplements showed significantly less Ca2+-independent activity, less nitrotyrosine accumulation, greater glutathione (GSH)–to–glutathione disulfide (GSSG) ratio and less gastrocnemius muscle necrosis, on both macroscopic and microscopic levels. In conclusion, co-supplementation with BH4 + l-arginine + vitamin C significantly increased blood flow recovery after hindlimb ischemia by reducing oxidant stress, increasing NO bioavailability, enlarging collateral arteries and reducing muscle necrosis. Oral cosupplementation of BH4, l-arginine and vitamin C holds promise as a biological therapy to induce collateral artery enlargement. PMID:23212846

Grand European and Asian-Pacific multi-model seasonal forecasts: maximization of skill and of potential economical value to end-users

NASA Astrophysics Data System (ADS)

Alessandri, Andrea; Felice, Matteo De; Catalano, Franco; Lee, June-Yi; Wang, Bin; Lee, Doo Young; Yoo, Jin-Ho; Weisheimer, Antije

2018-04-01

Multi-model ensembles (MMEs) are powerful tools in dynamical climate prediction as they account for the overconfidence and the uncertainties related to single-model ensembles. Previous works suggested that the potential benefit that can be expected by using a MME amplifies with the increase of the independence of the contributing Seasonal Prediction Systems. In this work we combine the two MME Seasonal Prediction Systems (SPSs) independently developed by the European (ENSEMBLES) and by the Asian-Pacific (APCC/CliPAS) communities. To this aim, all the possible multi-model combinations obtained by putting together the 5 models from ENSEMBLES and the 11 models from APCC/CliPAS have been evaluated. The grand ENSEMBLES-APCC/CliPAS MME enhances significantly the skill in predicting 2m temperature and precipitation compared to previous estimates from the contributing MMEs. Our results show that, in general, the better combinations of SPSs are obtained by mixing ENSEMBLES and APCC/CliPAS models and that only a limited number of SPSs is required to obtain the maximum performance. The number and selection of models that perform better is usually different depending on the region/phenomenon under consideration so that all models are useful in some cases. It is shown that the incremental performance contribution tends to be higher when adding one model from ENSEMBLES to APCC/CliPAS MMEs and vice versa, confirming that the benefit of using MMEs amplifies with the increase of the independence the contributing models. To verify the above results for a real world application, the Grand ENSEMBLES-APCC/CliPAS MME is used to predict retrospective energy demand over Italy as provided by TERNA (Italian Transmission System Operator) for the period 1990-2007. The results demonstrate the useful application of MME seasonal predictions for energy demand forecasting over Italy. It is shown a significant enhancement of the potential economic value of forecasting energy demand when using the better combinations from the Grand MME by comparison to the maximum value obtained from the better combinations of each of the two contributing MMEs. The above results demonstrate for the first time the potential of the Grand MME to significantly contribute in obtaining useful predictions at the seasonal time-scale.

A novel resistance gene, lnu(H), conferring resistance to lincosamides in Riemerella anatipestifer CH-2.

PubMed

Luo, Hong-Yan; Liu, Ma-Feng; Wang, Ming-Shu; Zhao, Xin-Xin; Jia, Ren-Yong; Chen, Shun; Sun, Kun-Feng; Yang, Qiao; Wu, Ying; Chen, Xiao-Yue; Biville, Francis; Zou, Yuan-Feng; Jing, Bo; Cheng, An-Chun; Zhu, De-Kang

2018-01-01

The Gram-negative bacterium Riemerella anatipestifer CH-2 is resistant to lincosamides, having a lincomycin (LCM) minimum inhibitory concentration (MIC) of 128 µg/mL. The G148_1775 gene of R. anatipestifer CH-2, designated lnu(H), encodes a 260-amino acid protein with ≤41% identity to other reported lincosamide nucleotidylyltransferases. Escherichia coli Rosetta TM (DE3) containing the pBAD24-lnu(H) plasmid showed four- and two-fold increases in the MICs of LCM and clindamycin (CLI), respectively. A kinetic assay of the purified Lnu(H) enzyme for LCM and CLI showed that the protein could inactive lincosamides. Mass spectrometry analysis demonstrated that the Lnu(H) enzyme catalysed adenylylation of lincosamides. In addition, an lnu(H) gene deletion strain exhibited 512- and 32-fold decreases in LCM and CLI MICs, respectively. The wild-type level of lincosamide resistance could be restored by complementation with a shuttle plasmid carrying the lnu(H) gene. The transformant R. anatipestifer ATCC 11845 [lnu(H)] acquired by natural transformation also exhibited high-level lincosamide resistance. Moreover, among 175 R. anatipestifer field isolates, 56 (32.0%) were positive for the lnu(H) gene by PCR. In conclusion, Lnu(H) is a novel lincosamide nucleotidylyltransferase that inactivates LCM and CLI by nucleotidylylation, thus conferring high-level lincosamide resistance to R. anatipestifer CH-2. Copyright © 2017. Published by Elsevier B.V.

Silencing of p53 RNA through transarterial delivery ameliorates renal tubular injury and downregulates GSK-3β expression after ischemia-reperfusion injury.

PubMed

Fujino, Takayuki; Muhib, Sharifi; Sato, Nobuyuki; Hasebe, Naoyuki

2013-12-01

p53, a pivotal protein in the apoptotic pathway, has been identified as a mediator of transcriptional responses to ischemia-reperfusion (IR) injury. The characteristics and functional significance of the p53 response in vivo are largely unknown in IR-induced kidney injury. Therapeutic opportunities of delivering small interfering RNA (siRNA) via venous injection have gained recognition; however, systemic adverse effects of siRNA therapy should be considered. To prevent IR-induced kidney injury, we tested the efficacy of transarterial administration of siRNA targeting p53 (p53 siRNA). Female C57BL/6 mice underwent unilateral renal artery ischemia for 30 min, followed by reperfusion. siRNA experiments utilized short hairpin (sh) RNA plasmid-based approaches. Transfection of shRNA was performed using cationic polymer transfection reagent. Injection of synthetic p53 shRNA into the left renal artery just after ischemia improved tubular injury, apoptosis, and the swelling of mitochondria in cells of the thick ascending limb of Henle (mTALH) at the outer medullary regions. Staining of upregulated p53 was colocalized with the inducible expression of glycogen synthase kinase-3β (GSK-3β) at mTALH after IR injury. p53 shRNA inhibited GSK-3β expression and restored β-catenin expression at mTALH. For IR-induced kidney injury, transarterial delivery of p53 siRNA is an effective pharmacological intervention. Targeting siRNA to p53 leads to an attenuation of apoptosis and mitochondrial damage through the downregulation of GSK-3β expression and upregulation of β-catenin. Local delivery of vectors such as p53 siRNA through a transaortic catheter is clinically useful in reducing the adverse effect of siRNA-related therapy.

Effect of limited ischemia time on the amount and function of mitochondria within human skeletal muscle cells.

PubMed

Jawhar, A; Ponelies, N; Schild, L

2016-12-01

The clinical success of total knee arthroplasty (TKA) depends substantially on the quadriceps muscle function. A frequently applied thigh tourniquet during TKA may induce ischemia related injuries to quadriceps muscle cells. Animal limb muscles subjected to 2-5 h ischemia revealed dysfunctional mitochondria, which in turn compromised the cellular bioenergetics and increased the level of reactive oxygen species. The hypothesis of the present study was that tourniquet application during TKA for 60 min (min) affects the amount and function of mitochondria within musculus vastus medialis cells. In a randomized clinical trial, 10 patients enrolled to undergo primary TKA. The patients were randomly assigned to the tourniquet (n = 5) or non-tourniquet group (n = 5) after obtaining a written informed consent. For each of the groups, the first muscle biopsy was harvested immediately after performing the surgical approach and the second biopsy exactly 60 min later. All biopsies (5 × 5 × 5 mm) 125 mm 3 were harvested from musculus vastus medialis and snap-frozen in liquid nitrogen. The biochemical analysis of the prepared muscle tissues included the measurement of activities of mitochondrial respiratory chain enzyme complexes I-III and citrate synthase. Tourniquet-induced 60 min ischemia time did not significantly change the activities of the mitochondrial respiratory chain enzymes complexes I-III of the skeletal muscle cells. The citrate synthase activities found to be not significantly different between both groups. The use of tourniquet during TKA within a limited time period of 60 min remained without substantial effects on the amount and function of mitochondria within human skeletal muscle cells.

Exploring Spinal Cord Protection by Remote Ischemic Preconditioning: An Experimental Study.

PubMed

Herajärvi, Johanna; Anttila, Tuomas; Sarja, Henna; Mustonen, Caius; Haapanen, Henri; Mäkelä, Tuomas; Yannopoulos, Fredrik; Starck, Tuomo; Kallio, Mika; Tuominen, Hannu; Puistola, Ulla; Karihtala, Peeter; Kiviluoma, Kai; Anttila, Vesa; Juvonen, Tatu

2017-03-01

Paraplegia is one of the most severe complications occurring after the repair of thoracic and thoracoabdominal aortic aneurysms. Remote ischemic preconditioning (RIPC) has been shown to mitigate neurologic damage, and this study assessed its efficacy in preventing spinal cord ischemia. The study randomized 16 female pigs into an RIPC group (n = 8) and a control group (n = 8). The RIPC group underwent four cycles of 5-minute ischemia-reperfusion episodes by intermittent occlusion of the left iliac artery. All animals underwent systematic closure of the left subclavian artery and segmental arteries of the descending thoracic aorta to the level of diaphragm. Motor-evoked potential monitoring was performed in both hind limbs. Continuous electrocardiogram and hemodynamics were monitored, and pulmonary artery blood samples were collected. A neurologic assessment was performed 6 hours after the procedure. The thoracic and lumbar portions of the spinal cord were collected for histologic and immunohistochemical analysis. The bilateral motor-evoked potential amplitude responses were higher in the RIPC group (p < 0.05) than in the control group; the difference was detected already before spinal cord ischemia. Paraplegia occurred in 1 control animal. Immunohistochemical total scores of antioxidant response regulator nuclear factor erythroid 2-related factor 2 were better in the RIPC group (11.0; range, 8.5 to 14.0) than in the control group (5.2; range, 1.0 to 9.0; p = 0.023). RIPC induces electrophysiologic changes in the central nervous system that may confer spinal cord protection extending the resistance to ischemia. The significantly higher nuclear factor erythroid 2-related factor 2 scores suggest better neuronal cell protection against oxidative stress in the RIPC group. Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Palena, Luis Mariano, E-mail: marianopalena@hotmail.com; Cester, Giacomo; Manzi, Marco

In-stent reocclusion is a frequent complication of endovascular treatment and stenting, especially in the superficial femoral artery. Neointimal hyperplasia is the main cause of this problem, but in many cases, it occurs as a result of the presence of stent strut fractures. The two treatment options are endovascular and surgical intervention. The effectiveness of endovascular interventions in patients with critical limb ischemia has been well established, but in some cases, crossing the occluded stent is difficult. We describe a new technique to recanalize long in-stent superficial femoral artery occlusions characterized by direct stent puncture, followed by retrograde-antegrade recanalization after antegrademore » failures.« less

Femoropopliteal Bypass with Varicose Greater Saphenous Vein

PubMed Central

Mun, Yun Su; Cho, Byung Sun; Jang, Je-Ho; Lee, Moon-Soo; Kwon, Oh Sang

2015-01-01

Surgical bypass for peripheral arterial occlusive disease can be performed using different graft materials. Autogenous greater saphenous vein (GSV) is the treatment of choice because of its superior long-term patency. We report a case of femoropopliteal bypass with varicose GSV in a 77-year-old man who was presented with limb ischemia and both varicose veins. We successfully performed bypass with varicose vein. He has been doing well for 15 months after the operation, and a computed tomography angiography of the lower leg, performed on the 15th postoperative month, demonstrated widely patent femoropopliteal bypass graft and no structural change. PMID:28031670

NRF2 Activation as Target to Implement Therapeutic Treatments

NASA Astrophysics Data System (ADS)

Bocci, Velio; Valacchi, Giuseppe

2015-02-01

A chronic increase of oxidative stress is typical of serious pathologies such as myocardial infarction, stroke, chronic limb ischemia, chronic obstructive pulmonary disease (COPD), type II-diabetes, age-related macular degeneration leads to an epic increase of morbidity and mortality in all countries of the world. The initial inflammation followed by an excessive release of reactive oxygen species (ROS) implies a diffused cellular injury that needs to be corrected by an inducible expression of the innate detoxifying and antioxidant system. The transcription factor Nrf2, when properly activated, is able to restore a redox homeostasis and possibly improve human health.

Contemporary Results of Surgical Management of Peripheral Mycotic Aneurysms.

PubMed

Salzler, Gg; Long, B; Avgerinos, Ed; Chaer, Ra; Leers, S; Hager, E; Makaroun, Ms; Eslami, Mh

2018-06-07

Mycotic aneurysms of the extremities occur infrequently but can cause severe life and limb complications. Traditional treatment typically includes debridement and revascularization, though in select patients ligation may be well tolerated. We reviewed our experience with these aneurysms treated with these two modalities. A retrospective review of patients treated for peripheral mycotic aneurysms at one institution from January 2005 to December 2015 was performed under an Institutional Review Board-approved protocol. Demographics, perioperative details, and long-term outcomes were collected and standard statistical methods were used to compare treatments. We identified 28 patients with 29 peripheral mycotic aneurysms. The majority of patients (19: 67.9%) were male with an average age of 60.1 ± 17 years. Among cases with a known cause, direct injury to artery was the most common precursor to mycotic aneurysm formation; iatrogenic causes were the most common (15: 51.7%) followed by intravenous drug use (5: 17.2%). Distal bacterial translocation was the other cause of mycotic aneurysm formation due to osteomyelitis (2:10.5%) and bacterial endocarditis (1:3.5%). The causes of the remainder of cases (6:20.7%) were unknown. Symptoms included fever (46.4%), drainage (42.9%), rupture (35.7%), erythema (21.4%), and limb ischemia (17.9%). Staphylococcus aureus was the most common bacteria isolated (38.5%, from 7 positive blood cultures and 3 positive wound culture) with 30% of these being MRSA, followed by Streptococcus species (11.5%), and other Staphylococcus (7.7%). Eight (30.7%) patients had negative cultures. The most common location of arterial aneurysm was the common femoral artery (17:58.6%), with 17.2% (5) occurring in the popliteal artery, 13.8% (4) in the brachial artery, 10.3% (3) in the radial or ulnar artery, and 3.5%(1) in the external iliac artery. 18 patients underwent revascularization, while 11 had resection/ligation without revascularization (4 femoral, 2 popliteal, 3 radial/ulnar, 1 brachial, and 1 external iliac). There was no significant difference in limb threatening ischemia between these two groups (p=0.14). Of those who were not revascularized, one developed significant initial ischemia but died prior to amputation and the other underwent revascularization within one year after tolerating the initial ligation. Upper extremity aneurysms were more likely to be reintervention-free than those in the lower extremities (p=0.01). In this series, resection or ligation of peripheral mycotic aneurysms without revascularization was well tolerated. With close follow-up of these patients, resection or ligation may obviate the more extensive initial revascularization procedures in these infected fields. Copyright © 2018 Elsevier Inc. All rights reserved.

Improved method for efficient imaging of intracellular Cl(-) with Cl-Sensor using conventional fluorescence setup.

