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Sample records for critical limb-threatening ischemia

  1. Impact of angiosome- and non-angiosome-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

    2017-07-26

    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 WIf

  2. Critical Limb Ischemia (CLI)

    MedlinePlus

    ... High blood pressure Family history of vascular disease Warning Signs You may have critical limb ischemia if ... blood flow to the limb. Other treatments include laser atherectomy, where small bits of plaque are vaporized ...

  3. Critical Limb Ischemia (CLI)

    MedlinePlus

    ... Get Involved Get Involved Resources Educational Flyers Video Library Types of Vascular Diseases Papers & Presentations News News Items Press Releases Newsletters Events Donate Donate Now Ways to Give Individual Donors Corporate Sponsors Donor Privacy Policy Critical Limb Ischemia (CLI) ...

  4. The costs of managing lower limb-threatening ischaemia.

    PubMed

    Singh, S; Evans, L; Datta, D; Gaines, P; Beard, J D

    1996-10-01

    One hundred and fifty consecutive patients presenting with limb-threatening ischaemia were studied prospectively to determine treatment and rehabilitation costs in the first year. Limb salvage was attempted in 104 (69%) patients but failed in 13%. Mortality at 1 year was 27%. The cost of treatment, inpatient stay, occupational therapy, physiotherapy, convalescence, disablement services, home adaptations, home care, district nursing, transportation and outpatient visits were determined for each patient. The patients were classified according to their presentation and initial treatment into five groups (number of patients) whose median management costs (interquartile range) for 12 months were: Gp 1 (23 - Revascularisation for acute ischaemia = 3970 pounds (2984-5511) Gp 2 (29) - Angioplasty for critical ischaemia = 6611 pounds (3630-10,200) Gp 3 (52) - Reconstruction for critical ischaemia = 6766 pounds (4337-9677) Gp 4 (34) - Primary amputation = 10,162 pounds (7894-13,026) Gp 5 (12) - Primary bilateral amputations = 13,848 pounds (11,440-18,056) At 1 year, there was no significant difference in the cost of managing a patient with a critically ischaemic limb by angioplasty or surgical reconstruction. The cost of revascularisation for acute ischaemia was comparatively low because these patients required minimal rehabilitation. The median cost of managing a patient following amputation was almost twice that of successful limb salvage justifying an aggressive revascularisation policy. However, justification of such a policy on economic grounds requires salvage failure episode to be minimised as they increase costs considerably.

  5. [Critical limb ischemia--update].

    PubMed

    Melamed, Eitan; Kotyba, Baydousi; Galili, Offer; Karmeli, Ron

    2010-12-01

    Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery occlusive disease. Without timely diagnosis and revascularization, patients with CLI are at risk of devastating complications including loss of limb and life. Therapeutic goals in treating patients with CLI include reducing cardiovascular risk factors, relieving ischemic pain, heating ulcers, preventing major amputation, improving quality of life and increasing survival. These aims may be achieved through medical therapy, revascularization or amputation. The past decade has seen substantial growth in endovascular therapies and options now exist for treating long segment occlusive disease, but surgical bypass may still yield more durable results. Patients who are younger, more active, and at low risk for surgery, may have better outcomes undergoing an operation. This is also indicated for endovascular failures, which may include technical failures or late occlusions after stents or other procedures. In contrast, frail patients with a limited life expectancy may experience better outcomes with endovascular therapy. For patients who are non-ambulatory, demented, or unfit to undergo revascularization, an amputation should be considered.

  6. Management of Critical Limb Ischemia

    PubMed Central

    Kinlay, Scott

    2016-01-01

    Critical limb ischemia (CLI) is a clinical syndrome of ischemic pain at rest or tissue loss, such as non-healing ulcers or gangrene, related to peripheral artery disease. CLI has a high short-term risk of limb loss and cardiovascular events. Non-invasive or invasive angiography help determine the feasibility and approach to arterial revascularization. An “endovascular-first” approach is often advocated based on a lower procedural risk, however, specific patterns of disease may be best treated by open surgical revascularization. Balloon angioplasty and stenting form the backbone of endovascular techniques, with drug-eluting stents and drug-coated balloons offering low rates of repeat revascularization. Combined antegrade and retrograde approaches can increase success in long total occlusions. Below the knee, angiosome-directed angioplasty may lead to greater wound healing, but failing this, any straight line flow into the foot is pursued. Hybrid surgical techniques such as iliac stenting and common femoral endarterectomy are commonly used to reduce operative risk. Lower extremity bypass grafting is most successful with a good quality, long, single-segment autogenous vein of at least 3.5mm diameter. Minor amputations are often required for tissue loss as part of the treatment strategy. Major amputations (at or above the ankle) limit functional independence and their prevention is a key goal of CLI therapy. Medical therapy after revascularization targets risk factors for atherosclerosis and assesses wound healing and new or recurrent flow limiting disease. The ongoing NIH sponsored BEST-CLI study is a randomized trial of the contemporary endovascular versus open surgical techniques in patients with CLI. PMID:26858079

  7. Stem cell use in critical limb ischemia.

    PubMed

    Kolvenbach, R; Kreissig, C; Ludwig, E; Cagiannos, C

    2007-02-01

    The following paper gives an overview of the current status of stem cell use in vascular medicine. The role of endothelial progenitor cells (EPCs) is discussed. Different approaches to use cellular based concepts are outlined: among these are the treatment of patients with critical ischemia with bone marrow derived mononuclear cells as well as our own experience with purified and highly selected CD133 and CD34 cells. The pro and cons of these different treatment regimens are discussed. An outlook is given discussing a combination of gene therapy and stem cell injections. The clinical and laboratory results of 15 patients with end-stage critical ischemia are discussed with implications for future clinical trials. We conclude that, despite all open questions, the outlook for EPC-based therapies for tissue ischemia and blood vessel repair appears promising.

  8. [Epidemiology of critical ischemia of the limbs].

    PubMed

    Estevan, J M; Valle, A; Pacho, J

    1993-01-01

    Authors report their results from a study made during 1991. The study was made in order to analyze the clinical complications (morbidity and mortality) and the socioeconomic consequences that are related to the cure of patients with highly developed ischemic diseases (critical ischemia). Economic expenses mean a 1.5% from the total budget of the Public Sanity into the Asturian Autonomic Community.

  9. 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.

  10. Therapeutic Angiogenesis in Critical Limb Ischemia

    PubMed Central

    Ouma, Geoffrey O.; Zafrir, Barak; Mohler, Emile R.; Flugelman, Moshe Y.

    2013-01-01

    Critical limb ischemia (CLI) is a severe form of peripheral artery disease associated with high morbidity and mortality. The primary therapeutic goals in treating CLI are to reduce the risk of adverse cardiovascular events, relieve ischemic pain, heal ulcers, prevent major amputation, and improve quality of life (QoL) and survival. These goals may be achieved by medical therapy, endovascular intervention, open surgery, or amputation and require a multidisciplinary approach including pain management, wound care, risk factors reduction, and treatment of comorbidities. No-option patients are potential candidates for the novel angiogenic therapies. The application of genetic, molecular, and cellular-based modalities, the so-called therapeutic angiogenesis, in the treatment of arterial obstructive diseases has not shown consistent efficacy. This article summarizes the current status related to the management of patients with CLI and discusses the current findings of the emerging modalities for therapeutic angiogenesis. PMID:23129733

  11. Therapeutic angiogenesis for critical limb ischemia.

    PubMed

    Ko, Sae Hee; Bandyk, Dennis F

    2014-03-01

    The application of gene- and cell-based therapies to promote angiogenesis is a novel concept to treat lower-limb critical limb ischemia (CLI) and may provide an unmet need for patients with no options for revascularization. Proof of concept was demonstrated in animal models resulting in clinical trials that have confirmed the feasibility and short-term efficacy of intramuscular injection of angiogenetic tissue growth factors or bone marrow stem cells. The safety of these biologic therapies has been demonstrated in randomized clinical trials with no "off-target" angiogenesis, growth of occult tumors, or progression of diabetic retinopathy. Current phase III randomized clinical trials using a DNA plasmid with the hepatocyte growth factor gene or bone marrow aspirate concentrate of mesenchymal cells are designed to address several crucial issues, including proper patient selection criteria, relevant clinical endpoints, and long-term efficacy. Because effectiveness of these novel therapies remains to be established, ongoing and future randomized clinical trials should be placebo-controlled, investigator-blinded, and have amputation-free survival as the primary endpoint. Further development of efficient gene transfer techniques and keeping transplanted stem cells healthy have the potential to make biologic therapies more robust in promoting angiogenesis, tissue regeneration, and resolution of CLI symptoms. If sustained efficacy can be demonstrated, new therapeutic strategies for patients with CLI will be available for clinicians, ie, limb revascularization using angiogenic gene or stem cell therapy alone, or in conjunction with endovascular intervention.

  12. Critical limb ischemia: medical and surgical management.

    PubMed

    Slovut, David Paul; Sullivan, Timothy M

    2008-08-01

    Chronic critical limb ischemia (CLI), defined as > 2 weeks of rest pain, ulcers, or tissue loss attributed to arterial occlusive disease, is associated with great loss of both limb and life. Therapeutic goals in treating patients with CLI include reducing cardiovascular risk factors, relieving ischemic pain, healing ulcers, preventing major amputation, improving quality of life and increasing survival. These aims may be achieved through medical therapy, revascularization, or amputation. Medical therapy includes administration of analgesics, local wound care and pressure relief, treatment of infection, and aggressive therapy to modify atherosclerotic risk factors. For patients who are not candidates for revascularization, and who are unwilling or unable to undergo amputation, treatments such as intermittent pneumatic compression or spinal cord stimulation may offer symptom relief and promote wound healing. Revascularization offers the best option for limb salvage. The decision to perform surgery, endovascular therapy, or a combination of the two modalities ('hybrid' therapy) must be individualized. Patients who are relatively fit and able to withstand the rigors of an open procedure may benefit from the long-term durability of surgical repair. In contrast, frail patients with a limited life expectancy may experience better outcomes with endovascular reconstruction. Hybrid therapy is an attractive option for patients with limited autologous conduit, as it permits complete revascularization with a less extensive procedure, shorter duration of operation, and decreased risk of peri-operative complications. Amputation should be considered for patients who are non-ambulatory, demented, or unfit to undergo revascularization.