PubMed

Friedel, Perrine; Bregestovski, Piotr; Medina, Igor

2013-01-01

Chloride (Cl(-)) homeostasis is known to be fundamental for central nervous system functioning. Alterations in intracellular Cl(-) concentration ([Cl(-)]i) and changes in the efficacy of Cl(-) extrusion are involved in numerous neurological disorders. Therefore, there is a strong need for studies of the dynamics of [Cl(-)]i in different cell types under physiological conditions and during pathology. Several previous works reported having successfully achieved recording of [Cl(-)]i using genetically encoded Cl-Sensor that is composed of the cyan fluorescent protein (CFP) and Cl(-)-sensitive mutant of the yellow fluorescent protein (YFPCl). However, all reported works were performed using specially designed setups with ultra-sensitive CCD cameras. Our multiple attempts to monitor Cl(-)-dependent fluorescence of Cl-Sensor using conventional epifluorescence microscopes did not yield successful results. In the present work, we have analysed the reason of our failures and found that they were caused by a strong inactivation of the YFPCl component of Cl-Sensor during excitation of the CFP with 430 nm light. Based on the obtained results, we reduced 20-fold the intensity of the 430 nm excitation and modified the recording protocol that allows now stable long-lasting ratiometric measurements of Cl-Sensor fluorescence in different cell types including cultured hippocampal neurons and their tiny dendrites and spines. Simultaneous imaging and patch clamp recording revealed that in mature neurons, the novel protocol allows detection of as little as 2 mM changes of [Cl(-)]i from the resting level of 5-10 mM. We demonstrate also a usefulness of the developed [Cl(-)]i measurement procedure for large scale screening of the activity of exogenously expressed potassium-chloride co-transporter KCC2, a major neuronal Cl(-) extruder that is implicated in numerous neurological disorders and is a target for novel therapeutical treatments.

The sodium-activated potassium channel Slack is modulated by hypercapnia and acidosis.

PubMed

Ruffin, V A; Gu, X Q; Zhou, D; Douglas, R M; Sun, X; Trouth, C O; Haddad, G G

2008-01-24

Slack (Slo 2.2), a member of the Slo potassium channel family, is activated by both voltage and cytosolic factors, such as Na(+) ([Na(+)](i)) and Cl(-) ([Cl(-)](i)). Since the Slo family is known to play a role in hypoxia, and since hypoxia/ischemia is associated with an increase in H(+) and CO(2) intracellularly, we hypothesized that the Slack channel may be affected by changes in intracellular concentrations of CO(2) and H(+). To examine this, we expressed the Slack channel in Xenopus oocytes and the Slo 2.2 protein was allowed to be inserted into the plasma membrane. Inside-out patch recordings were performed to examine the response of Slack to different CO(2) concentrations (0.038%, 5%, 12%) and to different pH levels (6.3, 6.8, 7.3, 7.8, 8.3). In the presence of low [Na(+)](i) (5 mM), the Slack channel open probability decreased when exposed to decreased pH or increased CO(2) in a dose-dependent fashion (from 0.28+/-0.03, n=3, at pH 7.3 to 0.006+/-0.005, n=3, P=0.0004, at pH 6.8; and from 0.65+/-0.17, n=3, at 0.038% CO(2) to 0.22+/-0.07, n=3, P=0.04 at 12% CO(2)). In the presence of high [Na(+)](i) (45 mM), Slack open probability increased (from 0.03+/-0.01 at 5 mM [Na(+)](i), n=3, to 0.11+/-0.01, n=3, P=0.01) even in the presence of decreased pH (6.3). Since Slack activity increases significantly when exposed to increased [Na(+)](i), even in presence of increased H(+), we propose that Slack may play an important role in pathological conditions during which there is an increase in the intracellular concentrations of both acid and Na(+), such as in ischemia/hypoxia.

Pediatric Traumatic Limb Amputation: The Principles of Management and Optimal Residual Limb Lengths.

PubMed

Khan, Muhammad Adil Abbas; Javed, Ammar Asrar; Rao, Dominic Jordan; Corner, J Antony; Rosenfield, Peter

2016-01-01

Pediatric traumatic limb amputations are rare and their acute and long term management can be challenging in this subgroup of patients. The lengthy and costly hospital stays, and resulting physical and psychological implications leads to significant morbidity. We present a summary of treatment principles and the evidence base supporting the management options for this entity. The initial management focuses on resuscitating and stabilization of the patients, administration of appropriate and adequate analgesics, and broad spectrum antibiotics. The patient should ideally be managed by an orthopedic or a plastic surgeon and when an amputation is warranted, the surgical team should aim to conserve as much of the viable physis as possible aimed at allowing bone development in a growing child. A subsequent wound inspection should be performed to assess for signs of ischemia or non-viability of tissue. Depending on the child's age, approximations of the ideal residual limb length can be calculated using our guidelines, allowing an ideal stump length at skeletal maturity for a well-fitting and appropriate prosthesis. Myodesis and myoplasties can be performed according to the nature of the amputation. Removable rigid dressings are safe and cost effective offering better protection of the stump. Complications such as necrosis and exostosis, on subsequent examination, warrant further revisions. Other complications such as neuromas can be prevented by proximal division of the nerves. Successful rehabilitation can be accomplished with a multidisciplinary approach, involving physiotherapist, play therapist and a child psychiatrist, in addition to the surgeon and primary care providers.

[Ischemic origin of diabetic foot disease. Epidemiology, difficulties of diagnosis, options for prevention and revascularization].

PubMed

Kolossváry, Endre; Bánsághi, Zoltán; Szabó, Gábor Viktor; Járai, Zoltán; Farkas, Katalin

2017-02-01

"Diabetic foot" as definition covers a multifactorial clinical condition. According to the recent epidemiological data, the role of lower limb ischemia is getting more influential over other pathological causes, like neuropathy, infections and bone or soft tissue deformity. In diabetes, vascular disease leads to increased risk for leg ulcers and minor or major amputations. The traditional diagnostic tools for recognition of peripheral arterial disease have limited value because of diabetes specific clinical manifestations. Available vascular centers with special expertise and diagnostic tools are the prerequisite for efficient diagnosis supporting timely recognition of peripheral arterial disease. In course of treatment of diabetic foot with ischemic origin, beyond effective medical treatment revascularization (open vascular surgery or endovascular procedures) has paramount importance for prevention of limb loss. Vascular teams of vascular specialists, vascular surgeons and interventional radiologist in dedicated centers in multidisciplinary cooperation with other professions represent public health issue in effective prevention. Orv. Hetil., 2017, 158(6), 203-211.

Design of the Revascularization With Open Bypass vs Angioplasty and Stenting of the Lower Extremity Trial (ROBUST): a randomized clinical trial.

PubMed

Malas, Mahmoud B; Qazi, Umair; Glebova, Natalia; Arhuidese, Isibor; Reifsnyder, Thomas; Black, James; Perler, Bruce A; Freischlag, Julie A

2014-12-01

To our knowledge, there is no level 1 evidence comparing open bypass with angioplasty and stenting in TransAtlantic Inter-Society Consensus (TASC II) B and C superficial femoral artery lesions. The Revascularization With Open Bypass vs Angioplasty and Stenting of the Lower Extremity Trial (ROBUST) is the first prospective randomized clinical trial comparing both treatments. To report the design of the ROBUST trial. The primary aim of the trial is to compare (1) the patency rate (primary, primary assisted, and secondary patency at 6 and 12 months), (2) improvement of quality of life, (3) clinical improvement (at least 1 Rutherford category), and (4) wound healing and limb salvage in patients presenting with critical limb ischemia; secondary aims include (1) cost-effectiveness by factoring procedure and hospital admission costs including rehabilitation, readmission, and reintervention costs, (2) amputation-free survival, (3) reintervention rate, and (4) 30-day operative mortality, morbidity, and wound and access complications. ROBUST is a prospective randomized clinical trial with the aim to enroll 320 patients with intermittent claudication that does not respond to medical management and patients with critical limb ischemia. The maximum level of medical therapy will be administered using antiplatelet agents and statins, as well as measures to control hypertension and diabetes mellitus. Patients with TASC II B or C lesions are prospectively randomized to receive either femoropopliteal bypass or percutaneous transluminal angioplasty and stenting; patients with TASC II A and D lesions are not randomized and receive percutaneous transluminal angioplasty and stenting or femoropopliteal bypass, respectively. All patients will be evaluated at 1, 6, and 12 months postoperatively with physical examination, ankle brachial index, duplex, and a quality-of-life questionnaire. The trial is actively enrolling participants. At the time of writing, 29 patients have been enrolled; most are male (60%) and white (65%). Providing level 1 evidence, ROBUST may help to establish guidelines for the treatment of superficial femoral artery lesions, eliminate unnecessary procedures, and reduce health care costs. clinicaltrials.gov Identifier: NCT01602159.

A Porcine Model for Endolaparoscopic Abdominal Aortic Repair and Endoscopic Training

PubMed Central

Zarins, Christopher K.; Daunt, David A.; Coleman, Leslie A.; Saenz, Yamil; Fogarty, Thomas J.; Hermann, George D.; Nezhat, Camran R.; Olsen, Eric K.

2003-01-01

Objective: The goals of this laboratory model were to evaluate the performance of the surgical team and endolaparoscopic techniques in the porcine model of infrarenal abdominal aortic repair. Methods: Twenty-four pigs underwent full endolaparoscopic aorto-aortic graft implantation with voice-activated computerized robotics. The first group of 10 pigs (acute) was sacrificed while under anesthesia at 0.5 hours (5 animals) and 2 hours (5 animals). The second group of 14 pigs (survival) were recovered from anesthesia and maintained for 7 hours (5 pigs) and 7 days (9 pigs) prior to sacrifice. Survival animals were observed for evidence of hind limb dysfunction. All grafts were visually inspected at autopsy. Results: All animals survived the operation. All grafts were successfully implanted, and all were patent with intact anastomoses at autopsy. Mean aortic clamp time for each group was as follows: acute, 92.9±28.04 minutes; survival, 59.6±13.8 minutes; P=0.0008. Total operative time for each group was as follows: acute, 179±39.6 minutes; survival, 164.6±48 minutes; P=0.44 ns. Estimated blood loss for each group was as follows: acute, 214±437.8 mL; survival 169.2±271 mL; P=0.76 ns. The following outcomes were observed: 1 animal died from respiratory arrest; 1 animal suffered motor sensory dysfunction of the hind limbs (spinal cord ischemia); significant bleeding occurred in 6 of 24 pigs; 8 of the 9 seven-day survivors required minimal pain medication and had normal hind limb function. Conclusions: The reduction in aortic clamp time, total operative time, and blood loss as the study progressed indicate the feasibility of this surgical protocol and the maturation of the learning process, which is paramount in prevention of 2 main sources of morbidity: bleeding and spinal cord ischemia. The reduction in aortic clamp time between the acute and survival groups was dramatic and statistically significant. An intensive formal training program combining dry and live surgical laboratories is deemed essential for the development of endoscopic skill sets necessary for this challenging procedure. PMID:12856843

Addressing Value and Belief Systems on Climate Literacy in the Southeastern United States

NASA Astrophysics Data System (ADS)

McNeal, K. S.

2012-12-01

The southeast (SEUS; AL, AR, GA, FL, KY, LA, NC, SC, TN, E. TX) faces the greatest impacts as a result of climate change of any region in the U.S. which presents considerable and costly adaptation challenges. Paradoxically, people in the SEUS hold attitudes and perceptions that are more dismissive of climate change than those of any other region. An additional mismatch exists between the manner in which climate science is generally communicated and the underlying core values and beliefs held by a large segment of people in the SEUS. As a result, people frequently misinterpret and/or distrust information sources, inhibiting efforts to productively discuss and consider climate change and related impacts on human and environmental systems, and possible solutions and outcomes. The Climate Literacy Partnership in the Southeast (CLiPSE) project includes an extensive network of partners throughout the SEUS from faith, agriculture, culturally diverse, leisure, and K-20 educator communities that aim to address this educational need through a shared vision. CLiPSE has conducted a Climate Stewardship Survey (CSS) to determine the knowledge and perceptions of individuals in and beyond the CLiPSE network. The descriptive results of the CSS indicate that religion, predominantly Protestantism, plays a minor role in climate knowledge and perceptions. Likewise, political affiliation plays a minimal role in climate knowledge and perceptions between religions. However, when Protestants were broken out by political affiliation, statistically significant differences (t(30)=2.44, p=0.02) in knowledge related to the causes of climate change exist. Those Protestants affiliated with the Democratic Party (n=206) tended to maintain a statistically significant stronger knowledge of the causes of global climate change than their Republican counterparts. When SEUS educator (n=277) group was only considered, similar trends were evidenced, indicating that strongly held beliefs potentially influence classroom climate instruction. In order to assist this educator group, CLiPSE has aligned a sub-set of the Climate and Energy Awareness Network (CLEAN) education resources to 11 SEUS state standards in order to better enable educators to implement climate topics in their classrooms. As a potential method to address the unique belief systems in the SEUS, CLiPSE has determined that the best way to engage individuals in the SEUS on the topic of climate change is to invite them into an honest dialogue surrounding climate. To facilitate these conversations effectively, CLiPSE utilizes a dialogical community model that values diversity, encourages respect for one another, recognizes and articulates viewpoints, and prioritizes understanding over resolution. CLiPSE emphasizes people's values and beliefs as they relate to climate change information. Results from pilot studies indicate that this is a promising method to bring together diverse individuals on the climate change topic and initiate the conversation about this very important issue that can often be considered "taboo" in the SEUS.

GenCLiP 2.0: a web server for functional clustering of genes and construction of molecular networks based on free terms.

PubMed

Wang, Jia-Hong; Zhao, Ling-Feng; Lin, Pei; Su, Xiao-Rong; Chen, Shi-Jun; Huang, Li-Qiang; Wang, Hua-Feng; Zhang, Hai; Hu, Zhen-Fu; Yao, Kai-Tai; Huang, Zhong-Xi

2014-09-01

Identifying biological functions and molecular networks in a gene list and how the genes may relate to various topics is of considerable value to biomedical researchers. Here, we present a web-based text-mining server, GenCLiP 2.0, which can analyze human genes with enriched keywords and molecular interactions. Compared with other similar tools, GenCLiP 2.0 offers two unique features: (i) analysis of gene functions with free terms (i.e. any terms in the literature) generated by literature mining or provided by the user and (ii) accurate identification and integration of comprehensive molecular interactions from Medline abstracts, to construct molecular networks and subnetworks related to the free terms. http://ci.smu.edu.cn. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The assembly dynamics of the cytolytic pore toxin ClyA

PubMed Central

Benke, Stephan; Roderer, Daniel; Wunderlich, Bengt; Nettels, Daniel; Glockshuber, Rudi; Schuler, Benjamin

2015-01-01

Pore-forming toxins are protein assemblies used by many organisms to disrupt the membranes of target cells. They are expressed as soluble monomers that assemble spontaneously into multimeric pores. However, owing to their complexity, the assembly processes have not been resolved in detail for any pore-forming toxin. To determine the assembly mechanism for the ring-shaped, homododecameric pore of the bacterial cytolytic toxin ClyA, we collected a diverse set of kinetic data using single-molecule spectroscopy and complementary techniques on timescales from milliseconds to hours, and from picomolar to micromolar ClyA concentrations. The entire range of experimental results can be explained quantitatively by a surprisingly simple mechanism. First, addition of the detergent n-dodecyl-β-D-maltopyranoside to the soluble monomers triggers the formation of assembly-competent toxin subunits, accompanied by the transient formation of a molten-globule-like intermediate. Then, all sterically compatible oligomers contribute to assembly, which greatly enhances the efficiency of pore formation compared with simple monomer addition. PMID:25652783

Thrombospondins deployed by thrombopoietic cells determine angiogenic switch and extent of revascularization

PubMed Central

Kopp, Hans-Georg; Hooper, Andrea T.; Broekman, M. Johan; Avecilla, Scott T.; Petit, Isabelle; Luo, Min; Milde, Till; Ramos, Carlos A.; Zhang, Fan; Kopp, Tabitha; Bornstein, Paul; Jin, David K.; Marcus, Aaron J.; Rafii, Shahin

2006-01-01

Thrombopoietic cells may differentially promote or inhibit tissue vascularization by releasing both pro- and antiangiogenic factors. However, the molecular determinants controlling the angiogenic phenotype of thrombopoietic cells remain unknown. Here, we show that expression and release of thrombospondins (TSPs) by megakaryocytes and platelets function as a major antiangiogenic switch. TSPs inhibited thrombopoiesis, diminished bone marrow microvascular reconstruction following myelosuppression, and limited the extent of revascularization in a model of hind limb ischemia. We demonstrate that thrombopoietic recovery following myelosuppression was significantly enhanced in mice deficient in both TSP1 and TSP2 (TSP-DKO mice) in comparison with WT mice. Megakaryocyte and platelet levels in TSP-DKO mice were rapidly restored, thereby accelerating revascularization of myelosuppressed bone marrow and ischemic hind limbs. In addition, thrombopoietic cells derived from TSP-DKO mice were more effective in supporting neoangiogenesis in Matrigel plugs. The proangiogenic activity of TSP-DKO thrombopoietic cells was mediated through activation of MMP-9 and enhanced release of stromal cell–derived factor 1. Thus, TSP-deficient thrombopoietic cells function as proangiogenic agents, accelerating hemangiogenesis within the marrow and revascularization of ischemic hind limbs. As such, interference with the release of cellular stores of TSPs may be clinically effective in augmenting neoangiogenesis. PMID:17143334

Pooled analysis of the CONFIRM registries: impact of gender on procedure and angiographic outcomes in patients undergoing orbital atherectomy for peripheral artery disease.

PubMed

Lee, Michael S; Canan, Timothy; Rha, Seung-Woon; Mustapha, Jihad; Adams, George L

2015-02-01

To compare the acute procedure and angiographic outcomes of peripheral artery disease (PAD) patients treated with orbital atherectomy stratified by gender. The CONFIRM I, II, and III registries are US multicenter, nonrandomized, all-comers registries of PAD patients who were treated with orbital atherectomy. All patients with gender specified in the registry database were included in the current analysis, which compared the final residual stenosis achieved after atherectomy and the rate of acute complications in female and male patients. The 3 registries included 3131 patients with 4761 lesions: 1261 women (mean age 73.2 ± 10.7 years) with 1874 lesions and 1870 men (mean age 70.4 ± 10.2) with 2887 lesions. The women were older (p < 0.001) and had a higher but nonsignificant prevalence of critical limb ischemia (p = 0.075). After treatment, the final residual stenosis in women vs. men was 9% ± 11% vs. 11% ± 11%, respectively (p < 0.001). Women had a higher rate of all types of dissection (13.3% vs. 9.9%, p<0.001). However, both genders had similar rates of flow-limiting dissections (1.6% vs. 1.4%, p = 0.61), perforation, slow flow, vessel closure, spasm, embolism, and thrombus formation. The gender analysis of the CONFIRM registries revealed that there was successful lesion modification with orbital atherectomy in both men and women; however, women had a higher rate of dissection (all types). This difference is likely because of the older age and higher percentage of critical limb ischemia in women in this cohort. These results, however, suggest that additional studies should be completed to further understand the increased risks for women vs. men during endovascular procedures. © The Author(s) 2015.

Transplantation of cord blood mesenchymal stem cells as spheroids enhances vascularization.

PubMed

Bhang, Suk Ho; Lee, Seahyoung; Shin, Jung-Youn; Lee, Tae-Jin; Kim, Byung-Soo

2012-10-01

Despite promising results from the therapeutic use of stem cells for treating ischemic diseases, the poor survival of cells transplanted into ischemic regions is one of the major problems that undermine the efficacy of stem cell therapy. Cord blood mononuclear cells (CBMNCs) are an alternative source of mesenchymal stem cells (MSCs) without disadvantages, such as the painful and invasive harvesting procedure, of MSCs derived from bone marrow or adipose tissue. In the present study, we investigated whether the angiogenic efficacy of cord blood mesenchymal stem cells (CBMSCs) can be enhanced by grafting as spheroids in a mouse hindlimb ischemia model. Human CBMSC (hCBMSC) spheroids were prepared by using the hanging-drop method. Mouse hindlimb ischemia was induced by excising the femoral artery and its branches. After surgery, the animals were divided into no-treatment, dissociated hCBMSC, and spheroid hCBMSC groups (n=8 per group) and received corresponding hCBMSC treatments. After surgery, the ischemic hindlimbs were monitored for 4 weeks, and then, the ischemic hindlimb muscles were harvested for histological analysis. Apoptotic signaling, angiogenesis-related signal pathways, and blood vessel formation were investigated in vitro and/or in vivo. The transplantation of hCBMSCs as spheroids into mouse ischemic hindlimbs significantly improved the survival of the transplanted cells by suppressing apoptotic signaling while activating antiapoptotic signaling. Furthermore, the transplantation of hCBMSCs as spheroids significantly increased the number of microvessels and smooth muscle α-actin-positive vessels in the ischemic limbs of mice, and attenuated limb loss and necrosis. Human CBMNC can be considered an alternative source of MSC, and spheroid-based hCBMSC delivery can be considered a simple and effective strategy for enhancing the therapeutic efficacy of hCBMSCs.

Hyperbaric oxygen therapy in the pediatric patient: the experience of the Israel Naval Medical Institute.

PubMed

Waisman, D; Shupak, A; Weisz, G; Melamed, Y

1998-11-01

The pediatric patient is to be found in hyperbaric facilities throughout the world, receiving hyperbaric oxygen (HBO) therapy for both life-threatening and chronic diseases. To review the experience accumulated at the Israel Naval Medical Institute in the treatment of pediatric patients. A retrospective analysis and review of all records of patients younger than age 18 years. Between 1980 and 1997, 139 pediatric patients age 2 months to 18 years (mean, 7.7 years) received HBO treatment at the Israel Naval Medical Institute. Of the children, 111 (79%) suffered from acute carbon monoxide (CO) poisoning; 13 (9.2%) were treated after crush injury, traumatic ischemia, or compartment syndrome; 4 (2.8%) had clostridial myonecrosis; 1 (0.7%) had necrotizing fasciitis; 5 (3.6%) had refractory osteomyelitis; 2 (1.4%) had suffered massive air embolism; 2 (1.4%) had purpura fulminans; and 1 (0.7%) suffered from decompression sickness. Outcome, judged by neurologic sequelae, mortality, and extent of soft tissue loss and limb amputation, was favorable in 129 patients (93%). Two patients (1.4%) died, 1 as a result of CO poisoning and the other, gas gangrene; 2 of the patients in the CO group (1.4%) remained with neurologic sequelae, and 6 patients in the acute traumatic ischemia group (4.3%) underwent limb amputation. We had a favorable experience with 129 of a total 139 pediatric patients treated at our facility for the indications listed. A basic knowledge of HBO therapy is needed to refer the pediatric patient for treatment when indicated. The needs of the pediatric patient, especially the critically ill, require specific skills and equipment inside the hyperbaric chamber. Close collaboration between the pediatrician and the hyperbaric medicine physician is essential to ensure adequate care for infants and children.

Physiologic Cryoamputation in Managing Critically Ill Patients with Septic, Advanced Acute Limb Ischemia.

PubMed

Chen, Samuel L; Kuo, Isabella J; Kabutey, Nii-Kabu; Fujitani, Roy M

2017-07-01

Certain critically ill patients with advanced acute limb ischemia with a nonviable extremity may be unsuitable for transport to the operating room to undergo definitive amputation. In these unstable patients, rapid regional cryotherapy allows for prompt infectious source control and correction of hemodynamic and metabolic abnormalities, thereby lessening the risk associated with definitive surgical amputation. We describe our refined technique for lower extremity physiologic cryoamputation and review our institutional experience. After adequate analgesia is administered to the patient, a heating pad is secured circumferentially at the proximal amputation margin and the affected extremity is placed in a customized Styrofoam cooler. A circumferential seal is secured at the proximal chill zone without use of a tourniquet and dry ice is placed into the cooler to surround the entire affected leg. Delayed definitive lower extremity amputation is later performed when hemodynamic and metabolic derangements are corrected. We reviewed 5 patients who underwent lower extremity cryoamputation with this technique identified at our institution between 2005 and 2015. Age ranged from 31 to 79 years old. All presented with severe foot infection and septic shock requiring vasopressor support. All 5 patients stabilized hemodynamically following the initial cryoamputation and later underwent definitive lower extremity amputation, with a median time of 3 days following initial cryoamputation. Lower extremity physiologic cryoamputation is an effective, immediate bedside procedure that can provide local source control and the opportunity for correction of metabolic derangements in initially unstable patients to lessen the risk for definitive major lower extremity amputation. Refinement of the cryoamputation technique, as described in this report, allows for a predictable and reproducible physiologic amputation. Copyright © 2017 Elsevier Inc. All rights reserved.

Diabetes Worsens Ischemia-Reperfusion Brain Injury in Rats Through GSK-3β.

PubMed

Liu, Hua; Ou, Shanshan; Xiao, Xiaoyu; Zhu, Yingxian; Zhou, Shaopeng

2015-09-01

Diabetes aggravates brain injury after cerebral ischemia/reperfusion (I/R). To investigate whether limb I/R causes cerebral injury in a rat diabetes model and whether glycogen synthase kinase-3β (GSK-3β) is involved. Male adult Sprague-Dawley rats were assigned into streptozotocin-induced diabetes (n = 30; blood glucose ≥16.7 mmol/L) or control (n = 20) groups, further subdivided into diabetes I/R (3-hour femoral artery/vein clamping), diabetes-I/R + TDZD-8 (I/R plus GSK-3β inhibitor), diabetes-sham, control-sham and control-I/R groups (n = 10 each). Cortical and hippocampal morphology (hematoxylin/eosin); hippocampal CA1 apoptosis (TUNEL assay); cleaved caspase-3 (apoptosis), and Iba1 (microglial activation) protein expression (immunohistochemistry); phosphorylated/total GSK-3β and nuclear factor-κB (NF-κB) protein levels (Western blotting); and serum and brain tissue tumor necrosis factor (TNF)-α levels (enzyme-linked immunosorbent assay) were analyzed. The diabetes-I/R group showed greater cortical and hippocampal injury, apoptosis, cleaved caspase-3 expression and Iba1 expression than the control-I/R group; TDZD-8 reduced injury/apoptosis and cleaved caspase-3/Iba1 expressions. The diabetes-I/R group had lower p-GSK-3β and p-NF-κBp65 expression than the control-I/R group (P < 0.05); TDZD-8 increased p-GSK-3β expression but decreased p-NF-κBp65 expression (P < 0.05). The diabetes-I/R group showed higher elevation of serum and brain tissue TNF-α than the control-I/R group (P < 0.05); TDZD-8 reduced TNF-α production. Diabetes exacerbates limb I/R-induced cerebral damage and activates NF-κB and GSK-3β.

Wound Healing and Angiogenesis through Combined Use of a Vascularized Tissue Flap and Adipose-Derived Stem Cells in a Rat Hindlimb Irradiated Ischemia Model.

PubMed

Yoshida, Shuhei; Yoshimoto, Hiroshi; Hirano, Akiyoshi; Akita, Sadanori

2016-05-01

Treatment of critical limb ischemia is sometimes difficult because of the patient's condition, and some novel approaches are needed. The hindlimbs of Sprague-Dawley rats, after 20-Gy x-ray irradiation and surgical occlusion, were divided into four groups: with a superficial fascial flap, 5.0 × 10 adipose-derived stromal/stem cells, and both combined. The rats were tested for laser tissue blood flow, immunohistologic blood vessel density, and foot paw punch hole wound healing. Green fluorescent protein-tagged Sprague-Dawley rats were used for further investigation by cell tracking for 2 weeks. Laser tissue blood flow demonstrated a significant increase in the combined treatment of flap and adipose-derived stem cells at both 1 and 2 weeks. There were no significant differences between the treatment groups treated with flaps alone and those treated with adipose-derived stem cells alone. Wound healing was significantly increased following combined treatment at 1 week, and there was no wound by 2 weeks except for the no-flap and no-adipose-derived stem cell group. The number of vessels depicted by von Willebrand factor showed a significant increase in the combined treatment group, at both 1 week and 2 weeks. In the cell tracking group, at 2 weeks, the green fluorescent protein-tagged adipose-derived stem cells were significantly more positive in the no-flap group than in the flap group. Adipose-derived stem cells may be a potent cell source in irradiated and occluded limbs by enhancing tissue blood flow and blood vessel density. Adipose-derived stem cells may play an important role in some difficult ischemic conditions in terms of wound healing.

Comparative efficacies of amoxicillin, clindamycin, and moxifloxacin in prevention of bacteremia following dental extractions.

PubMed

Diz Dios, P; Tomás Carmona, I; Limeres Posse, J; Medina Henríquez, J; Fernández Feijoo, J; Alvarez Fernández, M

2006-09-01

We evaluated the efficacies of oral prophylactic treatment with amoxicillin (AMX), clindamycin (CLI), and moxifloxacin (MXF) in the prevention of bacteremia following dental extractions (BDE). Two hundred twenty-one adults who required dental extractions under general anesthesia were randomly assigned to a control group, an AMX group, a CLI group, and an MXF group (the individuals in the drug treatment groups received 2 g, 600 mg, and 400 mg, respectively, 1 to 2 h before anesthesia induction). Venous blood samples were collected from each patient at the baseline and 30 s, 15 min, and 1 h after the dental extractions. The samples were inoculated into BACTEC Plus aerobic and anaerobic blood culture bottles and were processed in a BACTEC 9240 instrument. Subculture and the further identification of the isolated bacteria were performed by conventional microbiological techniques. The prevalences of BDE in the control group, AMX group, CLI group, and MXF group were 96, 46, 85, and 57%, respectively, at 30 s; 64, 11, 70, and 24%, respectively, at 15 min; and 20, 4, 22, and 7%, respectively, at 1 h. Streptococcus spp. were the most frequently identified bacteria in all groups (44 to 68%), with the lowest percentage being detected in the AMX group (44%). AMX and MXF prophylaxis showed high efficacies in reducing the prevalence and duration of BDE, but CLI prophylaxis was noneffective. As a consequence, MXF prophylaxis is a promising antibiotic alternative for the prevention of BDE when beta-lactams are not indicated.

Comparative Efficacies of Amoxicillin, Clindamycin, and Moxifloxacin in Prevention of Bacteremia following Dental Extractions

PubMed Central

Diz Dios, P.; Tomás Carmona, I.; Limeres Posse, J.; Medina Henríquez, J.; Fernández Feijoo, J.; Álvarez Fernández, M.

2006-01-01

We evaluated the efficacies of oral prophylactic treatment with amoxicillin (AMX), clindamycin (CLI), and moxifloxacin (MXF) in the prevention of bacteremia following dental extractions (BDE). Two hundred twenty-one adults who required dental extractions under general anesthesia were randomly assigned to a control group, an AMX group, a CLI group, and an MXF group (the individuals in the drug treatment groups received 2 g, 600 mg, and 400 mg, respectively, 1 to 2 h before anesthesia induction). Venous blood samples were collected from each patient at the baseline and 30 s, 15 min, and 1 h after the dental extractions. The samples were inoculated into BACTEC Plus aerobic and anaerobic blood culture bottles and were processed in a BACTEC 9240 instrument. Subculture and the further identification of the isolated bacteria were performed by conventional microbiological techniques. The prevalences of BDE in the control group, AMX group, CLI group, and MXF group were 96, 46, 85, and 57%, respectively, at 30 s; 64, 11, 70, and 24%, respectively, at 15 min; and 20, 4, 22, and 7%, respectively, at 1 h. Streptococcus spp. were the most frequently identified bacteria in all groups (44 to 68%), with the lowest percentage being detected in the AMX group (44%). AMX and MXF prophylaxis showed high efficacies in reducing the prevalence and duration of BDE, but CLI prophylaxis was noneffective. As a consequence, MXF prophylaxis is a promising antibiotic alternative for the prevention of BDE when beta-lactams are not indicated. PMID:16940094

Reducing Uncertainty in Chemistry Climate Model Predictions of Stratospheric Ozone

NASA Technical Reports Server (NTRS)

Douglass, A. R.; Strahan, S. E.; Oman, L. D.; Stolarski, R. S.