  13. Outpatient follow-up for critical limb ischemia.

    PubMed

    Watch, Libby

    2014-09-01

    Outpatient follow-Up for critical limb ischemia offers the clinician the opportunity to monitor the patient for risk factor modification and wound healing. Routine surveillance following intervention will improve long-term patency.

  14. Critical appraisal of surgical revascularization for critical limb ischemia.

    PubMed

    Conte, Michael S

    2013-02-01

    Peripheral artery disease is growing in global prevalence and is estimated to afflict between 8 and 12 million Americans. Its most severe form, critical limb ischemia (CLI), is associated with high rates of limb loss, morbidity, and mortality. Revascularization is the cornerstone of limb preservation in CLI, and has traditionally been accomplished with open surgical bypass. Advances in catheter-based technologies, coupled with their broad dissemination among specialists, have led to major shifts in practice patterns in CLI. There is scant high-quality evidence to guide surgical decision making in this arena, and market forces have exerted profound influences. Despite this, available data suggest that the expected outcomes for both endovascular and open surgery in CLI are strongly dependent on definable patient factors such as anatomic distribution of disease, vein quality, and comorbidities. Optimal patient selection is paramount for maximizing benefit with each technique. This review summarizes some of the existing data and suggests a selective approach to revascularization in CLI, which continues to rely on vein bypass surgery as a primary option in appropriately selected patients.

  15. Limb-Threatening Ischemia in a Young Man with Cathinone "Bath Salt" Intoxication: A Case Report.

    PubMed

    Saleh, Asem; Tittley, Jacques; Anand, Sonia

    2016-10-01

    "Bath salts" are synthetic designer drugs that have stimulant properties and are a growing medical concern. The chemical compounds in the mixtures have an affinity for receptors in the brain resulting in a stimulant effect similar to that seen with methamphetamines and cocaine. Although illegal in Canada, these drugs are widely available online with over 20 synthetic drugs marketed as "bath salts" and used increasingly among recreational drug users. Much of the medical literature regarding these drugs comes from emergency medicine case reports, which outline the acute, severe medical, and psychiatric effects of "bath salt" toxicity. In this report, we outline severe vascular limb compromise, which occurred in a 24-year-old man who took large doses of bath salts obtained online from China. We detail our experience to re-establish perfusion to the limbs, and the morbidities encountered due to the ischemic insult our patient experienced. The duration and clinical presentation of "bath salt" toxicity are frequently complicated by lack of toxicology screens for the agents on board, and lack of any pharmacokinetic evidence surrounding these synthetic compounds. Although "bath salts" are now illegal in Canada, these drugs are widely available online and have become an increasing public health concern that involves significant morbidity and mortality to users. Creating a base of knowledge and front-line experience are the only current tool in combating the diverse detrimental aftermath of these synthetic agents' abuse.

  16. Intraarterial Infusion Therapy via a Subcutaneous Port for Limb-Threatening Ischemia: A Pilot Study

    SciTech Connect

    Strecker, Ernst-Peter K.; Ostheim-Dzerowycz, Wladimir; Boos, Irene B.L.

    1998-03-15

    Purpose: To present the initial results of a new percutaneously implantable catheter port system (PIPS) used for long-term intraarterial infusion therapy in patients with severe ischemic limb disease. Methods: Ten patients with deep, extended ischemic ulcerations (all 10) and osteomyelitis (6/10) of the foot received intraarterial infusions of prostaglandine E{sub 1} and antibiotics, if indicated, via a new port catheter system with the port placed subcutaneously above the groin after percutaneous introduction and the catheter tip placed into the superficial or deep femoral artery. Results: Port implantation and repeated port access were uncomplicated. During the follow-up period (mean 11 months, range 1 week-50 months), port migration, leakage, or infection was not observed. Three catheters thrombosed and were opened by fibrinolysis with recombinant tissue plasminogen activator instilled via the port. Treatment success was achieved in 8 patients: relief from rest pain (8 patients), reduction of ulcer size (4/8), and complete healing (4/8). Limb savage rate was 80%. In 2 patients amputation could not be avoided. Conclusion: Selective long-term arterial infusion therapy presents a valuable therapeutic regimen for limb salvage. With the new catheter port system, repeated local intraarterial infusion is safe and simple.

  17. Critical Limb Ischemia: Cell and Molecular Therapies for Limb Salvage

    PubMed Central

    2012-01-01

    There is a growing interest in developing new limb salvage therapies for patients with severe peripheral artery disease who have no alternative to amputation. Cell and gene therapy studies are showing promise in controlling pain and minor ulceration in patients with significant critical limb ischemia. Among cardiovascular cell and molecular therapy programs, The Methodist Hospital is one of the leading centers in both gene and cell therapy for critical limb ischemia. Randomized controlled trials continue to be performed, and these experimental therapies will move from research to pharmacy within the decade. In conjunction with aggressive medical and surgical management, these emergent therapies may help patients with critical limb ischemia avoid a major amputation and are one of the foundations of any advanced limb salvage program. PMID:23342184

  18. A prognostic model for amputation in critical lower limb ischemia.

    PubMed

    Klomp, H M; Steyerberg, E W; Wittens, C H A; van Urk, H; Habbema, J D F

    2009-05-01

    In a (negative) multicenter randomized trial on management for inoperable critical lower limb ischemia, comparing spinal cord stimulation and best medical treatment, a number of pre-defined factors were analyzed for prognostic value. We included a radiological arterial disease score, modified from the SVS/ISCVS runoff score. The purpose of this analysis was to evaluate clinical factors and commonly used circulatory measurements for prognostic modeling in patients with critical lower limb ischemia. We determined the incidence of amputation and its relation to various pre-defined risk factors. A total of 120 patients with critical limb ischemia were included in the study. The integrity of circulation in the affected limb was evaluated on five levels: suprainguinal, infrainguinal, popliteal, infrapopliteal and pedal. A total radiological arterial disease score was calculated from 1 (full integrity of circulation) to 20 (maximally compromised state). We used Cox regression analysis to quantify prognostic effects and differential treatment (predictive) effects. Major amputation occurred in 33% of the patients at 6 months and in 51% at 2 years. The presence of ischemic skin lesions and the radiological arterial disease score were independent prognostic factors for amputation. Patients with ulcerations or gangrene had a higher amputation risk (hazard ratio 2.38, p = 0.018 and 2.30, p = 0.036 respectively) as well as patients with a higher radiological arterial disease score (hazard ratio 1.17 per increment, p = 0.003). We did not observe significant interactions between prognostic factors and the effect of spinal cord stimulation. In conclusion, in patients with critical lower limb ischemia, the presence of ischemic skin lesions and the described radiological arterial disease score can be used to estimate amputation risk.

  19. Characteristics of physical activity in patients with critical limb ischemia

    PubMed Central

    Sakaki, Satoko; Takahashi, Tetsuya; Matsumoto, Junichi; Kubo, Kasuya; Matsumoto, Takuya; Hishinuma, Ryo; Terabe, Yuuta; Ando, Hiroshi

    2016-01-01

    [Purpose] The purpose of this study was to evaluate the amount of physical activity of the patients with critical limb ischemia consecutively in order to clarify the characteristics of physical activity of critical limb ischemia. [Subjects and Methods] Twelve patients who were eligible for the 2 months of consecutive evaluation of the amount of physical activity were enrolled in the study (men: 11; woman: 1; mean age: 64.4 [range: 44–80]). A pedometer with an accelerometer was used for the measurement of the number of steps walked as an index of the amount of physical activity. Participants were asked to lead a regular life and no instruction was given as to the number of steps. [Results] The average number of daily steps walked was 2,323 steps (range: 404–6,505). There was no clear tendency in the number of amputation site-specific steps walked. There was also no correlation between the number of steps walked and age as well as the maximum strength of the knee-extension muscle, skin perfusion pressure of the sole and the dorsum, and QOL scores. [Conclusion] The number of steps walked of the patients with critical limb ischemia was remarkably low and no significant association with health-related QOL. PMID:28174472

  20. Contemporary Outcomes of Endovascular Intervention for Critical Limb Ischemia.

    PubMed

    Dalal, Pratik K; Prasad, Anand

    2017-04-01

    Critical limb ischemia (CLI) remains a significant cause of morbidity and mortality in patients with peripheral arterial disease. Optimal treatment strategies for CLI remain controversial. The only randomized trial comparing surgical with endovascular revascularization suggests no significant difference in limb salvage between open surgical bypass and angioplasty. Although novel endovascular strategies are now available, their efficacies remain largely untested in a randomized fashion. This review provides an overview of the data surrounding contemporary outcomes of endovascular therapy with an emphasis on current knowledge gaps.

  1. 2014 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report

    PubMed Central

    2016-01-01

    Since 2013, the Japanese Society for Vascular Surgery (JSVS) has started the project of nationwide registration and a tracking database for patients with critical limb ischemia (CLI) who are treated by vascular surgeons. The purpose of this project is to clarify the current status of the medical practice for patients with CLI to contribute to the improvement of the quality of medical care. This database, called JAPAN Critical Limb Ischemia Database (JCLIMB), is created on the National Clinical Database (NCD) and collects data of patients’ background, therapeutic measures, early results, and long-term prognosis as long as 5 years after the initial treatment. The limbs managed conservatively are also registered in JCLIMB, together with those treated by surgery and/or endovascular treatment (EVT). In 2014, 1347 CLI limbs (male 936 limbs: 69%) were registered by 95 facilities. Arteriosclerosis obliterans (ASO) has accounted for 97% of the pathogenesis of these limbs. In this manuscript, the background data and the early prognosis of the registered limbs are reported. (This is a translation of Jpn J Vasc Surg 2016;25:293–310.) PMID:28018516

  2. 2013 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report

    PubMed Central

    2016-01-01

    Since 2013, the Japanese Society for Vascular Surgery (JSVS) has started the project of nationwide registration and a tracking database for patients with critical limb ischemia (CLI) who are treated by vascular surgeons. The purpose of this project is to clarify the current status of the medical practice for patients with CLI to contribute to the improvement of the quality of medical care. This database, called JAPAN Critical Limb Ischemia Database (JCLIMB), is created on the National Clinical Database (NCD) and collects data of patients’ background, therapeutic measures, early results, and long term prognosis as long as five years after the initial treatment. The limbs managed conservatively are also registered in JCLIMB, together with those treated by surgery and/or EVT. In 2013, 1207 CLI limbs (male 874 limbs: 72%) were registered by 87 facilities. ASO has accounted for 98% of the pathogenesis of these limbs. In this manuscript, the background data and the early prognosis of the registered limbs are reported. (This is a translation of Jpn J Vasc Surg 2016; 25: 215–232.) PMID:28018515

  3. 2013 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report.

    PubMed

    2016-01-01

    Since 2013, the Japanese Society for Vascular Surgery (JSVS) has started the project of nationwide registration and a tracking database for patients with critical limb ischemia (CLI) who are treated by vascular surgeons. The purpose of this project is to clarify the current status of the medical practice for patients with CLI to contribute to the improvement of the quality of medical care. This database, called JAPAN Critical Limb Ischemia Database (JCLIMB), is created on the National Clinical Database (NCD) and collects data of patients' background, therapeutic measures, early results, and long term prognosis as long as five years after the initial treatment. The limbs managed conservatively are also registered in JCLIMB, together with those treated by surgery and/or EVT. In 2013, 1207 CLI limbs (male 874 limbs: 72%) were registered by 87 facilities. ASO has accounted for 98% of the pathogenesis of these limbs. In this manuscript, the background data and the early prognosis of the registered limbs are reported. (This is a translation of Jpn J Vasc Surg 2016; 25: 215-232.).

  4. 2014 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report.

    PubMed

    2016-01-01

    Since 2013, the Japanese Society for Vascular Surgery (JSVS) has started the project of nationwide registration and a tracking database for patients with critical limb ischemia (CLI) who are treated by vascular surgeons. The purpose of this project is to clarify the current status of the medical practice for patients with CLI to contribute to the improvement of the quality of medical care. This database, called JAPAN Critical Limb Ischemia Database (JCLIMB), is created on the National Clinical Database (NCD) and collects data of patients' background, therapeutic measures, early results, and long-term prognosis as long as 5 years after the initial treatment. The limbs managed conservatively are also registered in JCLIMB, together with those treated by surgery and/or endovascular treatment (EVT). In 2014, 1347 CLI limbs (male 936 limbs: 69%) were registered by 95 facilities. Arteriosclerosis obliterans (ASO) has accounted for 97% of the pathogenesis of these limbs. In this manuscript, the background data and the early prognosis of the registered limbs are reported. (This is a translation of Jpn J Vasc Surg 2016;25:293-310.).

  5. [Long term results after invasive treatment of critical limb ischemia].

    PubMed

    Ruzsa, Zoltán; Kuti, Ferenc; Berta, Balázs; Tóth, Károly; Bánsághi, Zoltán; Vámosi, Zoltán; Hüttl, Kálmán

    2017-03-01

    Surgical tibial bypass for critical limb ischemia is associated with significant morbidity, mortality, and graft failure, whereas percutaneous angioplasty and stenting has promising results. The objective of this study was the investigation of the long term results of below-knee percutaneous angioplasty for restoring straight inline arterial flow in patients with critical limb ischemia. The clinical and angiographic data of 281 consecutive patients with critical limb ischemia treated by PTA between 2008 and 2011 was evaluated in a prospective register. The aim of the revascularization was to achieve a straight inline flow to the wound with balloon angioplasty. Stent implantation was done in the case of recoil and flow limiting dissection. Primary end points were clinical success (relief of resting pain, healing of ulceration, limb survival) and major adverse events (death, myocardial infarction, major unplanned amputation, need for surgical revascularization, or major bleeding). Secondary end points were the angiographic result of the intervention, procedural data and consumption of angioplasty equipment. The impact of diabetic leg syndrome and the result of the angioplasty on the limb salvage was also investigated. We have analysed the impact of major amputation on long term mortality. Mean age of patients was 72.5 ± 10.6 years and the follow-up period was 40.8 ± 9.7 months. Technical success was reached in 255 (90.7%) of the patient's: 255 limbs straight inline flow with good angiographic result was restored to at least one tibial vessel. Balloon angioplasty, stent implantation and rotational atherectomy was performed in 278 (98.9%), 74 (26.3%) and 2 patients (0.7%). From clinical end points the rest pain was ceased in 56.6%, the ulcer and the gangrena was healed in 73.5% and 46.5%. The long term limb survival was 73.5%; 65.8% in diabetic and 89.6% in non-diabetic leg syndrome (p = 0.001). The major adverse events at long-term follow-up occured in 122 (43

  6. Cell Therapy in Patients with Critical Limb Ischemia

    PubMed Central

    Compagna, Rita; Amato, Bruno; Massa, Salvatore; Amato, Maurizio; Grande, Raffaele; Butrico, Lucia; de Franciscis, Stefano; Serra, Raffaele

    2015-01-01

    Critical limb ischemia (CLI) represents the most advanced stage of peripheral arterial obstructive disease (PAOD) with a severe obstruction of the arteries which markedly reduces blood flow to the extremities and has progressed to the point of severe rest pain and/or even tissue loss. Recent therapeutic strategies have focused on restoring this balance in favor of tissue survival using exogenous molecular and cellular agents to promote regeneration of the vasculature. These are based on stimulation of angiogenesis by extracellular and cellular components. This review article carries out a systematic analysis of the most recent scientific literature on the application of stem cells in patients with CLI. The results obtained from the detailed analysis of the recent literature data have confirmed the beneficial role of cell therapy in reducing the rate of major amputations in patients with CLI and improving their quality of life. PMID:26300924

  7. [Management of a patient with critical limb ischemia].

    PubMed

    Bura-Rivière, Alessandra; Julia, Pierre; Sapoval, Marc

    2005-06-15

    The severity of the prognostic of critical limb ischemia imposes a multidisciplinary approach, done by a highly specialised centre. A delay in managing this condition increases significantly the risk of amputation. For most patients, a revascularisation procedure, surgical or endovascular, can be considered, since the aim of the treatment is to restore an arterial flux to permit cicatrisation and relieve pain. When the choice is possible, endovascular techniques are preferred, because more simple, done without anaesthesia and charged of less complications rate. The choice between two techniques is never simple and imposes the intervention of a multidisciplinary staff composed by vascular specialist, vascular surgeons and interventional radiologists. The aim of the medical treatment, waiting for the revascularisation, is to control the pain and the infection, prevent progression of the lesions and to optimise respiratory and cardiac functions.

  8. [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.

  9. Contemporary Treatment for Critical Ischemia: The Evidence for Interventional Radiology or Surgery

    PubMed Central

    Hussey, Keith; Chandramohan, Sivanathan

    2014-01-01

    This article is a review of the evidence regarding the management of patients with critical limb ischemia. The aim of the study is to discuss the definition, incidence, and clinical importance of critical limb ischemia, as well as the aims of treatment in terms of quality of life and limb salvage. Endovascular and surgical treatments should not be viewed as competing therapies. In fact, these are complementary techniques each with strengths and weaknesses. The authors will propose a strategy based on the available evidence for deciding the optimal approach to management of patients with critical limb ischemia. PMID:25435654

  10. The impact of nutritional status on treatment outcomes of patients with limb-threatening diabetic foot ulcers.

    PubMed

    Gau, Bing-Ru; Chen, Hsin-Yun; Hung, Shih-Yuan; Yang, Hui-Mei; Yeh, Jiun-Ting; Huang, Chung-Huei; Sun, Jui-Hung; Huang, Yu-Yao

    2016-01-01

    This study aimed to investigate the nutritional status of patients with limb-threatening diabetic foot ulcers (DFUs) and its impact on treatment outcomes. A total of 478 consecutive patients (mean age, 65.4years) treated for limb-threatening DFUs were enrolled. Nutritional status assessment using the Mini Nutritional Assessment (MNA) and Geriatric Nutritional Risk Index (GNRI) was performed by three qualified dieticians within 48hours of admission. Limb-preservation outcomes were stratified into major lower extremity amputation (LEA) (above the ankle, n=33), minor LEA (distal to ankle, n=117) and no amputation (non-LEA, n=328). Most patients were identified as being at risk of malnutrition (70.5%) or malnourished (14.6%) (mean MNA score, 20.6±3.4). MNA scores decreased with increasing severity of LEA (mean, 21.1, 20.0, and 17.9, respectively; P for linear trend <0.001), associated inversely with the tendency to require LEA (P for linear trend was 0.001), and associated independently with both major and minor LEA outcomes (adjusted odds ratio [aOR]=0.80, 95% confidence interval [CI], 0.65-0.99, P=0.042 and aOR=0.89, 95% CI, 0.80-0.99, P=0.032, respectively). The predictive value was sustained in patients younger than age 65years. Though GNRI results had similar associations with outcomes, its predictive value was limited in minor LEA and younger population. Patients' nutritional status was shown to have significant influence on limb-preservation outcomes for limb-threatening DFUs. Nutritional assessment of this patient population using the MNA is recommended. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia

    PubMed Central

    Ryan, Terence E.; Schmidt, Cameron A.; Green, Tom D.; Brown, David A.; Neufer, P. Darrell; McClung, Joseph M.