2014-01-01

Chemistry climate models (CCMs) are used to predict the future evolution of stratospheric ozone as ozone-depleting substances decrease and greenhouse gases increase, cooling the stratosphere. CCM predictions exhibit many common features, but also a broad range of values for quantities such as year of ozone-return-to-1980 and global ozone level at the end of the 21st century. Multiple linear regression is applied to each of 14 CCMs to separate ozone response to chlorine change from that due to climate change. We show that the sensitivity of lower atmosphere ozone to chlorine change deltaO3/deltaCly is a near linear function of partitioning of total inorganic chlorine (Cly) into its reservoirs; both Cly and its partitioning are controlled by lower atmospheric transport. CCMs with realistic transport agree with observations for chlorine reservoirs and produce similar ozone responses to chlorine change. After 2035 differences in response to chlorine contribute little to the spread in CCM results as the anthropogenic contribution to Cly becomes unimportant. Differences among upper stratospheric ozone increases due to temperature decreases are explained by differences in ozone sensitivity to temperature change deltaO3/deltaT due to different contributions from various ozone loss processes, each with their own temperature dependence. In the lower atmosphere, tropical ozone decreases caused by a predicted speed-up in the Brewer-Dobson circulation may or may not be balanced by middle and high latitude increases, contributing most to the spread in late 21st century predictions.

Purple Glove Syndrome after Phenytoin or Fosphenytoin Administration: Review of Reported Cases and Recommendations for Prevention.

PubMed

Garbovsky, Lyudmila A; Drumheller, Byron C; Perrone, Jeanmarie

2015-12-01

The aim of our study was to identify all previously reported cases of phenytoin- or fosphenytoin-associated purple glove syndrome (PGS) and summarize the most current understanding of the pathophysiology, clinical presentation, diagnosis, and treatment of the disease. We searched the English language references from MEDLINE, EMBASE, CINAHL, TOXNET, and gray literature that featured one or more case descriptions of phenytoin- or fosphenytoin-associated PGS after administration and provided information on the clinical setting of the event and associated outcome(s). Descriptive statistics were employed to summarize relevant facts about the cases. We identified 82 unique cases of parenteral phenytoin-associated PGS and 5 cases of fosphenytoin-associated PGS that were published from 1984 to 2015. Additionally, we found two cases of PGS associated with oral formulation of phenytoin published from 1999 to 2015. The spectrum of tissue injury ranged from mild local cutaneous reactions around the infusion site to frank limb ischemia. Just over a half of cases reported symptoms after one dose of IV phenytoin. Pathologic findings included evidence for microvascular thrombosis and possible microvascular or subclinical extravasation as a contributing mechanism. Dopper ultrasound and conventional angiography were used in some patients to identify arterial or venous thrombosis. Various treatments were documented including the use of supportive care such as limb elevation and heat or cold application, utilization of systemic antibiotics, anticoagulants, or vasodilators, and local infiltration of hyaluronidase, heparin, or other compounds. In a small number of patients, invasive interventions such as regional anesthesia, thrombectomy, fasciotomy, and debridement were described. Time to resolution varied from days to weeks. Resolution of PGS without deficits was documented in the majority of cases. Skin changes followed by sensory and motor deficits were described in 16, 6, and 5 cases, respectively. Four patients underwent skin grafting and eight patients required limb amputation. Death as a result of PGS was documented in two patients. PGS associated with oral and injectable phenytoin or parenteral fosphenytoin has been documented in the literature and sometimes includes significant vascular thrombosis and potentially limb-threatening ischemia. Avoidance of small hand veins, adherence to recommended IV administration guidelines and monitoring of the infusion site for reactions should be considered to decrease the morbidity of IV phenytoin or fosphenytoin use. Patients with PGS and evidence of decreased distal perfusion should undergo prompt vascular imaging and potential intervention to avoid ischemic sequelae. Alternative anticonvulsant drugs should be considered in patients at risk for PGS when possible.

Retrograde Transpedal Access for Revascularization of Below-the-Knee Arteries in Patients with Critical Limb Ischemia after an Unsuccessful Antegrade Transfemoral Approach.

PubMed

Goltz, J P; Planert, M; Horn, M; Wiedner, M; Kleemann, M; Barkhausen, J; Stahlberg, E

2016-10-01

To evaluate the safety and technical and clinical success of endovascular below-the-knee (BTK) artery revascularization by a retrograde transpedal access. We retrospectively identified 16/172 patients (9.3 %) with endovascular BTK revascularization in whom a transfemoral approach had failed and transpedal access had been attempted. The dorsal pedal (n = 13) or posterior tibial (n = 3) artery was accessed using a dedicated access set and ultrasound guidance. The procedure was finished in antegrade fashion by plain old balloon angioplasty (POBA). Comorbidities, vessel diameter and calcification at the access site were recorded. The analyzed outcomes were technical success, procedural complications, procedure time, crossing (guidewire beyond lesion and intra-luminal) and procedural (residual stenosis < 30 % after POBA) success, and limb salvage. Diabetes, coronary artery disease and hypertension were present in 15 patients (93.8 %), and both renal impairment and previous amputations in 7 (43.8 %). Pedal access vessel calcification was present in 5/16 patients (31.3 %). The mean diameter was 1.75 +/-0.24 mm. The procedure time was 92.4 +/-23 min. The success rate for achieving retrograde access was 100 %. Retrograde crossing was successful in 12/16 patients (75.0 %). Procedural success was observed in 10/16 patients (68.8 %). Minor complications occurred in 2/16 patients (12.5 %). The rate of limb salvage was 72.9 %, and the overall survival was 100 % at 12 months. Major amputations after revascularization occurred in 2/16 patients (12.5 %). If an antegrade transfemoral approach to BTK lesions fails, a retrograde transpedal approach may nevertheless facilitate treatment. This approach appears to be safe and offers high technical and acceptable clinical success rates. • Retrograde approaches via transpedal or transtibial vessels are safe and offer high technical success.• One problem after technically successful puncture might be the re-entry following subintimal retrograde lesion crossing.• After a failed attempt at antegrade revascularization of a BTK occlusion, a retrograde approach should be performed. Citation Format: • Goltz JP, Planert M, Horn M et al. Retrograde Transpedal Access for Revascularization of Below-the-Knee Arteries in Patients with Critical Limb Ischemia after an Unsuccessful Antegrade Transfemoral Approach. Fortschr Röntgenstr 2016; 188: 940 - 948. © Georg Thieme Verlag KG Stuttgart · New York.

Genetic characterization of 11 microsatellite loci in Egyptian pigeons (Columba livia domestica) and their cross-species amplification in other Columbidae populations.

PubMed

Ramadan, Sherif; Dawod, Ahmed; El-Garhy, Osama; Nowier, Amira M; Eltanany, Marwa; Inoue-Murayama, Miho

2018-04-01

This study aimed to analyze the genetic diversity and relationships of 10 Egyptian pigeon populations belonging to Columba livia domestica speciesusing 11 microsatellite markers and to investigate the success of these markers amplification across another eight pigeon species. Genomic DNA was isolated from feather samples of179 pigeon samples from 10 Egyptian breeds: Asfer Weraq (n=14), Austoraly (n=20), Reehani (n=21), Messawed (n=17), Nemssawy (n=27), Otatti (n=12), Morasla (n=17), Tumbler (n=22), Halaby Asfer (n=10), and Karakandy (n=19) in addition to Japanese feral pigeons (n=30). Genotyping was done using 11 specific polymorphic microsatellite makers. Moreover, 37 samples not belonging to C. livia domestica but belonging to another eight pigeon species were genotyped. The polymerase chain reaction (PCR) products were electrophoresed on an ABI 3130xl DNA Sequencer. The basic measures of genetic diversity and phylogenetic trees were computed using bioinformatics software. Across the 10 studied Egyptian populations, the number of alleles per locus ranged from 3 to 19 and the average number of alleles observed was 9.091. The lowest value of expected heterozygosity (0.373) was obtained for the Reehani breed, and the highest value (0.706) was found for Morasla breed. The overall expected heterozygosity of Egyptian pigeons was 0.548. The F ST coefficient which indicates fixation coefficients of subpopulations within the total population for the 11 loci varied from 0.318 to 0.114 with a relatively high mean (0.226). In our study, the F IS showed a relatively high average(0.037). The pairwise Reynolds's genetic distance between the11 studied pigeon populations recorded lower values between Otatti and Austoraly (0.025) and between Morasla and Japanese feral pigeons (0.054). These results are supported by clustering pattern either by the neighbor-joining phylogenetic tree or by a Bayesian clustering of STRUCTURE with the admixture method. We confirm the applicability of the CliµD17, CliµT17, CliµD16, CliµD32, CliµT13 , CliµD01 , PG1, PG2, PG4, PG6 , and PG7 microsatellite markers among Egyptian domestic pigeons and across other pigeon species using cross-species amplification method. The information from this study should be useful for genetic characterization and for developing conservation programs of this important species.

Genetic characterization of 11 microsatellite loci in Egyptian pigeons (Columba livia domestica) and their cross-species amplification in other Columbidae populations

PubMed Central

Ramadan, Sherif; Dawod, Ahmed; El-Garhy, Osama; Nowier, Amira M.; Eltanany, Marwa; Inoue-Murayama, Miho

2018-01-01

Aim This study aimed to analyze the genetic diversity and relationships of 10 Egyptian pigeon populations belonging to Columba livia domestica speciesusing 11 microsatellite markers and to investigate the success of these markers amplification across another eight pigeon species. Methods Genomic DNA was isolated from feather samples of179 pigeon samples from 10 Egyptian breeds: Asfer Weraq (n=14), Austoraly (n=20), Reehani (n=21), Messawed (n=17), Nemssawy (n=27), Otatti (n=12), Morasla (n=17), Tumbler (n=22), Halaby Asfer (n=10), and Karakandy (n=19) in addition to Japanese feral pigeons (n=30). Genotyping was done using 11 specific polymorphic microsatellite makers. Moreover, 37 samples not belonging to C. livia domestica but belonging to another eight pigeon species were genotyped. The polymerase chain reaction (PCR) products were electrophoresed on an ABI 3130xl DNA Sequencer. The basic measures of genetic diversity and phylogenetic trees were computed using bioinformatics software. Results Across the 10 studied Egyptian populations, the number of alleles per locus ranged from 3 to 19 and the average number of alleles observed was 9.091. The lowest value of expected heterozygosity (0.373) was obtained for the Reehani breed, and the highest value (0.706) was found for Morasla breed. The overall expected heterozygosity of Egyptian pigeons was 0.548. The FST coefficient which indicates fixation coefficients of subpopulations within the total population for the 11 loci varied from 0.318 to 0.114 with a relatively high mean (0.226). In our study, the FIS showed a relatively high average(0.037). The pairwise Reynolds’s genetic distance between the11 studied pigeon populations recorded lower values between Otatti and Austoraly (0.025) and between Morasla and Japanese feral pigeons (0.054). These results are supported by clustering pattern either by the neighbor-joining phylogenetic tree or by a Bayesian clustering of STRUCTURE with the admixture method. Conclusions We confirm the applicability of the CliµD17, CliµT17, CliµD16, CliµD32, CliµT13, CliµD01, PG1, PG2, PG4, PG6, and PG7 microsatellite markers among Egyptian domestic pigeons and across other pigeon species using cross-species amplification method. The information from this study should be useful for genetic characterization and for developing conservation programs of this important species. PMID:29805216

Segmental heterogeneity in Bcl-2, Bcl-xL and Bax expression in rat tubular epithelium after ischemia-reperfusion.

PubMed

Valdés, Francisco; Pásaro, Eduardo; Díaz, Inmaculada; Centeno, Alberto; López, Eduardo; García-Doval, Sandra; González-Roces, Severino; Alba, Alfonso; Laffon, Blanca

2008-06-01

Studies in rats with bilateral clamping of renal arteries showed transient Bcl-2, Bcl-xL and Bax expression in renal tubular epithelium following ischemia-reperfusion. However, current data on the preferential localization of specific mRNAs or proteins are limited because gene expression was not analysed at segmental level. This study analyses the mRNA expression of Bcl-2, Bcl-xL and Bax in four segments of proximal and distal tubules localized in the renal cortex and outer medulla in rat kidneys with bilateral renal clamping for 30 min and seven reperfusion times versus control animals without clamp. Proximal convoluted tubule (PCT), distal convoluted tubule (DCT), proximal straight tubule (PST) and medullary thick ascending limb (MTAL) were obtained by manual microdissection. RT-PCR was used to analyse mRNA expression at segmental level. Proximal convoluted tubule and MTAL showed early, persistent and balanced up-regulation of Bcl-2, Bcl-xL and Bax, while PST and DCT revealed only Bcl-2 and Bcl-xL, when only Bax was detected in PST. DCT expressed Bcl-xL initially, and persistent Bcl-2 later. These patterns suggest a heterogeneous apoptosis regulatory response in rat renal tubules after ischemia-reperfusion, independently of cortical or medullary location. This heterogeneity of the expression patterns of Bcl-2 genes could explain the different susceptibility to undergo apoptosis, the different threshold to ischemic damage and the different adaptive capacity to injury among these tubular segments.

Successful penetration and bougie dilatation with Brockenbrough needle for severely calcified occlusion in superficial femoral artery.

PubMed

Makita, Toshio; Suzuki, Kenji; Takizawa, Kaname; Ootomo, Tatsushi; Inoue, Naoto; Meguro, Taiichirou

2014-04-01

A 75-year-old hemodialysis patient with right critical limb ischemia received endovascular therapy for a chronic total occlusion (CTO) in a diffusely calcified superficial femoral artery (SFA). During a retrograde approach, a Brockenbrough needle (BN) was able to penetrate the calcified hard plaque formed in the middle segment of the CTO. Moreover, bougie dilatation with the BN allowed balloon crossing and stent deployment, even after failure to pass a 2.0-mm monorail balloon across the plaque. These results suggest that the BN offers a new therapeutic option in the penetration and modification of severely calcified CTO in SFA.

Treatment of hand ischemia following angioaccess surgery using the distal revascularization interval-ligation technique with preservation of vascular access: description of an 18-case series.