    2015-01-01

    Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial disease and manifests as chronic limb pain at rest and/or tissue necrosis. Current clinical interventions are largely ineffective and therapeutic angiogenesis based trials have shown little efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. Despite a decade of research related to skeletal muscle as a determinant of morbidity and mortality outcomes in CLI, very little progress has been made toward an effective therapy aimed directly at the muscle myopathies of this disease. Within the muscle cell, mitochondria are well positioned to modulate the ischemic cellular response, as they are the principal sites of cellular energy production and the major regulators of cellular redox charge and cell death. In this mini review, we update the crucial importance of skeletal muscle to CLI pathology and examine the evolving influence of muscle and endothelial cell mitochondria in the complex ischemic microenvironment. Finally, we discuss the novelty of muscle mitochondria as a therapeutic target for ischemic pathology in the context of the complex co-morbidities often associated with CLI. PMID:26635622

  12. Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia.

    PubMed

    Ryan, Terence E; Schmidt, Cameron A; Green, Tom D; Brown, David A; Neufer, P Darrell; McClung, Joseph M

    2015-01-01

    Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial disease and manifests as chronic limb pain at rest and/or tissue necrosis. Current clinical interventions are largely ineffective and therapeutic angiogenesis based trials have shown little efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. Despite a decade of research related to skeletal muscle as a determinant of morbidity and mortality outcomes in CLI, very little progress has been made toward an effective therapy aimed directly at the muscle myopathies of this disease. Within the muscle cell, mitochondria are well positioned to modulate the ischemic cellular response, as they are the principal sites of cellular energy production and the major regulators of cellular redox charge and cell death. In this mini review, we update the crucial importance of skeletal muscle to CLI pathology and examine the evolving influence of muscle and endothelial cell mitochondria in the complex ischemic microenvironment. Finally, we discuss the novelty of muscle mitochondria as a therapeutic target for ischemic pathology in the context of the complex co-morbidities often associated with CLI.

  13. 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

    2017-07-21

    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.

  14. Infrainguinal bypass for critical limb ischemia: tips and tricks.

    PubMed

    Wayne Causey, Marlin; Eichler, Charles

    2014-03-01

    A thoughtful but aggressive approach to care of patients with critical limb ischemia (CLI) is required to alleviate lower-extremity pain/tissue injury and achieve durable limb salvage. Specific subsets of CLI patients have been identified to clearly benefit from open surgical revascularization based on presenting signs (extensive tissue loss), multi-level, long-segment arterial occlusive disease, healthy saphenous conduit, and nondiseased tibial artery target vessel with continuous patency to the pedal arch. When other clinical scenarios exist, the treatment strategy requires consideration of patient's medical and surgical risk factors, anatomic distribution of atherosclerotic disease, and the clinical status of the limb affected by CLI. Infrainguinal saphenous vein bypass is the most durable technique for limb salvage and when properly performed is associated with excellent wound healing rates and improvement in quality of life. In this review, we detail our approach to infrainguinal arterial vein bypass in patients with CLI, including patient selection criteria, surgical planning based on arterial imaging studies, and operative technical requirements required for successful open lower-extremity bypass procedures. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. Critical ischemia time in a model of spinal cord section. A study performed on dogs

    PubMed Central

    Garcia Martinez, David; Rosales Corral, Sergio A.; Flores Soto, Mario E.; Velarde Silva, Gustavo; Portilla de Buen, Eliseo

    2006-01-01

    Vascular changes after acute spinal cord trauma are important factors that predispose quadriplegia, in most cases irreversible. Repair of the spinal blood flow helps the spinal cord recovery. The average time to arrive and perform surgery is 3 h in most cases. It is important to determine the critical ischemia time in order to offer better functional prognosis. A spinal cord section and vascular clamping of the spinal anterior artery at C5–C6 model was used to determine critical ischemia time. The objective was to establish a critical ischemia time in a model of acute spinal cord section. Four groups of dogs were used, anterior approach and vascular clamp of spinal anterior artery with 1, 2, 3, and 4 h of ischemia and posterior hemisection of spinal cord at C5–C6 was performed. Clinical evaluation was made during 12 weeks and morphological evaluation at the end of this period. We obtained a maximal neurological coordination at 23 days average. Two cases showed sequels of right upper limb paresis at 1 and 3 ischemia hours. There was nerve conduction delay of 56% at 3 h of ischemia. Morphological examination showed 25% of damaged area. The VIII and IX Rexed’s laminae were the most affected. The critical ischemia time was 3 h. Dogs with 4 h did not exhibit any recovery. PMID:17024402

  16. Ischemia

    NASA Astrophysics Data System (ADS)

    Byeon, Suk Ho; Kim, Min; Kwon, Oh Woong

    "Ischemia" implies a tissue damage derived from perfusion insufficiency, not just an inadequate blood supply. Mild thickening and increased reflectivity of inner retina and prominent inner part of synaptic portion of outer plexiform layer are "acute retinal ischemic changes" visible on OCT. Over time, retina becomes thinner, especially in the inner portion. Choroidal perfusion supplies the outer portion of retina; thus, choroidal ischemia causes predominant change in the corresponding tissue.

  17. Prognosis of critical limb ischemia: Major vs. minor amputation comparison.

    PubMed

    Matsuzaki, Kyoichi; Hayashi, Ruka; Okabe, Keisuke; Aramaki-Hattori, Noriko; Kishi, Kazuo

    2015-09-01

    Healthcare providers treating wounds have difficulties assessing the prognosis of patients with critical limb ischemia who had been discharged after complete healing of major amputation wounds. The word "major" in "major amputation" gives the impression of "being more severe" than "minor amputation." Therefore, even if wounds are healed after major amputation, they imagine that prognosis after major amputation would be poorer than that after minor amputation. We investigated the prognosis of diabetic nephropathy patients 2 years after amputations. Those patients underwent dialysis as well as amputation following percutaneous transluminal angioplasty for their foot wounds. They were ambulatory prior to these surgeries. Among 56 cases of minor amputation, 45 were males and 11 were females, and mortality was 41.1%. The mortality of cases with and without a coronary intervention history was 53.1% and 25.0%, respectively (p = 0.034). Among 10 cases of major amputation, 9 were males and 1 was female, and mortality was 60%. The mortality of cases with and without a coronary intervention history was 75.0% and 0%, respectively. Although we predicted poor prognosis in cases with major amputation, there was no significant difference in mortality 2 years after amputations (p = 0.267). Thus far poor prognosis has been reported for major amputation. It might be due to inclusion of the following patients: patients with wounds proximal to ankle joints, patients with extensive gangrene spreading to the lower legs, patients with septicemia from wound infection and who died around the time of operation, and patients with malnutrition. The results of our present study showed that the outcomes at 2 years postoperatively were similar between patients with major amputations and those with minor amputations, if surgical wounds were able to heal. We should not estimate the prognosis by the level of amputation, rather we should consider the effect of coronary intervention history on

  18. Understanding objective performance goals for critical limb ischemia trials.

    PubMed

    Conte, Michael S

    2010-09-01

    Critical limb ischemia (CLI), the most advanced form of peripheral arterial disease, is associated with a high rate of limb loss and substantial mortality. Revascularization remains the cornerstone of limb salvage in the CLI patient, and surgical bypass is the established standard. Endovascular therapies, such as angioplasty, atherectomy, and stenting offer a less-invasive option, but evidence of efficacy is lacking, and no devices are currently approved specifically for CLI. Design and execution of clinical trials in the CLI population are challenging, in part because of the lack of consensus on cohort definitions and relevant endpoints. Recently, the Society for Vascular Surgery undertook an initiative to define therapeutic benchmarks, objective performance goals (OPGs), for CLI. Using surgical bypass with autogenous vein as the standard for comparison, OPGs were developed for nine safety and efficacy measures that could be utilized in the premarket assessment of new devices in CLI. Data from three large randomized controlled trials of surgical bypass for CLI were analyzed. We defined a major adverse limb event (MALE) as a key endpoint for revascularization therapies in CLI--inclusive of amputation (transtibial or above) or any major vascular reintervention (thrombectomy, thrombolysis, or major surgical procedure [new bypass graft, jump/interposition graft revision]) in the index limb. Freedom from perioperative (30-day) death or any MALE (MALE + POD) was suggested as the primary efficacy endpoint for a single-arm trial design in CLI, with an observed rate of 76.9% for the surgical bypass controls at 1 year. Specific high-risk subgroups were also defined from the surgical dataset--based on clinical (age older than 80 years and tissue loss), arterial anatomy (infrapopliteal disease), and conduit quality (inadequate saphenous vein) characteristics. Risk-adjusted OPG were developed for these subgroups of interest. These OPGs define a new set of benchmarks for

  19. Medical and endovascular management of critical limb ischemia.

    PubMed

    Lumsden, Alan B; Davies, Mark G; Peden, Eric K

    2009-04-01

    Critical limb ischemia (CLI) is the term used to designate the condition in which peripheral artery disease has resulted in resting leg or foot pain or in a breakdown of the skin of the leg or foot, causing ulcers or tissue loss. If not revascularized, CLI patients are at risk for limb loss and for potentially fatal complications from the progression of gangrene and the development of sepsis. The management of CLI requires a multidisciplinary team of experts in different areas of vascular disease, from atherosclerotic risk factor management to imaging, from intervention to wound care and physical therapy. In the past decade, the most significant change in the treatment of CLI has been the increasing tendency to shift from bypass surgery to less invasive endovascular procedures as first-choice revascularization techniques, with bypass surgery then reserved as backup if appropriate. The goals of intervention for CLI include the restoration of pulsatile, inline flow to the foot to assist wound healing, the relief of rest pain, the avoidance of major amputation, preservation of mobility, and improvement of patient function and quality of life. The evaluating physician should be fully aware of all revascularization options in order to select the most appropriate intervention or combination of interventions, while taking into consideration the goals of therapy, risk-benefit ratios, patient comorbidities, and life expectancy. We discuss the incidence, risk factors, and prognosis of CLI and the clinical presentation, diagnosis, available imaging modalities, and medical management (including pain and ulcer care, pharmaceutical options, and molecular therapies targeting angiogenesis). The endovascular approaches that we review include percutaneous transluminal angioplasty (with or without adjunctive stenting); subintimal angioplasty; primary femoropopliteal and infrapopliteal deployment of bare nitinol, covered, drug-eluting, or bioabsorbable stents; cryoplasty; excimer

  20. Critical Hand Ischemia After Radial Access for Coronary Angiography – Case Report

    PubMed Central

    Bojakowski, Krzysztof; Zawadzki, Michał; Mruk, Bartosz; Andziak, Piotr; Walecki, Jerzy

    2017-01-01

    Summary Background Radial artery is now the most frequent access for coronary angiography and intervention. Despite the common opinion that it is safer than femoral access, it has the potential for serious complications. One of them is upper limb ischemia caused by radial artery thrombosis. Case Report We are presenting a case of critical hand ischemia after coronary angiography performed through radial access despite existing risk factors, which may be considered as relative contraindications. Conclusions In the presented case, decision was made to use radial access despite several risk factors of upper limb ischemia – diabetes, end-stage renal failure, hyperparathyroidism, or even symptoms of left upper limb ischemia. Furthermore, for diagnostic coronary angiography 5F instead of 4F introducer was used. PMID:28144386

  1. Evaluation of the patient who presents with critical limb ischemia: diagnosis, prognosis, and medical management.

    PubMed

    Conde, Ian Del; Erwin, Phillip A

    2014-09-01

    Patients with critical limb ischemia usually have severe atherosclerotic disease and are at a high risk of limb loss as well as major adverse cardiovascular events. The current article provides a description of the clinical presentation of patients with critical limb ischemia and also discusses the initial evaluation of these patients, including physical examination, use of noninvasive vascular tests, and other imaging modalities. An overview of the general management of these patients is also provided, including the identification of patients who benefit from revascularization or primary amputation, principles of wound care, and therapies for cardiovascular risk reduction. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Intra-arterial Autologous Bone Marrow Cell Transplantation in a Patient with Upper-extremity Critical Limb Ischemia

    SciTech Connect

    Madaric, Juraj; Klepanec, Andrej; Mistrik, Martin; Altaner, Cestmir; Vulev, Ivan

    2013-04-15

    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.

  3. Systematic investigation of transcription factors critical in the protection against cerebral ischemia by Danhong injection

    PubMed Central

    Wei, Junying; Zhang, Yanqiong; Jia, Qiang; Liu, Mingwei; Li, Defeng; Zhang, Yi; Song, Lei; Hu, Yanzhen; Xian, Minghua; Yang, Hongjun; Ding, Chen; Huang, Luqi

    2016-01-01

    Systematic investigations of complex pathological cascades during ischemic brain injury help to elucidate novel therapeutic targets against cerebral ischemia. Although some transcription factors (TFs) involved in cerebral ischemia, systematic surveys of their changes during ischemic brain injury have not been reported. Moreover, some multi-target agents effectively protected against ischemic stroke, but their mechanisms, especially the targets of TFs, are still unclear. Therefore, a comprehensive approach by integrating network pharmacology strategy and a new concatenated tandem array of consensus transcription factor response elements method to systematically investigate the target TFs critical in the protection against cerebral ischemia by a medication was first reported, and then applied to a multi-target drug, Danhong injection (DHI). High-throughput nature and depth of coverage, as well as high quantitative accuracy of the developed approach, make it more suitable for analyzing such multi-target agents. Results indicated that pre-B-cell leukemia transcription factor 1 and cyclic AMP-dependent transcription factor 1, along with six other TFs, are putative target TFs for DHI-mediated protection against cerebral ischemia. This study provides, for the first time, a systematic investigation of the target TFs critical to DHI-mediated protection against cerebral ischemia, as well as reveals more potential therapeutic targets for ischemic stroke. PMID:27431009

  4. [Omniflow-II(TM) for critical limb ischemia : Long-term results].

    PubMed

    Dünschede, F; Youssef, M; Stabrauskaite, J; Ahmed, S; Espinola-Klein, C; Dorweiler, B; Vahl, C-F

    2017-03-01

    For the surgical treatment of critical limb ischemia one of the decisive influencing factors for short-term and long-term limb salvage is the use of autologous veins as bypass material. There is currently a lack of studies on the long-term assessment of alternative bypass materials, which can be used for critical limb ischemia due to a lack of autologous vein material. A prospective database was established that included all patients with critical limb ischemia who received a bypass with the Omniflow-II™ prosthesis. From 2006 until 2014 bypass surgery with the Omniflow-II™ prosthesis was carried out in 123 patients. The mortality was 5 % while the morbidity was 14 % and the 5‑year survival rate was 37 %. In patients with a popliteal bypass (n = 62), the primary and secondary patency rates were 34 % and 69 %, respectively after 5 years. The corresponding results for the crural position (n = 61) over the same time period were 32 % and 34 %, respectively. After 5 years, the group receiving popliteal bypass surgery showed a limb salvage rate of 98 % whereas the crural group had a rate of 70 %. In this study we could demonstrate very promising results using the Omniflow-II™ prosthesis for the surgical treatment of critical limb ischemia.

  5. Amputation-Free Survival after Crural Percutaneous Transluminal Angioplasty for Critical Limb Ischemia.

    PubMed

    Strøm, M; Konge, L; Lönn, L; Schroeder, T V; Rørdam, P

    2016-03-01

    To evaluate the amputation-free survival after below the knee percutaneous transluminal angioplasty in a consecutive group of patients with critical ischemia of the lower extremity. A total of 70 consecutive patients with critical ischemia were treated with below the knee percutaneous transluminal angioplasty at the vascular center at Rigshospitalet with the purpose of limb salvage. All patients were deemed unfit for major surgery due to anatomical limitations or severe co-morbidity, and no prior attempts of revascularization were performed. Follow-up clinical examinations were performed within 6 weeks and after 1 year. All medical records were crosschecked with the national vascular registry ensuring a valid 1-year status in 97% of the patients. A total of 15 major amputations were performed during follow-up, with 11 amputations performed within the first year. Complications after percutaneous transluminal angioplasty were rare. Cumulative mortality after 1 and 2 years was 22% and 34%, respectively. Amputation-free survival at 1 and 2 years of follow-up was 68% and 58%, respectively. There were no association between known risk factors such as diabetes, ischemic ulcers, cardiac disease, history of smoking, major amputation, or overall amputation. Below the knee percutaneous transluminal angioplasty in patients with end-stage peripheral arterial disease and critical limb ischemia is a safe procedure in relieving critical ischemia, reducing the short-term rate of a major amputation as opposed to best medical treatment alone. © The Finnish Surgical Society 2015.

  6. RESTING ENERGY EXPENDITURE IN PATIENTS WITH INTERMITTENT CLAUDICATION AND CRITICAL LIMB ISCHEMIA

    PubMed Central

    Gardner, Andrew W.; Montgomery, Polly S.

    2010-01-01

    Purpose The primary aim was to compare the resting energy expenditure of patients with intermittent claudication and critical limb ischemia. A secondary aim was to identify predictors of resting energy expenditure, Design One hundred patients limited by intermittent claudication and 40 patients with critical limb ischemia participated in this study. Patients were assessed on resting energy expenditure, body composition, ankle/brachial index (ABI), and calf blood flow. Results Patients with critical limb ischemia had a lower resting energy expenditure than patients with intermittent claudication (1429 ± 190 kcal/day vs. 1563 ± 229 kcal/day; p = 0.004), as well as higher body fat percentage (34.8 ± 7.8% vs. 31.5 ± 7.8%; p = 0.037), higher fat mass (30.0 ± 9.3 kg vs. 26.2 ± 8.9 kg; p = 0.016), and lower ABI (0.31 ± 0.11 vs. 0.79 ± 0.23; p < 0.001). Resting energy expenditure was predicted by fat free mass (p < 0.0001), age (p < 0.0001), ABI (p < 0.0001), ethnicity (p < 0.0001), calf blood flow (p = 0.005), and diabetes (p = 0.008). Resting energy expenditure remained lower in the patients with critical limb ischemia after adjusting for clinical characteristics plus fat free mass (1473 ± 27.8 kcal/day [mean ± SEM] vs. 1527 ± 19.3 kcal/day; p = 0.031), but was no longer different between groups after further adjustment for ABI and calf blood flow (1494 ± 25.2 kcal/day vs. 1505 ± 17.7 kcal/day (p = 0.269). Conclusion Resting energy expenditure is decreased with a progression in PAD symptoms from intermittent claudication to critical limb ischemia. Furthermore, patients with critical limb ischemia who are most susceptible for decline in resting energy expenditure are older, African-American patients with diabetes. The lower resting energy expenditure of patients with critical limb ischemia, combined with their sedentary lifestyle, suggests that they are at high risk for long-term positive energy balance and weight gain. PMID:20382493

  7. Critical ischemia of the fingers in an auto mechanic as a result of occupational exposure.

    PubMed

    Rabczyński, Maciej; Kuźnik, Edwin; Guziński, Maciej; Adamiec, Rajmund

    2014-09-10

    Hypothenar hammer syndrome is a rare cause of ischemic fingers observed mainly in young men smoking cigarettes and it is associated with repeated trauma of the ulnar artery in the area of the hypothenar eminence of the dominant-hand arm, resulting in a deficit of blood supply with the occurrence of hand symptoms typical for chronic and sometimes critical ischemia. Artery injury in this location is most often the result of multiple repetitions of the same activity being mostly the result of occupational exposure. We present a case of a 27-year-old car mechanic admitted to the hospital with symptoms of critical ischemia of the fingers III, IV, and V of the right hand, which resolved after conservative treatment.

  8. Critical ischemia of the fingers in an auto mechanic as a result of occupational exposure.

    PubMed

    Rabczyński, Maciej; Kuźnik, Edwin; Guziński, Maciej; Adamiec, Rajmund

    2015-01-01

    Hypothenar hammer syndrome is a rare cause of ischemic fingers observed mainly in young men smoking cigarettes and it is associated with repeated trauma of the ulnar artery in the area of the hypothenar eminence of the dominant-hand arm, resulting in a deficit of blood supply with the occurrence of hand symptoms typical for chronic and sometimes critical ischemia. Artery injury in this location is most often the result of multiple repetitions of the same activity being mostly the result of occupational exposure. We present a case of a 27-year-old car mechanic admitted to the hospital with symptoms of critical ischemia of the fingers III, IV, and V of the right hand, which resolved after conservative treatment.