PubMed

Sessa, Carmine; Riehl, Gregory; Porcu, Paolo; Pichot, Olivier; Palacin, Pedro; Maghlaoua, Mohamed; Magne, Jean-Luc

2004-11-01

Hand ischemia is a rare complication of angioaccess surgery for hemodialysis. Management usually requires ligation of the arteriovenous fistula (AVF). The purpose of this report is to describe our experience with the use of the distal revascularization interval-ligation (DRIL) technique for treatment of ischemia without ligation of the AVF. From January 1999 to September 2002, the DRIL technique was used to treat 18 patients (10 men, 8 women, 10 diabetic patients) with severe paresthesia of the hand (n = 9) and finger necrosis (n = 10). The AVF was located at the elbow in 16 patients and at the wrist in 2 patients. Mean flow distal to the AVF was less than 10 mL in 5 patients, less than 5 mL in 10, and unmeasurable in 3. The conduit used for all DRIL arterial bypasses, including 15 brachiobrachial bypasses, 1 axillobrachial bypass, 1 brachioradial bypass, and 1 radioradial bypass, was the great saphenous vein graft. Trophic manifestations required finger amputation in five patients, pulpar necrosis resection in four, and transmetacarpal amputation of the index finger in one patient. Symptoms disappeared in 13 patients (73%) and improved in 5 (27%). The time required for healing of finger amputations and trophic manifestations ranged from 15 days to 2 months. Mean arterial flow through the DRIL bypass was 50 mL/min (range, 20-90 mL/min). With a mean follow-up interval of 16 months (range, 5-48 months), primary patency of the DRIL artery bypass and AVF was 94% and the limb salvage rate was 100%. The DRIL technique is the most effective procedure for treatment of angioaccess-induced hand ischemia. This technique can be used to achieve persistent relief of symptoms with continued access patency. The DRIL artery bypass improves vacularization of the hand, and ligature of the artery stops the vascular steal without affecting hemodialysis access. The DRIL technique should be proposed as first-line treatment for hand ischemia due to AVF for hemodialysis.

Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase C674 promotes ischemia- and hypoxia-induced angiogenesis via coordinated endothelial cell and macrophage function.

PubMed

Mei, Yu; Thompson, Melissa D; Shiraishi, Yasunaga; Cohen, Richard A; Tong, Xiaoyong

2014-11-01

Ischemia is a complex phenomenon modulated by the concerted action of several cell types. We have identified that sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase 2 (SERCA 2) cysteine 674 (C674) S-glutathiolation is essential for ischemic angiogenesis, vascular endothelial growth factor (VEGF)-mediated endothelial cell (EC) migration and network formation. A heterozygote SERCA 2 C674S knockin (SKI) mouse shows impaired ischemic blood flow recovery after femoral artery ligation, and its ECs show depleted endoplasmic reticulum (ER) Ca(2+) stores and impaired angiogenic behavior. Here we studied the role of SERCA 2 C674 in the interaction between ECs and macrophages in the context of ischemia and discovered the involvement of the ER stress response protein, ER oxidoreductin-1α (ERO1). In wild type (WT) mice, expression of ERO1 was increased in the ischemic hind limb in vivo, as well as in ECs and macrophages exposed to hypoxia in vitro. The increase in ERO1 to ischemia/hypoxia was less in SKI mice. In WT ECs, both vascular cell adhesion molecule 1 (VCAM1) expression and bone marrow-derived macrophage adhesion to ECs were increased by hypoxia, and both were attenuated in SKI ECs. In WT ECs, ERO1 siRNA blocked hypoxia-induced VCAM1 expression and macrophage adhesion. In WT macrophages, hypoxia also stimulated both ERO1 and VEGF expression, and both were less in SKI macrophages. Compared with conditioned media of hypoxic SKI macrophages, conditioned media from WT macrophages had a greater effect on EC angiogenic behavior, and were blocked by VEGF neutralizing antibody. Taken together, under hypoxic conditions, SERCA 2 C674 and ERO1 enable increased VCAM1 expression and macrophage adhesion to ECs, as well as macrophage VEGF production that, in turn, promote angiogenesis. This study highlights the hitherto unrecognized interaction of two ER proteins, SERCA 2 C674 and ERO1, which mediate the EC and macrophage angiogenic response to ischemia/hypoxia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Natural sorbents modified by divalent Cu2+- and Zn2+- ions and their corresponding antimicrobial activity.

PubMed

Đolić, Maja B; Rajaković-Ognjanović, Vladana N; Štrbac, Svetlana B; Dimitrijević, Suzana I; Mitrić, Miodrag N; Onjia, Antonije E; Rajaković, Ljubinka V

2017-10-25

The objective of this study was to investigate the modification of materials used in wastewater treatment for possible antimicrobial application(s). Granulated activated carbon (GAC) and natural clinoptilolite (CLI) were activated using Cu 2+ - and Zn 2+ - ions and the disinfection ability of the resulting materials was tested. Studies of the sorption and desorption kinetics were performed in order to determine and clarify the antimicrobial activity of the metal-activated sorbents. The exact sorption capacities of the selected sorbents, GAC and CLI, activated through use of Cu 2+ - ions, were 15.90 and 3.60mg/g, respectively, while for the materials activated by Zn 2+ - ions, the corresponding capacities were 14.00 and 4.72mg/g,. The desorption rates were 2 and 3 orders of magnitude lower than their sorption efficacy for the Cu 2+ -, and Zn 2+ -activated sorbents, respectively. The intermediate sorption capacity and low desorption rate indicated that the overall antimicrobial activity of the metal-modified sorbents was a result of metal ions immobilized onto surface sites. The effect of antimicrobial activity of free ions desorbed from the metal-activated surface may thus be disregarded. The antimicrobial activities of Cu/GAC, Zn/GAC, Cu/CLI and Zn/CLI were also tested against Escherichia coli, Staphylococcus aureus, and Candida albicans. After 15min exposure, the highest levels of cell inactivation were obtained through the Cu/CLI and the Cu/GAC against E. coli, 100.0 and 98.24%, respectively. However, for S. aureus and yeast cell inactivation, all Cu 2+ - and Zn 2+ -activated sorbents proved to be unsatisfactory. A characterization of the sorbents was performed by X-ray diffraction (XRD), X-ray photo electron spectroscopy (XPS), and field emission scanning electron microscopy (FE-SEM). A concentration of the adsorbed and released ions was determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) and mass spectrometry (ICP-MS). The results showed that the antimicrobial performance of the activated sorbents depended on the surface characteristics of the material, which itself designates the distribution and the bioavailability of the activating agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Fluid management in critically ill patients: the role of extravascular lung water, abdominal hypertension, capillary leak, and fluid balance

PubMed Central

2012-01-01

Introduction Capillary leak in critically ill patients leads to interstitial edema. Fluid overload is independently associated with poor prognosis. Bedside measurement of intra-abdominal pressure (IAP), extravascular lung water index (EVLWI), fluid balance, and capillary leak index (CLI) may provide a valuable prognostic tool in mechanically ventilated patients. Methods We performed an observational study of 123 mechanically ventilated patients with extended hemodynamic monitoring, analyzing process-of-care variables for the first week of ICU admission. The primary outcome parameter was 28-day mortality. ΔmaxEVLWI indicated the maximum difference between EVLWI measurements during ICU stay. Patients with a ΔmaxEVLWI <−2 mL/kg were called 'responders'. CLI was defined as C-reactive protein (milligrams per deciliter) over albumin (grams per liter) ratio and conservative late fluid management (CLFM) as even-to-negative fluid balance on at least two consecutive days. Results CLI had a biphasic course. ΔmaxEVLWI was lower if CLFM was achieved and in survivors (−2.4 ± 4.8 vs 1.0 ± 5.5 mL/kg, p = 0.001; −3.3 ± 3.8 vs 2.5 ± 5.3 mL/kg, p = 0.001, respectively). No CLFM achievement was associated with increased CLI and IAPmean on day 3 and higher risk to be nonresponder (odds ratio (OR) 2.76, p = 0.046; OR 1.28, p = 0.011; OR 5.52, p = 0.001, respectively). Responders had more ventilator-free days during the first week (2.5 ± 2.3 vs 1.5 ± 2.3, p = 0.023). Not achieving CLFM and being nonresponder were strong independent predictors of mortality (OR 9.34, p = 0.001 and OR 7.14, p = 0.001, respectively). Conclusion There seems to be an important correlation between CLI, EVLWI kinetics, IAP, and fluid balance in mechanically ventilated patients, associated with organ dysfunction and poor prognosis. In this context, we introduce the global increased permeability syndrome. PMID:22873410

Flexible radioluminescence imaging for FDG-guided surgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

King, Martin T., E-mail: mking@lroc.harvard.edu; J

Purpose: Flexible radioluminescence imaging (Flex-RLI) is an optical method for imaging {sup 18}F-fluorodeoxyglucose (FDG)-avid tumors. The authors hypothesize that a gadolinium oxysulfide: terbium (GOS:Tb) flexible scintillator, which loosely conforms to the body contour, can enhance tumor signal-to-background ratio (SBR) compared with RLI, which utilizes a flat scintillator. The purpose of this paper is to characterize flex-RLI with respect to alternative modalities including RLI, beta-RLI (RLI with gamma rejection), and Cerenkov luminescence imaging (CLI). Methods: The photon sensitivity, spatial resolution, and signal linearity of flex-RLI were characterized with in vitro phantoms. In vivo experiments utilizing 13 nude mice inoculated with themore » head and neck (UMSCC1-Luc) cell line were then conducted in accordance with the institutional Administrative Panel on Laboratory Animal Care. After intravenous injection of {sup 18}F-FDG, the tumor SBR values for flex-RLI were compared to those for RLI, beta-RLI, and CLI using the Wilcoxon signed rank test. Results: With respect to photon sensitivity, RLI, beta-RLI, and flex-RLI produced 1216.2, 407.0, and 98.6 times more radiance per second than CLI. Respective full-width half maximum values across a 0.5 mm capillary tube were 6.9, 6.4, 2.2, and 1.5 mm, respectively. Flex-RLI demonstrated a near perfect correlation with {sup 18}F activity (r = 0.99). Signal uniformity for flex-RLI improved after more aggressive homogenization of the GOS powder with the silicone elastomer during formulation. In vivo, the SBR value for flex-RLI (median 1.29; interquartile range 1.18–1.36) was statistically greater than that for RLI (1.08; 1.02–1.14; p < 0.01) by 26%. However, there was no statistically significant difference in SBR values between flex-RLI and beta-RLI (p = 0.92). Furthermore, there was no statistically significant difference in SBR values between flex-RLI and CLI (p = 0.11) in a more limited dataset. Conclusions: Flex-RLI provides high quality images with SBRs comparable to those from CLI and beta-RLI in a single 10 s acquisition.« less

Pediatric Traumatic Limb Amputation: The Principles of Management and Optimal Residual Limb Lengths

PubMed Central

Khan, Muhammad Adil Abbas; Javed, Ammar Asrar; Rao, Dominic Jordan; Corner, J Antony; Rosenfield, Peter

2016-01-01

Pediatric traumatic limb amputations are rare and their acute and long term management can be challenging in this subgroup of patients. The lengthy and costly hospital stays, and resulting physical and psychological implications leads to significant morbidity. We present a summary of treatment principles and the evidence base supporting the management options for this entity. The initial management focuses on resuscitating and stabilization of the patients, administration of appropriate and adequate analgesics, and broad spectrum antibiotics. The patient should ideally be managed by an orthopedic or a plastic surgeon and when an amputation is warranted, the surgical team should aim to conserve as much of the viable physis as possible aimed at allowing bone development in a growing child. A subsequent wound inspection should be performed to assess for signs of ischemia or non-viability of tissue. Depending on the child’s age, approximations of the ideal residual limb length can be calculated using our guidelines, allowing an ideal stump length at skeletal maturity for a well-fitting and appropriate prosthesis. Myodesis and myoplasties can be performed according to the nature of the amputation. Removable rigid dressings are safe and cost effective offering better protection of the stump. Complications such as necrosis and exostosis, on subsequent examination, warrant further revisions. Other complications such as neuromas can be prevented by proximal division of the nerves. Successful rehabilitation can be accomplished with a multidisciplinary approach, involving physiotherapist, play therapist and a child psychiatrist, in addition to the surgeon and primary care providers. PMID:27308235

A Randomized Crossover Study Comparing Cervical Spine Motion During Intubation Between Two Lightwand Intubation Techniques in Patients With Simulated Cervical Immobilization: Laryngoscope-Assisted Versus Conventional Lightwand Intubation.

PubMed

Kim, Tae Kyong; Son, Je-Do; Seo, Hyungseok; Lee, Yun-Seok; Bae, Jinyoung; Park, Hee-Pyoung

2017-08-01

In patients with cervical immobilization, jaw thrust can cause cervical spine movement. Concurrent use of a laryngoscope may facilitate lightwand intubation, allowing midline placement and free movement of the lightwand in the oral cavity without jaw thrust. We compared the effects of laryngoscope-assisted lightwand intubation (LALI) versus conventional lightwand intubation (CLI) on cervical spine motion during intubation in patients with simulated cervical immobilization. In this randomized crossover study, the cervical spine angle was measured before and during intubation at the occiput-C1, C1-C2, and C2-C5 segments in 20 patients with simulated cervical immobilization who underwent intubation using both the LALI and CLI techniques. Cervical spine motion was defined as the change from baseline in angle measured at each cervical segment during intubation. Cervical spine motion at the occiput-C1 segment was 5.6° (4.3) and 9.3° (4.5) when we used the LALI and CLI techniques, respectively (mean difference [98.33% CI]; -3.8° [-7.2 to -0.3]; P = .007). At other cervical segments, it was not significantly different between the 2 techniques (-0.1° [-2.6 to 2.5]; P = .911 in the C1-C2 segment and -0.2° [-2.8 to 2.5]; P = .795 in the C2-C5 segment). The LALI technique produces less upper cervical spine motion during intubation than the CLI technique in patients with simulated cervical immobilization.

Evaluation of the impact of the revised National Institute for Occupational Safety and Health Lifting Equation

PubMed Central

Lu, Ming-Lun; Putz-Anderson, Vern; Garg, Arun; Davis, Kermit

2016-01-01

Objective To evaluate the impact of the revised National Institute for Occupational Safety and Health lifting equation (RNLE). Background The RNLE has been used extensively as a risk assessment method for prevention of low back pain (LBP). However, the impact of the RNLE has not been documented. Methods A systematic review of the literature on the RNLE was conducted. The review consisted of three parts: characterization of the RNLE publications; assessment of the impact of the RNLE; and evaluation of the influences of the RNLE on ergonomic standards. The literature for assessing the impact was categorized into four research areas: methodology, laboratory, field and risk assessment studies using the Lifting Index (LI) or Composite LI (CLI), both of which are the products of the RNLE. Results The impact of the RNLE has been both widespread and influential. We found 24 studies that examined the criteria used to define lifting capacity used by the RNLE, 28 studies that compared risk assessment methods for identifying LBP, 23 studies that found the RNLE useful in identifying the risk of LBP with different work populations, and 13 studies on the relationship between LI/CLI and LBP outcomes. We also found evidence on the adoption of the RNLE as an ergonomic standard for use by various local, state, and international entities. Conclusion The review found 13 studies that link LI/CLI to adverse LBP outcomes. These studies showed a positive relationship between LI/CLI metrics and the severity of LBP outcomes. PMID:26822795

Growth in stratospheric chlorine from short-lived chemicals not controlled by the Montreal Protocol.

PubMed

Hossaini, R; Chipperfield, M P; Saiz-Lopez, A; Harrison, J J; von Glasow, R; Sommariva, R; Atlas, E; Navarro, M; Montzka, S A; Feng, W; Dhomse, S; Harth, C; Mühle, J; Lunder, C; O'Doherty, S; Young, D; Reimann, S; Vollmer, M K; Krummel, P B; Bernath, P F

2015-06-16

We have developed a chemical mechanism describing the tropospheric degradation of chlorine containing very short-lived substances (VSLS). The scheme was included in a global atmospheric model and used to quantify the stratospheric injection of chlorine from anthropogenic VSLS ( ClyVSLS) between 2005 and 2013. By constraining the model with surface measurements of chloroform (CHCl 3 ), dichloromethane (CH 2 Cl 2 ), tetrachloroethene (C 2 Cl 4 ), trichloroethene (C 2 HCl 3 ), and 1,2-dichloroethane (CH 2 ClCH 2 Cl), we infer a 2013 ClyVSLS mixing ratio of 123 parts per trillion (ppt). Stratospheric injection of source gases dominates this supply, accounting for ∼83% of the total. The remainder comes from VSLS-derived organic products, phosgene (COCl 2 , 7%) and formyl chloride (CHClO, 2%), and also hydrogen chloride (HCl, 8%). Stratospheric ClyVSLS increased by ∼52% between 2005 and 2013, with a mean growth rate of 3.7 ppt Cl/yr. This increase is due to recent and ongoing growth in anthropogenic CH 2 Cl 2 -the most abundant chlorinated VSLS not controlled by the Montreal Protocol.

Growth in stratospheric chlorine from short-lived chemicals not controlled by the Montreal Protocol

NASA Astrophysics Data System (ADS)

Hossaini, R.; Chipperfield, M. P.; Saiz-Lopez, A.; Harrison, J. J.; Glasow, R.; Sommariva, R.; Atlas, E.; Navarro, M.; Montzka, S. A.; Feng, W.; Dhomse, S.; Harth, C.; Mühle, J.; Lunder, C.; O'Doherty, S.; Young, D.; Reimann, S.; Vollmer, M. K.; Krummel, P. B.; Bernath, P. F.

2015-06-01

We have developed a chemical mechanism describing the tropospheric degradation of chlorine containing very short-lived substances (VSLS). The scheme was included in a global atmospheric model and used to quantify the stratospheric injection of chlorine from anthropogenic VSLS ( ClyVSLS) between 2005 and 2013. By constraining the model with surface measurements of chloroform (CHCl3), dichloromethane (CH2Cl2), tetrachloroethene (C2Cl4), trichloroethene (C2HCl3), and 1,2-dichloroethane (CH2ClCH2Cl), we infer a 2013 ClyVSLS mixing ratio of 123 parts per trillion (ppt). Stratospheric injection of source gases dominates this supply, accounting for ˜83% of the total. The remainder comes from VSLS-derived organic products, phosgene (COCl2, 7%) and formyl chloride (CHClO, 2%), and also hydrogen chloride (HCl, 8%). Stratospheric ClyVSLS increased by ˜52% between 2005 and 2013, with a mean growth rate of 3.7 ppt Cl/yr. This increase is due to recent and ongoing growth in anthropogenic CH2Cl2—the most abundant chlorinated VSLS not controlled by the Montreal Protocol.

The effect of epsilon-caproyl/D,L-lactyl unit composition on the hydrolytic degradation of poly(D,L-lactide-ran-epsilon-caprolactone)-poly(ethylene glycol)-poly(D,L-lactide-ran-epsilon-caprolactone).

PubMed

Cho, Hanjin; An, Jeongho

2006-02-01

The degradation of P(DLAX-ran-CLY)-b-PEG-b-P(DLAX-ran-CLY)s ( P(DLAX-ran-CLY): Poly(D,L-lactide-ran-epsilon-caprolactone), PEG: Poly(ethylene glycol), X: D,L-lactyl unit fraction, Y: epsilon-caproyl unit fraction) is investigated. The fraction of DLA in the both end blocks is varied while the overall molecular weight and molecular weight of PEG are kept constant. DSC, XRD and GPC are employed to track the degradation process up to 200 days. Also the change in the surface and cross-sectional morphology is provided by SEM micro-photographs. The result of water absorption and weight loss characterization reveals that the incorporation of DLA in the polyester block could be an effective tool to facilitate degradation as well as water absorption. By tracking the change of molecular weight and polydispersity, chain scission and transport or removal of degraded product from the specimen were found to play a complex role in overall degradation.

Al7CX (X=Li-Cs) clusters: Stability and the prospect for cluster materials

NASA Astrophysics Data System (ADS)

Ashman, C.; Khanna, S. N.; Pederson, M. R.; Kortus, J.

2000-12-01

Al7C clusters, recently found to have a high-electron affinity and exceptional stability, are shown to form ionic molecules when combined with alkali-metal atoms. Our studies, based on an ab initio gradient-corrected density-functional scheme, show that Al7CX (X=Li-Cs) clusters have a very low-electron affinity and a high-ionization potential. When combined, the two- and four-atom composite clusters of Al7CLi units leave the Al7C clusters almost intact. Preliminary studies indicate that Al7CLi may be suitable to form cluster-based materials.

[Intramuscular injection of lentivirus-mediated EPAS1 gene improves hind limb ischemia and its mechanism in a rat model of peripheral artery vascular disease].

PubMed

Wang, Zhihong; Gu, Hongbin; Yang, Fan; Xie, Huajie; Sheng, Lei; Li, Mingfei

2017-11-01

Objective To investigate the effect of over-expressed endothelial Per-Arnt-Sim domain protein 1 (EPAS1) on peripheral arterial disease (PAD) in a rat model. Methods PAD rat model was established by external iliac artery ligation followed by lentivirus-mediated EPAS1 gene injection into rat right adductor magnus. The models were evaluated by quantitative analysis of gait disturbance. The changes of blood flow in the posterior extremity of the rats were detected using laser Doppler. The expressions of EPAS1, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) mRNAs were tested by real-time quantitative PCR. The expression of α-smooth muscle actin (αSMA) was detected by immunohistochemical staining. Results Compared with lenti-EGFP group, rat hind limb function and circulation got recovered obviously 7 days after lenti-EPAS1 injection. The mRNA expressions of EPAS1, HGF, bFGF, and VEGF were up-regulated in the lenti-EPAS1-treated sites.The expression of αSMA showed an obvious increase in the lenti-EPAS1-treated muscles. Conclusion Over-expressed lenti-EPAS1 can promote angiogenesis via the up-regulation of EPAS1-related angiogenic factors in the muscles of the affected hind limb and reduce gait disturbance.

Modulating the Vascular Response to Limb Ischemia Angiogenic and Cell Therapies

PubMed Central

Cooke, John P.; Losordo, Douglas W.

2016-01-01

The age-adjusted prevalence of peripheral arterial disease in the US population has been estimated to approach 12%. The clinical consequences of occlusive peripheral arterial disease include pain on walking (claudication), pain at rest, and loss of tissue integrity in the distal limbs; the latter may ultimately lead to amputation of a portion of the lower extremity. Surgical bypass techniques and percutaneous catheter-based interventions may successfully reperfuse the limbs of certain patients with peripheral arterial disease. In many patients, however, the anatomic extent and distribution of arterial occlusion is too severe to permit relief of pain and healing of ischemic ulcers. No effective medical therapy is available for the treatment of such patients, for many of whom amputation represents the only hope for alleviation of symptoms. The ultimate failure of medical treatment and procedural revascularization in significant numbers of patients has led to attempts to develop alternative therapies for ischemic disease. These strategies include administration of angiogenic cytokines, either as recombinant protein or as gene therapy, and more recently, to investigations of stem/progenitor cell therapy. The purpose of this review is to provide an outline of the preclinical basis for angiogenic and stem cell therapies, review the clinical research that has been done, summarize the lessons learned, identify gaps in knowledge, and suggest a course toward successfully addressing an unmet medical need in a large and growing patient population. PMID:25908729

Scapulothoracic Dissociation: Evaluation and Management.

PubMed

Choo, Andrew M; Schottel, Patrick C; Burgess, Andrew R

2017-05-01

Scapulothoracic dissociation is a rare, potentially limb- and life-threatening injury of the shoulder girdle. The injury is characterized by lateral displacement of the scapula resulting from traumatic disruption of the scapulothoracic articulation. The typical physical examination findings consist of substantial swelling of the shoulder girdle, along with weakness, numbness, and pulselessness in the ipsilateral upper extremity. Radiographic evaluation includes measurement of the scapular index on a nonrotated chest radiograph and assessment for either a distracted clavicle fracture or a disrupted acromioclavicular or sternoclavicular joint. Although vascular injury occurs in most patients, emergent surgery is performed only in patients with either limb-threatening ischemia or active arterial hemorrhage. Management of neurologic injury can be delayed if necessary. The location and severity of neurologic injury determine whether observation, nerve grafting, nerve transfer, or above-elbow amputation is performed. Skeletal stabilization procedures include plate fixation of clavicle fractures and reduction of distracted acromioclavicular or sternoclavicular joints. The extent of neurologic injury determines clinical outcomes. Medical Outcomes Study 36-Item Short Form scores are significantly lower in patients with complete brachial plexus avulsion injury than in patients with postganglionic injury.

High prevalence of self-reported symptoms of digital ischemia in elite male volleyball players in the Netherlands: a cross-sectional national survey.

PubMed

van de Pol, Daan; Kuijer, P Paul F M; Langenhorst, Ton; Maas, Mario

2012-10-01

In the past 3 years, 6 volleyball players with ischemic digits and small microemboli in the digital arteries of the dominant hand presented themselves in our hospital. These complaints were caused by an aneurysmatic dilation of the posterior circumflex humeral artery (PCHA) with distal occlusion and digital emboli in the isolateral limb. All were elite male volleyball players active in the national top league. Little is known about the exact symptoms associated with PCHA pathological lesions with digital emboli (PCHAP with DE) and its prevalence in elite volleyball players. If vascular injury can be identified at an early stage, thromboembolic complications and irreversible damage to the digits might be prevented. To assess the prevalence of symptoms that are consistent with digital ischemia and may be caused by PCHAP with DE in elite male volleyball players in the Netherlands. Cross-sectional study; Level of evidence, 3. A questionnaire survey was performed among elite volleyball players in the Dutch national top league and the Dutch beach volleyball team. The questionnaire was constructed using literature-based data on symptoms associated with PCHAP with DE, together with data retrieved from medical files. A total of 99 of the 107 athletes participated, with a response rate of 93%. The most frequently reported symptoms associated with PCHAP with DE were cold, blue, or pale digits in the dominant hand during or immediately after practice or competition. The prevalence of these symptoms ranged from 11% to 27%. The prevalence of cold digits during practice and competition was 27%. The prevalence of cold, blue, and pale digits during or immediately after practice and competition was 12%. An unexpectedly high percentage of elite volleyball players reported symptoms that are associated with PCHAP with DE in the dominant hand. Because these athletes are considered potentially at risk for developing critical digital ischemia, further analysis of the presence of digital ischemia and PCHA injury is warranted.

Comparison of Hyperemic Impedance Echocardiography with Dobutamine Stress Echocardiography to Detect Inducible Myocardial Ischemia: A Pilot Study.

PubMed

Patel, Jijibhoy J; Gupta, Ankur; Nanda, Navin C

2016-03-01

Stress echocardiography using exercise or pharmacological stressors is either contraindicated or associated with significant side effects in some patients. This pilot study was designed to evaluate a new technique, hyperemic impedance echocardiography (HIE). It is based on reactive coronary hyperemia when transient limb ischemia is induced by tourniquet inflation. We hypothesized that this physiologic coronary hyperemia can identify inducible myocardial ischemia by assessment of regional wall motion abnormalities on echocardiography when compared with dobutamine stress echocardiography (DSE). Twenty consecutive outpatients with suspected stable coronary artery disease (CAD) who underwent clinically indicated DSE were recruited for performance of HIE after informed consent was obtained. Standard graded dobutamine infusion protocol from 5 to 40 μg/kg per min was used for DSE. HIE was performed by inflating tourniquets at a pressure of 10 mmHg below the systolic blood pressure for 1 minute in three of four extremities at a time for total of four cycles. Echocardiography was performed immediately after the last rotating tourniquet deflation. DSE and HIE were classified as abnormal for development of new or worsening wall motion abnormality in at least one myocardial segment. Test characteristics were also determined for a subset of these patients (n = 12) who underwent clinically indicated coronary angiography. Hyperemic impedance echocardiography showed 86% sensitivity, 67% specificity, 86% positive predictive value, and 67% negative predictive value with a test accuracy of 80% to detect inducible myocardial wall motion abnormalities when compared with DSE. HIE also showed 83% sensitivity, 75% negative predictive value with a test accuracy of 66.7% for detection of significant (≥50% diameter stenosis) CAD on coronary angiography. In this pilot study, HIE was a feasible, safe, and promising method for detection of inducible myocardial ischemia by assessment of regional wall motion abnormalities when compared to DSE and coronary angiography. Larger studies are needed to confirm these findings. © 2016, Wiley Periodicals, Inc.

Administration of exogenous adenosine triphosphate to ischemic skeletal muscle induces an energy-sparing effect: role of adenosine receptors.

PubMed

Maldonado, Claudio; Pushpakumar, Sathnur B; Perez-Abadia, Gustavo; Arumugam, Sengodagounder; Lane, Andrew N

2013-05-01

Ischemia-reperfusion injury is a devastating complication that occurs in allotransplantation and replantation of limbs. Over the years, several preservation strategies have been used to conserve the critical levels of intracellular adenosine triphosphate (ATP) during ischemia to sustain the ion gradients across the membranes and thus the tissue viability. The administration of exogenous ATP to ischemic tissues is known to provide beneficial effects during reperfusion, but it is unclear whether it provides protection during ischemia. The purpose of the present study was to determine the effect of ATP administration on high-energy phosphate levels in ischemic skeletal muscle and to examine the role of purinergic and adenosine receptors in mediating the response to exogenous ATP. The extensor digitorum longus muscles of Fischer rats were subjected to ischemia and treated with different concentrations of ATP with or without purinergic and adenosine receptor blockers. Phosphorus-31 nuclear magnetic resonance spectroscopy was used to measure the rate of decay of ATP, phosphocreatine (PCr), and the formation of adenosine monophosphate and acidification. Phosphorylated compounds were analyzed using a simple model of energy metabolism, and the PCr half-life was used as an index of internal depletion of ATP to distinguish between intracellular and extracellular ATP. PCr decay was rapid in all muscle groups and was followed by gradual ATP decay. The half-life of PCr was significantly longer in the ATP-treated muscles than in the vehicle controls and was maximally prolonged by treating with slow hydrolyzing adenosine 5'-O-(3-thio)triphosphate. Purinoceptor (P2X) blockade with ATP treatment significantly increased the half-life of PCr, and adenosine receptor blockers blunted the response. Administration of adenosine to ischemic muscles significantly increased the half-life of PCr compared with that in the vehicle controls. Exogenous ATP administration to ischemic skeletal muscles appears to spare intracellular energy by acting primarily through adenosine receptors. Copyright © 2013 Elsevier Inc. All rights reserved.

Coordinated Activation of VEGF/VEGFR-2 and PPARδ Pathways by a Multi-Component Chinese Medicine DHI Accelerated Recovery from Peripheral Arterial Disease in Type 2 Diabetic Mice

PubMed Central

He, Shuang; Zhao, Tiechan; Guo, Hao; Meng, Yanzhi; Qin, Gangjian; Goukassian, David A.; Han, Jihong; Gao, Xuimei; Zhu, Yan

2016-01-01

Diabetic mellitus (DM) patients are at an increased risk of developing peripheral arterial disease (PAD). Danhong injection (DHI) is a Chinese patent medicine widely used for several cardiovascular indications but the mechanism of action is not well-understood. We investigated the therapeutic potential of DHI on experimental PAD in mice with chemically induced as well as genetic (KKAy) type 2 DM and the overlapping signaling pathways regulating both therapeutic angiogenesis and glucose homeostasis. Compared with normal genetic background wild type (WT) mice, both DM mice showed impaired perfusion recovery in hind-limb ischemia (HLI) model. DHI treatment significantly accelerated perfusion recovery, lowered blood glucose and improved glucose tolerance in both DM models. Bioluminescent imaging demonstrated a continuous ischemia-induced vascular endothelial growth factor receptor 2 (VEGFR-2) gene expressions with a peak time coincident with the maximal DHI stimulation. Flow cytometry analysis showed a DHI-mediated increase in endothelial progenitor cell (EPC) mobilization from bone marrow to circulating peripheral blood. DHI administration upregulated the expression of vascular endothelial growth factor A (VEGF-A) and VEGF receptor-2 (VEGFR-2) in ischemic muscle. A cross talk between ischemia-induced angiogenesis and glucose tolerance pathways was analyzed by Ingenuity Pathway Analysis (IPA) which suggested an interaction of VEGF-A/VEGFR-2 and peroxisome proliferator-activated receptor δ (PPARδ)/peroxisome proliferator-activated receptor γ (PPARγ) genes. We confirmed that upregulation of VEGF-A/VEGFR-2 by DHI promoted PPARδ gene expression in both type 2 diabetic mice. Our findings demonstrated that a multi-component Chinese medicine DHI effectively increased blood flow recovery after tissue ischemia in diabetic mice by promoting angiogenesis and improving glucose tolerance through a concomitant activation of VEGF-A/VEGFR-2 and PPARδ signaling pathways. PMID:27930695

Coordinated Activation of VEGF/VEGFR-2 and PPARδ Pathways by a Multi-Component Chinese Medicine DHI Accelerated Recovery from Peripheral Arterial Disease in Type 2 Diabetic Mice.