  9. New aspects of delirium in elderly patients with critical limb ischemia

    PubMed Central

    van Eijsden, Willem A; Raats, Jelle W; Mulder, Paul GH; van der Laan, Lijckle

    2015-01-01

    Objective The primary objective was to identify possible risk factors for delirium in patients with critical limb ischemia undergoing surgery. The secondary objective was to study the effect of delirium on complications, the length of hospital stay, health care costs, and mortality. Methods All patients 65 years or older with critical limb ischemia undergoing surgery from February 2013 to July 2014 at Amphia Hospital, were included and followed up until December 31, 2014. Delirium was scored using the Delirium Observation Screening Scale (DOSS). Perioperative risk factors (age, comorbidity, factors of frailty, operation type, hemoglobulin, and transfusion) were collected and analyzed using logistic regression. Secondary outcomes were the number of complications, total hospital stay, extra health care costs per delirium, and mortality within 3 months and 6 months of surgery. Results We included 92 patients with critical limb ischemia undergoing surgery. Twenty-nine (32%) patients developed a delirium during admission, of whom 17 (59%) developed delirium preoperatively. After multivariable analysis, only diabetes mellitus (odds ratio [OR] =6.23; 95% confidence interval [CI]: 1.11–52.2; P=0.035) and Short Nutritional Assessment Questionnaire for Residential Care (SNAQ-RC) ≥3 (OR =5.55; 95% CI: 1.07–42.0; P=0.039) was significantly associated with the onset of delirium. Delirium was associated with longer hospital stay (P=0.001), increased health care costs, and higher mortality after 6 months (P<0.001). Conclusion Delirium is a common adverse event in patients with critical limb ischemia undergoing surgery with devastating outcome in the long term. Most patients developed delirium preoperatively, which indicates the need for early recognition and preventive strategies in the preoperative period. This study identified undernourishment and diabetes mellitus as independent risk factors for delirium. PMID:26451094

  10. [Prevalence of renal artery stenosis in patients with critical limb ischemia].

    PubMed

    Esteban, Carlos; Presas, Ana; Ara, Jordi; Pérez, Paulina; Martorell, Alberto; Lisbona, Carlos; Lerma, Rosa; Romero, Ramón; Callejas, José María

    2007-04-21

    Our purpose was to evaluate the prevalence of renal artery stenosis in patients with critical limb ischemia and to study any clinical or laboratory indicator that could predict this association. One hundred consecutive patients with critical limb ischemia evaluated by angiogram were included in the study from January to July 2003. Cardiovascular risk factors and renal function were analyzed. One hundred angiographic studies have been analyzed. Thirty nine (39%) of our patients had some type of pathology of the renal artery but the rest, 61 (61%), had normal and healthy renal arteries. In 5 patients, a bilateral renal pathology was found. Severe disease (> 60% stenosis, bilateral or renal occlusion) was present in 15 cases including 6 occlusions. Once we compared the patients with healthy renal arteries with the patients with different degrees of stenosis, we did not appreciate significant differences in hypertension, diabetes, coronary disease or smoking habit, nor with laboratory data such as creatinine, urea, c-reactive protein, total cholesterol or atherogenic index. No differences were found either comparing patients with normal renal artery with patients with bilateral pathology or with unilateral occlusion. There is a high prevalence of renal artery pathology in patients with critical limb ischemia although we have not found any clinical or laboratory factors useful to identify them.

  11. Which is the best revascularization for critical limb ischemia: Endovascular or open surgery?

    PubMed

    Beard, Jonathan D

    2008-12-01

    This review considers the roles of endovascular and open surgery for critical lower limb ischemia. The TransAtlantic Inter-Society Consensus document offers sensible guidelines for the treatment of both suprainguinal and infrainguinal disease. For bilateral/diffuse suprainguinal disease, aortobifemoral bypass remains the best option, but great care should be taken in this new era of hospital-acquired infection. Unilateral iliac occlusions should be treated by primary stenting, but an iliofemoral or femorofemoral bypass may be the best option when the disease extends down into the common femoral artery. Stents may reduce the risk of embolization in iliac stenoses but probably confer no benefit in long-term patency. Iliac stenoses should be treated by angioplasty, with stents reserved for flow-limiting complications. Although infrainguinal bypass surgery is in decline, probably due to better medical treatment and more endovascular intervention, bypass using autologous saphenous vein remains the gold standard. In the absence of leg veins, arm vein should be considered. Prosthetic grafts should be used as a last resort, and only with a venous cuff. The long-term results of the Bypass Versus Angioplasty in Severe Ischemia of the Leg (BASIL) trial favor surgery rather than angioplasty if there is a good vein and the patient is fit. Further randomized studies of infrainguinal stenting vs bypass are required. Some patients with critical lower limb ischemia are best treated by analgesia or primary amputation.

  12. Therapeutic potential for mesenchymal stem cell transplantation in critical limb ischemia

    PubMed Central

    2012-01-01

    The therapeutic potential of mesenchymal stem cell (MSC) transplantation for the treatment of ischemic conditions such as coronary artery disease, peripheral arterial disease, and stroke has been explored in animal models and early-phase clinical trials. A substantial database documents the safety profile of MSC administration to humans in a large number of disease states. The mechanism of the therapeutic effect of MSC transplantation in ischemic disease has been postulated to be due to paracrine, immunomodulatory, and differentiation effects. This review provides an overview of the potential role of MSC-based therapy for critical limb ischemia (CLI), the comparison of MSC cellular therapy with angiogenesis gene therapy in CLI, and the proposed mechanism of action of MSC therapy. Preclinical efficacy data in animal models of hindlimb ischemia, current early-phase human trial data, and considerations for future MSC-based therapy in CLI will also be discussed. PMID:22846185

  13. Autologous bone marrow mononuclear cells transplant in patients with critical leg ischemia: preliminary clinical results.

    PubMed

    Li, Min; Zhou, Hua; Jin, Xing; Wang, Mo; Zhang, Shiyi; Xu, Lei

    2013-10-01

    Stem cell transplant can induce vasculogenesis and improve the blood supply to an ischemic region, offering hope for chronic lower extremity ischemic diseases. Bone marrow mononuclear cells are one of the sources for stem cell transplants. We sought to observe the safety and efficacy of autologous bone marrow mononuclear cells transplant for treating critical limb ischemia. Eligible patients were randomized 1:1 to receive placebo (0.9% NaCl) or 1 × 107 piece/mL bone marrow mononuclear cell transplant. For 6 months, patients' skin ulcers, ankle-brachial index, and rest pain were examined and recorded before and after treatment. Six months after the bone marrow mononuclear cells transplant, clinical symptoms like rest pain and skin ulcers gradually abated (P < .05). Ankle-brachial index also increased after the transplant (P < .01). Autologous bone marrow mononuclear cells transplant for treatment of patients with chronic limb ischemia is safe, effective, and feasible.

  14. Impact of angiogenic therapy in the treatment of critical lower limb ischemia in an animal model.

    PubMed

    Reis, Paulo Eduardo Ocke; de Carvalho, Leonardo Pinto; Yasumura, Eduardo; da Silva, Flavia Helena; Garcia, Bianca Cristina; Beutel, Abram; Sacramento, Chester Bittencourt; Baptista-Silva, José Carlos Costa; de Campos, Ruy Ribeiro; Takiya, Christina Maeda; Borojevic, Radovan; Han, Sang Won

    2014-04-01

    Angiogenic therapies for critical limb ischemia were tested in a mouse model. The mice were anesthetized and their femoral arteries were ligated. The animals were treated with bone marrow mononuclear cells (BMMCs) alone, BMMCs combined with plasmid vector encoding granulocyte macrophage colony-stimulating factor (GM-CSF), received no treatment, or no intervention (controls). The degree of ischemia was monitored for 4 weeks using a visual scale. Muscle atrophy and strength were assessed at 4 weeks postoperatively; the mice were then killed. In treated animals, total necrosis of the limb was not found, the weight of the gastrocnemius and quadriceps muscles was significantly higher, functional ability and tissue regeneration were significantly increased, and muscle impairment and adipocyte presence were significantly reduced compared with untreated animals. At inducing angiogenesis, the BMMCs alone was more effective than BMMCs combined with plasmid vector encoding GM-CSF. Treated animals showed increased angiogenesis compared with ischemic untreated ones.

  15. Near-infrared angiography for critical limb ischemia in a diabetic murine model

    NASA Astrophysics Data System (ADS)

    Garcia, Missael; Zayed, Mohamed A.; Park, Kyoung-mi; Gruev, Viktor

    2017-04-01

    Peripheral arterial disease (PAD) is a highly prevalent disease process that afflicts more than 20% of individuals with diabetes. Progression of PAD in the setting of diabetes can lead to critical limb ischemia (CLI), which is associated with increased risk of wounds, gangrene, and limb loss. Prompt noninvasive evaluation of limbs affected by PAD progression and CLI is currently limited. Here, we evaluate the utility of a custom-designed multispectral imaging system for fluorescence-based near-infrared angiography and compare it to the existing gold standard of laser-scanning Doppler perfusion assessments. Due to its higher resolution and fluorescence sensitivity, near-infrared angiography demonstrates a greater capacity to characterize altered dynamic arterial perfusion in a clinically relevant diabetic murine model for CLI. Furthermore, we demonstrate that our imaging system can accurately track arterial perfusion recovery over time following induced ischemia, and reveal unique phenotypic differences in the setting of diabetes.