PubMed

He, Shuang; Zhao, Tiechan; Guo, Hao; Meng, Yanzhi; Qin, Gangjian; Goukassian, David A; Han, Jihong; Gao, Xuimei; Zhu, Yan

2016-01-01

Diabetic mellitus (DM) patients are at an increased risk of developing peripheral arterial disease (PAD). Danhong injection (DHI) is a Chinese patent medicine widely used for several cardiovascular indications but the mechanism of action is not well-understood. We investigated the therapeutic potential of DHI on experimental PAD in mice with chemically induced as well as genetic (KKAy) type 2 DM and the overlapping signaling pathways regulating both therapeutic angiogenesis and glucose homeostasis. Compared with normal genetic background wild type (WT) mice, both DM mice showed impaired perfusion recovery in hind-limb ischemia (HLI) model. DHI treatment significantly accelerated perfusion recovery, lowered blood glucose and improved glucose tolerance in both DM models. Bioluminescent imaging demonstrated a continuous ischemia-induced vascular endothelial growth factor receptor 2 (VEGFR-2) gene expressions with a peak time coincident with the maximal DHI stimulation. Flow cytometry analysis showed a DHI-mediated increase in endothelial progenitor cell (EPC) mobilization from bone marrow to circulating peripheral blood. DHI administration upregulated the expression of vascular endothelial growth factor A (VEGF-A) and VEGF receptor-2 (VEGFR-2) in ischemic muscle. A cross talk between ischemia-induced angiogenesis and glucose tolerance pathways was analyzed by Ingenuity Pathway Analysis (IPA) which suggested an interaction of VEGF-A/VEGFR-2 and peroxisome proliferator-activated receptor δ (PPARδ)/peroxisome proliferator-activated receptor γ (PPARγ) genes. We confirmed that upregulation of VEGF-A/VEGFR-2 by DHI promoted PPARδ gene expression in both type 2 diabetic mice. Our findings demonstrated that a multi-component Chinese medicine DHI effectively increased blood flow recovery after tissue ischemia in diabetic mice by promoting angiogenesis and improving glucose tolerance through a concomitant activation of VEGF-A/VEGFR-2 and PPARδ signaling pathways.

Development of GABA-sensitive spasticity and rigidity in rats after transient spinal cord ischemia: a qualitative and quantitative electrophysiological and histopathological study.

PubMed

Kakinohana, O; Hefferan, M P; Nakamura, S; Kakinohana, M; Galik, J; Tomori, Z; Marsala, J; Yaksh, T L; Marsala, M

2006-09-01

Transient spinal cord ischemia may lead to a progressive degeneration of spinal interneurons and subsequently to increased hind limb motor tone. In the present work we sought to characterize the rigidity and spasticity components of this altered motor function by: i) tonic electromyographic activity measured in gastrocnemius muscle before and after ischemia, ii) measurement of muscle resistance during the period of ankle flexion and corresponding changes in electromyographic activity, iii) changes in Hoffmann reflex, and, iv) motor evoked potentials. In addition the effect of intrathecal treatment with baclofen (GABAB receptor agonist; 1 microg), nipecotic acid (GABA uptake inhibitor; 300 microg) and dorsal L2-L5 rhizotomy on spasticity and rigidity was studied. Finally, the changes in spinal choline acetyltransferase (ChAT) and vesicular glutamate transporter 2 and 1 (VGLUT2 and VGLUT1) expression were characterized using immunofluorescence and confocal microscopy. At 3-7 days after ischemia an increase in tonic electromyographic activity with a variable degree of rigidity was seen. In animals with modest rigidity a velocity-dependent increase in muscle resistance and corresponding appearance in electromyographic activity (consistent with the presence of spasticity) was measured during ankle rotation (4-612 degrees /s rotation). Measurement of the H-reflex revealed a significant increase in Hmax/Mmax ratio and a significant loss of rate-dependent inhibition. In the same animals a potent increase in motor evoked potential amplitudes was measured and this change correlated positively with the increased H-reflex responses. Spasticity and rigidity were consistently present for a minimum of 3 months after ischemia. Intrathecal treatment with baclofen (GABA B receptor agonist) and nipecotic acid (GABA uptake inhibitor) provided a significant suppression of spasticity, rigidity, H-reflex or motor evoked potentials. Dorsal L2-L5 rhizotomy significantly decreased muscle resistance but had no effect on increased amplitudes of motor evoked potentials. Confocal analysis of spinal cord sections at 8 weeks-12 months after ischemia revealed a continuing presence of ChAT positive alpha-motoneurons, Ia afferents and VGLUT2 and VGLUT1-positive terminals but a selective loss of small presumably inhibitory interneurons between laminae V-VII. These data demonstrate that brief transient spinal cord ischemia in rat leads to a consistent development of spasticity and rigidity. The lack of significant suppressive effect of dorsal L2-L5 rhizotomy on motor evoked potentials response indicates that descending motor input into alpha-motoneurons is independent on Ia afferent couplings and can independently contribute to increased alpha-motoneuronal excitability. The pharmacology of this effect emphasizes the potent role of GABAergic type B receptors in regulating both the spasticity and rigidity.

Cost-Effectiveness Analysis of Initial Treatment Strategies for Nonembolic Acute Limb Ischemia Using Real-Word Data.

PubMed

Vaidya, Varun; Gangan, Nilesh; Comerota, Anthony; Lurie, Fedor

2017-02-01

Nonembolic acute limb ischemia (ALI) is a condition characterized by a sudden decrease in limb perfusion and requires immediate interventions. There are multiple treatment options available including surgery, catheter-directed thrombolysis (CDT), endovascular procedures, and hybrid treatment (a combination of open and endovascular techniques). Randomized trials provide information only on clinical efficacy, but not on economic outcomes. The objective of the study was to perform the cost-effective analysis comparing different treatment alternatives of ALI. The data were collected from 4r ProMedica community hospitals in the Northwest Ohio from January 2009 to December 2012. Patients were included if they were treated within 14 days of onset of symptoms for nonembolic ALI and were divided into groups of receiving CDT, surgery, endovascular, or hybrid treatments. Demographics, comorbidities, medications taken before admission, and smoking status were collected at baseline for all patients and were compared among the treatment groups. A cost-effectiveness decision tree was developed to calculate expected costs and life years gained associated with available treatment options. A probabilistic sensitivity analysis was also performed to check the robustness of the model. A population of 205 patients with the diagnosis of ALI was included and divided into different treatment groups. There was no major significant difference in baseline characteristics among the studied groups (P > 0.05). The total costs were $17,163.47 for surgery, $20,620.39 for endovascular, $21,277.61 for hybrid, and $30,675.42 for CDT. The life years gained were 17.25 for surgery, 18 for endovascular, 18 for hybrid, and 17 for CDT. CDT was dominated because of the high cost and the low effectiveness, while hybrid treatment was dominated when compared with endovascular treatment because these 2 treatments have similar outcomes. The incremental cost-effectiveness ratio of the endovascular group over the surgery group was found to be $4,609.23 per life year gained. The sensitivity analysis showed that the endovascular treatment was found to be cost-effective under willingness to pay $50,000. This study provides economic evaluation of ALI treatments for a defined clinical population in the real-world setting. Compared with other available alternatives, the endovascular treatment showed to be a cost-effective use of healthcare resources. Copyright © 2016 Elsevier Inc. All rights reserved.

Inferring gene ontologies from pairwise similarity data

PubMed Central

Kramer, Michael; Dutkowski, Janusz; Yu, Michael; Bafna, Vineet; Ideker, Trey

2014-01-01

Motivation: While the manually curated Gene Ontology (GO) is widely used, inferring a GO directly from -omics data is a compelling new problem. Recognizing that ontologies are a directed acyclic graph (DAG) of terms and hierarchical relations, algorithms are needed that: analyze a full matrix of gene–gene pairwise similarities from -omics data;infer true hierarchical structure in these data rather than enforcing hierarchy as a computational artifact; andrespect biological pleiotropy, by which a term in the hierarchy can relate to multiple higher level terms. Methods addressing these requirements are just beginning to emerge—none has been evaluated for GO inference. Methods: We consider two algorithms [Clique Extracted Ontology (CliXO), LocalFitness] that uniquely satisfy these requirements, compared with methods including standard clustering. CliXO is a new approach that finds maximal cliques in a network induced by progressive thresholding of a similarity matrix. We evaluate each method’s ability to reconstruct the GO biological process ontology from a similarity matrix based on (a) semantic similarities for GO itself or (b) three -omics datasets for yeast. Results: For task (a) using semantic similarity, CliXO accurately reconstructs GO (>99% precision, recall) and outperforms other approaches (<20% precision, <20% recall). For task (b) using -omics data, CliXO outperforms other methods using two -omics datasets and achieves ∼30% precision and recall using YeastNet v3, similar to an earlier approach (Network Extracted Ontology) and better than LocalFitness or standard clustering (20–25% precision, recall). Conclusion: This study provides algorithmic foundation for building gene ontologies by capturing hierarchical and pleiotropic structure embedded in biomolecular data. Contact: tideker@ucsd.edu PMID:24932003

Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models.

PubMed

Cristofaro, Brunella; Shi, Yu; Faria, Marcella; Suchting, Steven; Leroyer, Aurelie S; Trindade, Alexandre; Duarte, Antonio; Zovein, Ann C; Iruela-Arispe, M Luisa; Nih, Lina R; Kubis, Nathalie; Henrion, Daniel; Loufrani, Laurent; Todiras, Mihail; Schleifenbaum, Johanna; Gollasch, Maik; Zhuang, Zhen W; Simons, Michael; Eichmann, Anne; le Noble, Ferdinand

2013-04-01

Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta-like 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4(+/-) mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4(+/-) mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality.

Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models

PubMed Central

Cristofaro, Brunella; Shi, Yu; Faria, Marcella; Suchting, Steven; Leroyer, Aurelie S.; Trindade, Alexandre; Duarte, Antonio; Zovein, Ann C.; Iruela-Arispe, M. Luisa; Nih, Lina R.; Kubis, Nathalie; Henrion, Daniel; Loufrani, Laurent; Todiras, Mihail; Schleifenbaum, Johanna; Gollasch, Maik; Zhuang, Zhen W.; Simons, Michael; Eichmann, Anne; le Noble, Ferdinand

2013-01-01

Arteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Delta-like 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic loss- and gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4+/- mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4+/- mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality. PMID:23533173

Proteinase-Activated Receptor-2 Sensitivity of Amplified TRPA1 Activity in Skeletal Muscle Afferent Nerves and Exercise Pressor Reflex in Rats with Femoral Artery Occlusion

PubMed Central

Xing, Jihong; Li, Jianhua

2017-01-01

Background/Aims Limb ischemia occurs in peripheral artery disease (PAD). Sympathetic nerve activity (SNA) that regulates blood flow directed to the ischemic limb is exaggerated during exercise in this disease, and transient receptor potential channel A1 (TRPA1) in thin-fiber muscle afferents contributes to the amplified sympathetic response. The purpose of the present study was to determine the role of proteinase-activated receptor-2 (PAR2) in regulating abnormal TRPA1 function and the TRPA1-mediated sympathetic component of the exercise pressor reflex. Methods A rat model of femoral artery ligation was employed to study PAD. Dorsal root ganglion (DRG) tissues were obtained to examine the protein levels of PAR2 using western blot analysis. Current responses induced by activation of TRPA1 in skeletal muscle DRG neurons were characterized using whole-cell patch clamp methods. The blood pressure response to static exercise (i.e., muscle contraction) and stimulation of TRPA1 was also examined after a blockade of PAR2. Results The expression of PAR2 was amplified in DRG neurons of the occluded limb, and PAR2 activation with SL-NH2 (a PAR2 agonist) increased the amplitude of TRPA1 currents to a greater degree in DRG neurons of the occluded limb. Moreover, FSLLRY-NH2 (a PAR antagonist) injected into the arterial blood supply of the hindlimb muscles significantly attenuated the pressor response to muscle contraction and TRPA1 stimulation in rats with occluded limbs. Conclusions The PAR2 signal in muscle sensory nerves contributes to the amplified exercise pressor reflex via TRPA1 mechanisms in rats with femoral artery ligation. These findings provide a pathophysiological basis for autonomic responses during exercise activity in PAD, which may potentially aid in the development of therapeutic approaches for improvement of blood flow in this disease. PMID:29131007

Percutaneous intervention for infrainguinal occlusive disease in women: equivalent outcomes despite increased severity of disease compared with men.

PubMed

DeRubertis, Brian G; Vouyouka, Angela; Rhee, Soo J; Califano, Joseph; Karwowski, John; Angle, Niren; Faries, Peter L; Kent, K Craig

2008-07-01

Experience with open surgical bypass suggests similar overall outcomes in women compared with men, but significantly increased risk of wound complications. Percutaneous treatment of lower extremity occlusive disease is therefore an attractive alternative in women, although it is not clear whether there is a difference in outcomes between women and men treated with this technique. We sought to determine the results and predictors of failure in women treated by percutaneous intervention. Percutaneous infrainguinal revascularization was performed on 309 women between 2001 and 2006. Procedures, complications, demographics, comorbidities, and follow-up data were entered into a prospective database for review. Patency was assessed primarily by duplex ultrasonography. Outcomes were expressed by Kaplan-Meier curves and compared by log-rank analysis. A total of 447 percutaneous interventions performed in 309 women were analyzed and compared with 553 interventions in men. Mean age in women was 73.2 years; comorbidities included hypertension (HTN) (86%), diabetes melitus (DM) (58%), chronic renal insufficiency (CRI) (15%), hemodialysis (7%), hypercholesterolemia (52%), coronary artery disease (CAD) (42%), and tobacco use (47%). Indications in women included claudication (38.0%), rest pain (18.8%), and tissue loss (43.2%). Overall primary & secondary patency and limb-salvage rates for women were 38% +/- 4%, 66% +/- 3%, and 80% +/- 4% at 24 months. In this patient sample, women were significantly more likely than men to present with limb-threatening ischemia (61.6% vs 47.3%, P < 0.001) and have lesions of TASC C and D severity (71.4% vs 61.7%, P < .005). However, there were no significant differences in primary and secondary patency rates or limb-salvage rates between genders. Furthermore, while women with limb-threat, diabetes, and advanced TASC severity lesions were at increased risk of failure overall, there were no differences between women and men with these characteristics. Percutaneous infrainguinal revascularization is a very effective modality in women with lower extremity occlusive disease. Although women in this sample were more likely to present with limb-threat than men, patency and limb-salvage rates were equivalent between genders, even in high-risk subsets such as diabetics or those with lesions of increased TASC severity.