  16. Complement activation is critical for placental ischemia-induced hypertension in the rat.

    PubMed

    Lillegard, Kathryn E; Johnson, Alex C; Lojovich, Sarah J; Bauer, Ashley J; Marsh, Henry C; Gilbert, Jeffrey S; Regal, Jean F

    2013-11-01

    Preeclampsia is a major obstetric problem defined by new-onset hypertension and proteinuria associated with compromised placental perfusion. Although activation of the complement system is increased in preeclampsia compared to normal pregnancy, it remains unclear whether excess complement activation is a cause or consequence of placental ischemia. Therefore, we hypothesized that complement activation is critical for placental ischemia-induced hypertension. We employed the reduced utero-placental perfusion pressure (RUPP) model of placental ischemia in the rat to induce hypertension in the third trimester and evaluated the effect of inhibiting complement activation with a soluble recombinant form of an endogenous complement regulator, human complement receptor 1 (sCR1; CDX-1135). On day 14 of a 21-day gestation, rats received either RUPP or Sham surgery and 15 mg/kg/day sCR1 or saline intravenously on days 14-18. Circulating complement component 3 decreased and complement activation product C3a increased in RUPP vs. Sham (p<0.05), indicating complement activation had occurred. Mean arterial pressure (MAP) measured on day 19 increased in RUPP vs. Sham rats (109.8±2.8 mmHg vs. 93.6±1.6 mmHg). Treatment with sCR1 significantly reduced elevated MAP in RUPP rats (98.4±3.6 mmHg, p<0.05) and reduced C3a production. Vascular endothelial growth factor (VEGF) decreased in RUPP compared to Sham rats, and the decrease in VEGF was not affected by sCR1 treatment. Thus, these studies have identified a mechanistic link between complement activation and the pregnancy complication of hypertension apart from free plasma VEGF and have identified complement inhibition as a potential treatment strategy for placental ischemia-induced hypertension in preeclampsia.

  17. A randomized, controlled pilot study of autologous CD34+ cell therapy for critical limb ischemia.

    PubMed

    Losordo, Douglas W; Kibbe, Melina R; Mendelsohn, Farrell; Marston, William; Driver, Vickie R; Sharafuddin, Melhem; Teodorescu, Victoria; Wiechmann, Bret N; Thompson, Charles; Kraiss, Larry; Carman, Teresa; Dohad, Suhail; Huang, Paul; Junge, Candice E; Story, Kenneth; Weistroffer, Tara; Thorne, Tina M; Millay, Meredith; Runyon, John Paul; Schainfeld, Robert

    2012-12-01

    Critical limb ischemia portends a risk of major amputation of 25% to 35% within 1 year of diagnosis. Preclinical studies provide evidence that intramuscular injection of autologous CD34+ cells improves limb perfusion and reduces amputation risk. In this randomized, double-blind, placebo-controlled pilot study, we evaluated the safety and efficacy of intramuscular injections of autologous CD34+ cells in subjects with moderate or high-risk critical limb ischemia, who were poor or noncandidates for surgical or percutaneous revascularization (ACT34-CLI). Twenty-eight critical limb ischemia subjects were randomized and treated: 7 to 1 × 10(5) (low-dose) and 9 to 1 × 10(6) (high-dose) autologous CD34+ cells/kg; and 12 to placebo (control). Intramuscular injections were distributed into 8 sites within the ischemic lower extremity. At 6 months postinjection, 67% of control subjects experienced a major or minor amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.137). This trend continued at 12 months, with 75% of control subjects experiencing any amputation versus 43% of low-dose and 22% of high-dose cell-treated subjects (P=0.058). Amputation incidence was lower in the combined cell-treated groups compared with control group (6 months: P=0.125; 12 months: P=0.054), with the low-dose and high-dose groups individually showing trends toward improved amputation-free survival at 6 months and 12 months. No adverse safety signal was associated with cell administration. This study provides evidence that intramuscular administration of autologous CD34+ cells was safe in this patient population. Favorable trends toward reduced amputation rates in cell-treated versus control subjects were observed. These findings warrant further exploration in later-phase clinical trials. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00616980.

  18. Preclinical evaluation of mesenchymal stem cells overexpressing VEGF to treat critical limb ischemia

    PubMed Central

    Beegle, Julie R; Magner, Nataly Lessa; Kalomoiris, Stefanos; Harding, Aja; Zhou, Ping; Nacey, Catherine; White, Jeannine Logan; Pepper, Karen; Gruenloh, William; Annett, Geralyn; Nolta, Jan A; Fierro, Fernando A

    2016-01-01

    Numerous clinical trials are utilizing mesenchymal stem cells (MSC) to treat critical limb ischemia, primarily for their ability to secrete signals that promote revascularization. These cells have demonstrated clinical safety, but their efficacy has been limited, possibly because these paracrine signals are secreted at subtherapeutic levels. In these studies the combination of cell and gene therapy was evaluated by engineering MSC with a lentivirus to overexpress vascular endothelial growth factor (VEGF). To achieve clinical compliance, the number of viral insertions was limited to 1–2 copies/cell and a constitutive promoter with demonstrated clinical safety was used. MSC/VEGF showed statistically significant increases in blood flow restoration as compared with sham controls, and more consistent improvements as compared with nontransduced MSC. Safety of MSC/VEGF was assessed in terms of genomic stability, rule-out tumorigenicity, and absence of edema or hemangiomas in vivo. In terms of retention, injected MSC/VEGF showed a steady decline over time, with a very small fraction of MSC/VEGF remaining for up to 4.5 months. Additional safety studies completed include absence of replication competent lentivirus, sterility tests, and absence of VSV-G viral envelope coding plasmid. These preclinical studies are directed toward a planned phase 1 clinical trial to treat critical limb ischemia. PMID:27610394

  19. Innovations in the Endovascular Management of Critical Limb Ischemia: Retrograde Tibiopedal Access and Advanced Percutaneous Techniques.

    PubMed

    Mustapha, Jihad A; Diaz-Sandoval, Larry J; Saab, Fadi

    2017-08-01

    Retrograde tibiopedal access and interventions have contributed to advance of endovascular techniques to treat critical limb ischemia (CLI) patients. This review encompasses the spectrum from advanced diagnostic imaging and technical therapeutic approaches for infrapopliteal occlusions, to a discussion of current standards and future directions. Contemporary studies of infrapopliteal angioplasty show suboptimal short-term and 1-year clinical outcomes. Comparative data is needed to shift the focus from PTA to disruptive treatment modalities that can further improve outcomes. Retrograde pedal access has emerged as an important tool to facilitate successfully percutaneous revascularization and limb salvage in patients with CLI. To efficiently approach the complexity of CLI, new thought processes are needed to change the reigning paradigms. Retrograde tibial-pedal access has shown improvement in the rate of successful revascularizations and is an important tool in the amputation-prevention armamentarium. Additional technologies may further improve success rates. Drug-eluting stents have shown better outcomes than PTA in patients with focal infrapopliteal lesions. Registry data have demonstrated the advantage of several atherectomy devices in the tibial arteries. More recently, bioresorbable vascular scaffolds have been used successfully, and further studies with drug-coated balloons are underway. Interventional operators are now even working in the inframalleolar space to reconstitute the plantar arch. Well-conducted studies are needed to generate high-quality evidence in the field of critical limb ischemia management.

  20. Radiofrequency upper thoracic sympathectomy in the treatment of critical upper limb ischemia--a case series.

    PubMed

    Gabrhelik, Tomas; Stehlik, Daniel; Adamus, Milan; Zalesak, Bohumil; Michalek, Pavel

    2013-06-01

    Patients with significant medical and social problems resulting from impaired perfusion of the upper limbs caused by micro- or macro-angiopathy are now frequent in clinical practice. Vasospastic disease of the upper limbs of combined origin is a difficult condition to treat by conservative methods and therapeutic strategies are usually multidisciplinary. In addition to standard pharmacotherapy, treatment may involve regional anaesthesia, thoracoscopic or radiofrequency sympathectomy and surgical treatment of defects, including plastic surgery. This paper describes our successful work in the treatment of upper limb critical ischemia using radiofrequency upper thoracic sympathectomy. In three case reports we present the results of radiofrequency thermolysis applied to treat patients with chronic defects of the hand and fingers. These patients were diagnosed with upper limb critical ischemia of combined origin, standard conservative treatment methods failed and surgical intervention was originally not indicated, however, radiofrequency thermolysis proved to be beneficial. Radiofrequency thoracic sympathectomy could improve peripheral perfusion of the upper limbs and thereby contribute to healing of chronic defects, reduction of pain and improvement in the quality of life of the patients.

  1. Arteriographic findings in diabetic and non-diabetic with critical limb ischemia.

    PubMed

    Santos, Vanessa Prado dos; Alves, Carlos Alberto Silveira; Fidelis, Cícero; Araújo Filho, José Siqueira de

    2013-01-01

    To compare angiographic findings of diabetic and non-diabetic patients with critical limb ischemia. We included 161 patients with infrainguinal critical limb ischemia (CLI). We evaluated the clinical and arteriographic (number and presence of opacification of leg arteries) of the two groups of patients. Statistical analysis was performed using EPI-INFO. Most patients were category 5 of Rutherford's Classification and had femoropopliteal disease. Seventy-two percent of non-diabetic and 67% of diabetic had opacification of the fibular artery (p = 0.25), this is the most present artery in both groups. Diabetic patients had less opacification of the posterior tibial artery in the univariate analysis (29% vs. 47%, p = 0.008). But only female sex showed a significant risk for the absence of the posterior tibial artery in logistic regression (OR = 2.6; p = 0.01). The peroneal artery was the most frequently artery in angiograms of diabetic and non-diabetic patients with CLI. Diabetic and non-diabetic patients did not differ in angiographic findings of the leg. Copyright © 2012 Elsevier Editora Ltda. All rights reserved.