Peripheral post-ischemic vascular repair is impaired in a murine model of Alzheimer's disease.

PubMed

Merkulova-Rainon, Tatyana; Mantsounga, Chris S; Broquères-You, Dong; Pinto, Cristina; Vilar, José; Cifuentes, Diana; Bonnin, Philippe; Kubis, Nathalie; Henrion, Daniel; Silvestre, Jean-Sébastien; Lévy, Bernard I

2018-03-07

The pathophysiology of sporadic Alzheimer's disease (AD) remains uncertain. Along with brain amyloid-β (Aβ) deposits and neurofibrillary tangles, cerebrovascular dysfunction is increasingly recognized as fundamental to the pathogenesis of AD. Using an experimental model of limb ischemia in transgenic APPPS1 mice, a model of AD (AD mice), we showed that microvascular impairment also extends to the peripheral vasculature in AD. At D70 following femoral ligation, we evidenced a significant decrease in cutaneous blood flow (- 29%, P < 0.001), collateral recruitment (- 24%, P < 0.001), capillary density (- 22%; P < 0.01) and arteriole density (- 28%; P < 0.05) in hind limbs of AD mice compared to control WT littermates. The reactivity of large arteries was not affected in AD mice, as confirmed by unaltered size, and vasoactive responses to pharmacological stimuli of the femoral artery. We identified blood as the only source of Aβ in the hind limb; thus, circulating Aβ is likely responsible for the impairment of peripheral vasculature repair mechanisms. The levels of the majority of pro-angiogenic mediators were not significantly modified in AD mice compared to WT mice, except for TGF-β1 and PlGF-2, both of which are involved in vessel stabilization and decreased in AD mice (P = 0.025 and 0.019, respectively). Importantly, endothelin-1 levels were significantly increased, while those of nitric oxide were decreased in the hind limb of AD mice (P < 0.05). Our results suggest that vascular dysfunction is a systemic disorder in AD mice. Assessment of peripheral vascular function may therefore provide additional tools for early diagnosis and management of AD.

Bypass Surgery after Endovascular Therapy for Infrapopliteal Lesion Is Not a Poor Outcome Compared with Initial Bypass Surgery by Vascular Surgeons.

PubMed

Morisaki, Koichi; Yamaoka, Terutoshi; Iwasa, Kazuomi; Ohmine, Takahiro

2017-11-01

It is unclear whether prior endovascular therapy (EVT) adversely affects bypass surgery. The aim of this study is to investigate treatment outcomes between initial bypass (bypass-first) and bypass surgery after EVT (EVT-first). We conducted a retrospective analysis of critical limb ischemia patients undergoing infrapopliteal bypass between November 2006 and December 2015. Graft patency, limb salvage (LS), amputation-free survival (AFS), and overall survival (OS) were examined between bypass-first and EVT-first groups. The subjects in this study were 75 patients and 82 limbs in the bypass-first group and 24 patients and 24 limbs in the EVT-first group. The average age was higher in EVT-first group (P = 0.03). The percentage of inframalleolar bypass was higher in the EVT-first group (P = 0.002). Primary patency at 1 and 2 years was 72.0% and 67.5% for the bypass-first group and 53.1% and 47.2% for the EVT-first group, respectively (P = 0.04). Inframalleolar bypass was a risk factor for lower primary patency (hazard ratio 3.07, 95% confidence interval 1.18-8.51, P = 0.02) in multivariate analysis, while there were no differences in secondary patency, LS, AFS, and OS. Bypass surgery after EVT has lower primary patency rates in comparison with primary bypass in patients submitted to infrapopliteal revascularization. Although very heterogeneous study population with a lot of bias in the indication of the revascularization, LS, OS and AFS are not affected by previous EVT. Copyright © 2017 Elsevier Inc. All rights reserved.

Early outcomes with a single-sided access endovascular stent.

PubMed

Hofmann, Michael; Pecoraro, Felice; Planer, David; Pfammatter, Thomas; Puippe, Gilbert; Bettex, Dominique; Veith, Frank J; Lachat, Mario; Chaykovska, Lyubov

2018-03-27

The objective of this study was to report the 1-year follow-up study results of the new Horizon stent graft (Endospan, Herzliya, Israel) from two different prospective consecutive trials. The Horizon abdominal aortic aneurysm stent graft system is a 14F profile system requiring only a single access site. It consists of three modules, introduced separately: base limb (iliac to iliac limb); distal aortic limb; and proximal aortic limb with a bare suprarenal crown and active fixation. Data from the first in man (FIM) clinical study with 10 patients enrolled and the pivotal study with 30 patients were analyzed. Outcomes measured were freedom from major adverse events (MAEs) including all-cause mortality, myocardial infarction, renal failure, respiratory failure, paraplegia, stroke, bowel ischemia, and procedural blood loss ≥1000 mL. Performance end points included successful delivery and deployment of the device, freedom from aneurysm growth ≥5 mm, type I or type III endoleak, stent graft occlusion, conversion to open surgery, rupture, and stent graft migration. In the FIM study, one conversion to open surgery with >1000 mL of blood loss was registered perioperatively. In the pivotal study, no perioperative MAE was registered. Overall, at 1-year follow-up, two deaths and one aneurysm growth unrelated to endoleak were registered. The results of both the FIM and pivotal studies demonstrated that 39 of 40 procedures were successful for delivery and deployment of the Horizon stent graft. No MAE was registered during the follow-up. The primary safety and performance end points were met in both studies. Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Negative pressure wound therapy for high-risk wounds in lower extremity revascularization: study protocol for a randomized controlled trial.

PubMed

Murphy, Patrick; Lee, Kevin; Dubois, Luc; DeRose, Guy; Forbes, Thomas; Power, Adam

2015-11-04

Rates of surgical site infections (SSIs) following groin incision for femoral artery exposure are much higher than expected of a clean operation. The morbidity and mortality is high, particularly with the use of prosthetic grafts. The vascular surgery population is at an increased risk of SSIs related to peripheral vascular disease (PVD), diabetes, obesity, previous surgery and presence of tissue loss. Negative pressure wound therapy (NPWT) dressings have been used on primarily closed incisions to reduce surgical site infections in other surgical disciplines. We have not come across any randomized controlled trials to support the prophylactic use of negative pressure wound therapy in high-risk vascular patients undergoing lower limb revascularization. In this single-center, prospective randomized controlled trial, patients scheduled for a lower limb revascularization requiring open femoral artery exposure who are at a high risk (BMI > 30 kg/m(2), previous femoral cutdown or Rutherford V or VI category for chronic limb ischemia) will be eligible for the study. A total of 108 groin incisions will be randomized to the use of a negative pressure wound device or standard adhesive gauze dressing. Patients will be followed in hospital and reassessed within the first 30 days postoperatively. The primary outcome is SSI within the first 30 days of surgery and will be determined using the intention-to-treat principle. Secondary outcomes include length of stay, emergency room visits, reoperation, amputation and mortality. A cost analysis will be performed. The trial is expected to define the role of NPWT in SSI prophylaxis for lower limb revascularization in high-risk vascular patients. The results of the study will be used to inform current best practice for perioperative care and the minimization of SSIs. NCT02084017 , March 2014.

Peripheral arterial disease decreases muscle torque and functional walking capacity in elderly.

PubMed

Dziubek, Wioletta; Bulińska, Katarzyna; Stefańska, Małgorzata; Woźniewski, Marek; Kropielnicka, Katarzyna; Jasiński, Tomasz; Jasiński, Ryszard; Pilch, Urszula; Dąbrowska, Grażyna; Skórkowska-Telichowska, Katarzyna; Wojcieszczyk-Latos, Joanna; Kałka, Dariusz; Janus, Agnieszka; Zywar, Katarzyna; Paszkowski, Rafał; Szuba, Andrzej

2015-08-01

The aim of this study is to compare values of force-velocity and functional walking capacity in elderly patients with intermittent claudication with respect to the control group. The study involved 135 individuals: 85-peripheral arterial disease (PAD) group diagnosed with stage II chronic lower limb ischemia, according to Fontaine's classification, and 50-control group. The studies included an assessment of walking capacity using a six-minute walk test (6MWT) and measurement of force-velocity parameters (peak torque-PTQ, total work-TW, average power-AVGP) of the lower limbs obtained by means of a functional dynamometry under isokinetic conditions. The peripheral arterial disease group is characterized by significantly lower values of force-velocity parameters compared to the control group (p<0.005). Walking capacity in this group is significantly reduced due to significant differences in the distance covered (p<0.0001), walking speed (p<0.01), and its intensity (p<0.01). Further, a positive correlation was found between the maximum distance specified in the six-minute walk test and lower limb muscle strength in the isokinetic test. Mean values of all force-velocity parameters and walk distance were significantly higher in the control group than in the peripheral arterial disease group. In the PAD group, in both men and women, the value of the agonist/antagonist ratio of both lower limbs are lower in men and women comparing to the control group. A rehabilitation program for patients with intermittent claudication must consider exercises improving strength, exercise capacity, and endurance in patients with PAD. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Long-term results of in situ saphenous vein bypass. Analysis of 2058 cases.

PubMed Central

Shah, D M; Darling, R C; Chang, B B; Fitzgerald, K M; Paty, P S; Leather, R P

1995-01-01

OBJECTIVE: The authors evaluated the long-term patency and outcome of patients undergoing infrainguinal reconstruction using the in situ saphenous vein. SUMMARY BACKGROUND DATA: The in situ saphenous vein bypass has demonstrated excellent patency and limb salvage rates in numerous studies. The authors previously reported their early results with these bypass procedures, and this article represents their long-term experience with 2058 in situ saphenous vein bypasses during a 20-year period. This comprises the largest series with long-term follow-up of in situ saphenous vein bypasses in the literature. METHODS: From 1975 to 1995, 3148 autogenous vein bypasses were performed at the authors' institution, of which 2058 used the saphenous vein in situ. The indication for operation was limb-threatening ischemia in 1875 of 2058 patients (91%). In 88% of patients with an intact ipsilateral saphenous vein, an in situ bypass was completed successfully. One thousand twenty-three bypasses (69%) were terminated at the infrapopliteal level. Of these bypasses, 1562 of 2058 (76%) were completed using the closed in situ technique. RESULTS: The 30-day patency rate was 96%, and the cumulative secondary patency was 91%, 81%, and 70% at 1, 5, and 10 years, respectively. Limb salvage rates using the in situ bypass were 97%, 95%, and 90% at 1, 5, and 10 years, respectively. CONCLUSION: The infrainguinal inflow source, length of bypass, specific outflow vessel, or vein diameter did not have a significant effect on immediate or long-term bypass performance. These data suggest that the in situ saphenous vein is an excellent conduit for femoropopliteal and femoral to infrageniculate bypasses for limb salvage. PMID:7574925

Grand European and Asian-Pacific multi-model seasonal forecasts: maximization of skill and of potential economical value to end-users

NASA Astrophysics Data System (ADS)

Alessandri, A.; De Felice, M.; Catalano, F.; Lee, J. Y.; Wang, B.; Lee, D. Y.; Yoo, J. H.; Weisheimer, A.

2017-12-01

By initiating a novel cooperation between the European and the Asian-Pacific climate-prediction communities, this work demonstrates the potential of gathering together their Multi-Model Ensembles (MMEs) to obtain useful climate predictions at seasonal time-scale.MMEs are powerful tools in dynamical climate prediction as they account for the overconfidence and the uncertainties related to single-model ensembles and increasing benefit is expected with the increase of the independence of the contributing Seasonal Prediction Systems (SPSs). In this work we combine the two MME SPSs independently developed by the European (ENSEMBLES) and by the Asian-Pacific (APCC/CliPAS) communities by establishing an unprecedented partnerships. To this aim, all the possible MME combinations obtained by putting together the 5 models from ENSEMBLES and the 11 models from APCC/CliPAS have been evaluated. The Grand ENSEMBLES-APCC/CliPAS MME enhances significantly the skill in predicting 2m temperature and precipitation. Our results show that, in general, the better combinations of SPSs are obtained by mixing ENSEMBLES and APCC/CliPAS models and that only a limited number of SPSs is required to obtain the maximum performance. The selection of models that perform better is usually different depending on the region/phenomenon under consideration so that all models are useful in some cases. It is shown that the incremental performance contribution tends to be higher when adding one model from ENSEMBLES to APCC/CliPAS MMEs and vice versa, confirming that the benefit of using MMEs amplifies with the increase of the independence the contributing models.To verify the above results for a real world application, the Grand MME is used to predict energy demand over Italy as provided by TERNA (Italian Transmission System Operator) for the period 1990-2007. The results demonstrate the useful application of MME seasonal predictions for energy demand forecasting over Italy. It is shown a significant enhancement of the potential economic value of forecasting energy demand when using the better combinations from the Grand MME by comparison to the maximum value obtained from the better combinations of each of the two contributing MMEs. Above results are discussed in a Clim Dyn paper (Alessandri et al., 2017; doi:10.1007/s00382-016-3372-4).

Adult Heart Transplantation Under Tacrolimus (FK506) Immunosuppression: Histopathologic Observations and Comparison to a Cyclosporine-based Regimen with Lympholytic (ATG) Induction

PubMed Central

Tsamandas, Athanassios C.; Pham, Si M.; Seaberg, Eric C.; Pappo, Orit; Kormos, Robert L.; Kawai, Akihiko; Griffith, Bartley P.; Zeevi, Adriana; Duquesnoy, Rene; Fung, John J.; Starzl, Thomas E.; Demetris, Anthony J.

2011-01-01

Background Tacrolimus (FK506) is an effective immunosuppressant for human heart transplantation, but information about its effects on cardiac allograft and nonallograft kidney and liver histopathologic study is limited. Methods We therefore reviewed 1145 endomyocardial biopsy specimens and eight autopsy results from 80 heart transplant recipients who received tacrolimus as baseline immunosuppression. These were compared with 619 endomyocardial biopsy specimens and four autopsy results from 51 patients treated with cyclosporine-based immunosuppression with lympholytic induction (CLI) by use of rabbit anti-thymocyte globulin. Twenty-one histologic features including the International Society for Heart and Lung Transplantation histopathologic grade were retrospectively assessed without knowledge of the treatment regimen. The lymphocyte growth index on biopsy specimens obtained from these patients was also compared. Results In general, there were no qualitative differences in the histopathologic appearance of various allograft syndromes between tacrolimus- and CLI-treated patients. Thus histopathologic criteria used to diagnose various graft syndromes are applicable under tacrolimus immunosuppression. However, early (between 10 and 30 days) after transplantation, biopsy specimens from patients treated with tacrolimus showed a significantly higher percentage of inflamed fragments (p = 0.02), the inflammation tended to be more severe (p = 0.09), and the rejection grade tended to be slightly higher (p = 0.08). In contrast, during the late transplantation period (275 to 548 days), biopsy specimens from patients treated with CLI showed a significantly higher percentage of inflamed fragments (p = 0.03), more severe inflammation (p = 0.03), higher rejection grades (p = 0.01), and a higher frequency of Quilty lesions (p = 0.05). Although overall freedom from any grade 3A or higher rejection was greater in the CLI-treated arm, tacrolimus was successfully used to treat refractory rejection in three patients from the CLI-treated arm. Concern has been raised in the literature about the possibility of tacrolimus being a direct hepatotoxin and an accelerant of allograft obliterative arteriopathy. However, no evidence to support either of these contentions was detected in this patient population. In contrast, tacrolimus is clearly nephrotoxic, although similar to cyclosporine in this regard. Conclusions Tacrolimus is an effective immunosuppressive drug for heart transplantation. The cardiac allograft histopathologic study of patients treated with tacrolimus immunosuppression does not significantly differ from those given conventional, cyclosporine-based triple therapy with lympholytic induction. PMID:9257254