  2. Spinal Cord Stimulation Therapy for the Treatment of Concomitant Phantom Limb Pain and Critical Limb Ischemia.

    PubMed

    De Caridi, Giovanni; Massara, Mafalda; Serra, Raffaele; Risitano, Claudia; Giardina, Massimiliano; Acri, Ignazio Eduardo; Volpe, Pietro; David, Antonio

    2016-04-01

    Phantom limb pain (PLP) is a chronic condition experienced by about 80% of patients who have undergone amputation. In most patients, both the frequency and the intensity of pain attacks diminish with time, but severe pain persists in about 5-10%. Probably, factors in both the peripheral and central nervous system play a role in the occurrence and persistence of pain in the amputated lower limb. The classical treatment of PLP can be divided into pharmacologic, surgical, anesthetic, and psychological modalities. Spinal cord stimulation (SCS) does not represent a new method of treatment for this condition. However, the concomitant treatment of PLP and critical lower limb ischemia by using SCS therapy has not yet been described in the current literature. The aim of the present article is to highlight the possibility of apply SCS for the simultaneous treatment of PLP and critical lower limb ischemia on the contralateral lower limb after failure of medical therapy in a group of 3 patients, obtaining pain relief in both lower limbs, delaying an endovascular or surgical revascularization. After SCS implantation and test stimulation, the pain was reduced by 50% on both the right and the left side in all our patients. The main indications for permanent SCS therapy after 1 week of test stimulation were represented by transcutaneous oxygen (TcPO2) increase >75%, decrease of opioids analgesics use of at least 50% and a pain maintained to within 20-30/100 mm on visual analog scale.

  3. 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

  4. Treatment with Sildenafil and Donepezil Improves Angiogenesis in Experimentally Induced Critical Limb Ischemia

    PubMed Central

    Constantinescu, Ioana M.; Bolfa, Pompei; Mironiuc, Aurel I.

    2017-01-01

    Objectives. In this study, we aimed to demonstrate the role of sildenafil (an antagonist of phosphodiesterase type 5 (PDE-5)) and donepezil (a specific and reversible inhibitor of acetylcholinesterase (Ach)) in increasing ischemia-induced angiogenesis. Method. Critical limb ischemia was induced by ligation of the common femoral artery followed by ligation of the common iliac artery. The operated animals were divided into 3 groups: receiving sildenafil, receiving donepezil, and surgery alone; the contralateral lower limb was used as a negative control. The results were controlled based on clinical score and Doppler ultrasound. Gastrocnemius muscle samples were taken from all animals, both from the ischemic and nonischemic limb and were used for histopathological and immunohistochemical examination for the evaluation of the number of nuclei/field, endothelial cells (CD31), dividing cells (Ki-67), and vascular endothelial growth factor (VEGFR-3). Results. An increasing tendency of the number of nuclei/field with time was observed both in the case of sildenafil and donepezil treatment. The formation of new capillaries (the angiogenesis process) was more strongly influenced by donepezil treatment compared to sildenafil or no treatment. This treatment significantly influenced the capillary/fiber ratio, which was increased compared to untreated ligated animals. Sildenafil treatment led to a gradual increase in the number of dividing cells, which was significantly compared to the negative control group and compared to the ligation control group. The same effect (increase in the number of Ki-67 positive cells) was more obvious in the case of donepezil treatment. Conclusion. Donepezil treatment has a better effect in ligation-induced ischemia compared to sildenafil, promoting angiogenesis in the first place, and also arteriogenesis. PMID:28243607

  5. Percutaneous transluminal angioplasty improves glucose control and quality of life in patients with critical limb ischemia.

    PubMed

    Tolva, V S; Casana, R; Lonati, L; Invitti, C; Bertoni, G B; Bianchi, P G; Cireni, L V; Parati, G

    2012-12-01

    To evaluate the benefit of endovascular peripheral revascularization on glucose control in patients with chronic limb ischemia. Over a 12 month period, 61 patients (41 male, range 49-88 years of age) presenting with critical limb ischemia (CLI) were treated according to the Trans Atlantic Inter Society Consensus (TASC II) guidelines. After discharge, all patients were asked to measure their glucose level three times daily, and glycated hemoglobin was checked monthly up to 12 months, as well as to fill a questionnaire to assess their Quality of Life (QoL). The revascularization procedure was successful in 90% of cases. Glycemic control and glycated hemoglobin in 22 diabetic patients subgroup were significantly improved after the treatment and remained stable over the follow-up period. There was a significant improvement in QoL that increased steadily from the operation and to reach a plateau after six months. Peripheral percutaneous angioplasty in subjects with CLI significantly improves glycemic control and ameliorates QoL. Revascularization positively effects also long-term diabetes control as well as QoL.

  6. Adenoviral transfer of HIF-1α enhances vascular responses to critical limb ischemia in diabetic mice

    PubMed Central

    Sarkar, Kakali; Fox-Talbot, Karen; Steenbergen, Charles; Bosch-Marcé, Marta; Semenza, Gregg L.

    2009-01-01

    Diabetes is a major risk factor for ischemic disease. Treatment options for diabetic patients with peripheral arterial disease when revascularization is not possible are limited, resulting in a high incidence of limb amputation. We evaluated the therapeutic potential of AdCA5, an adenovirus encoding a constitutively active form of HIF-1α, in a diabetic model of critical limb ischemia. Diabetic db/db and nondiabetic db/+ mice were subjected to unilateral femoral artery ligation. Limb perfusion, tissue viability, and motor function were more severely impaired in db/db mice. Intramuscular injection of AdCA5 into the ischemic limb of db/db mice increased the recovery of limb perfusion and function, reduced tissue necrosis, rescued the diabetes-associated impairment of circulating angiogenic cells, enhanced endothelial nitric oxide synthase activation, and increased vessel density and luminal area in the ischemic limb. PMID:19841279

  7. Subintimal arterial flossing with antegrade-retrograde intervention (SAFARI) and rertograde access for critical limb ischemia.

    PubMed

    Hendricks, Nicholas J; Sabri, Saher S

    2014-09-01

    Retrograde access techniques involve the addition of a retrograde access into the distal target vessel to aid in recanalization of chronic total occlusions. Many patients with critical limb ischemia are also poor surgical candidates because of comorbidities or lack of suitable landing zone for bypass procedures. This approach may be helpful in the setting of chronic occlusions that cannot be crossed via conventional antegrade true-lumen approaches. Subintimal arterial flossing with antegrade-retrograde intervention technique can be used when the occlusion was crossed in the subintimal plane and antegrade re-entry techniques failed. It may also be useful for flush superficial femoral artery occlusions or those lesions that extend into the trifurcation vessels. Proficiency in these techniques allows limb salvage in patients who lack surgical options and would otherwise undergo amputation.

  8. Defining risks and predicting adverse events after lower extremity bypass for critical limb ischemia

    PubMed Central

    Siracuse, Jeffrey J; Huang, Zhen S; Gill, Heather L; Parrack, Inkyong; Schneider, Darren B; Connolly, Peter H; Meltzer, Andrew J

    2014-01-01

    Successful treatment of patients with critical limb ischemia (CLI), hinges on the adequacy of revascularization. However, CLI is associated with a severe burden of systemic atherosclerosis, and patients often suffer from multiple cardiovascular comorbidities. Therefore, CLI patients in general represent a cohort at increased risk for procedural complications and adverse events. Although endovascular therapy represents a minimally invasive alternative to open surgical bypass, the durability of surgical reconstruction is superior, and it remains the “gold standard” approach to revascularization in CLI. Therefore, selection of the optimal treatment modality for individual patients requires careful consideration of the procedural risks and likelihood of adverse events associated with surgery. Individualized decision-making with regard to revascularization strategy requires a comprehensive understanding of the likelihood of adverse outcomes after major surgery. Here we review the risks of surgical bypass in patients with CLI, with particular emphasis on the identification of preoperative variables that predict poor outcome. PMID:25018636

  9. Augmentation of arterial blood velocity with electrostimulation in patients with critical limb ischemia unsuitable for revascularization.

    PubMed

    Yilmaz, Seyhan; Mermi, Esra U; Zobaci, Ethem; Aksoy, Eray; Yastı, Çınar

    2017-04-01

    Aim This pilot study aimed to reveal whether combination of electrostimulation with iloprost treatment achieves better results compared to iloprost alone in patients with critical limb ischemia. Material and methods Patients were randomized into Group 1 ( n = 11, mean age: 65.3 ± 4.2 years, received iloprost infusion protocol alone) or Group 2 ( n = 11, mean age: 62.9 ± 6.7, received iloprost infusion plus standardized protocol of peroneal nerve electrostimulation). Electrostimulation was delivered with 1 Hz frequency, 27 mA current, and 200 ms pulse width. Peak blood flow velocities in the anterior and posterior tibialis arteries were measured with duplex ultrasound. Results There was a slight insignificant increase in blood velocity in anterior tibialis artery in Group 1 (from 17.6 ± 13.0 to 18.6 ± 13.1, p = 0.57), whereas the increase in Group 2 was marked (from 23.8 ± 18.3 to 32.2 ± 19.7, p = 0.01). Blood velocity in posterior tibialis artery also increased in both groups, but it was not of statistical significance. No significant difference was found between two groups in regard to final pulse oximetry oxygen saturation levels. Conclusion Electrostimulation of the peroneal nerve caused a substantial increase in anterior tibialis artery blood velocity when used as an adjunct to medical therapy in patients with critical limb ischemia.

  10. Use of the directional atherectomy for the treatment of femoro-popliteal lesions in patients with critical lower limb ischemia

    PubMed Central

    Bracale, Umberto Marcello; Vitale, Gaetano; Bajardi, Guido; Narese, Donatella; Dinoto, Ettore; Giribono, Anna Maria; Ferrara, Doriana; del Guercio, Luca; Midiri, Massimo; Pecoraro, Felice

    2016-01-01

    Femoro-popliteal PTA for the treatment of critical limb ischemia is frequently associated with unsatisfactory procedural success rates while directional atherectomy (DCA) has improved success rate since claudicant patients undergoing percutaneous treatment of femoro-popliteal obstructive disease. The aim of this prospective study is to evaluate the safety, efficacy and procedural success of DCA, at one year, in the percutaneous treatment of femoro-popliteal obstructive disease in patients with critical limb ischemia. Methods From March 2012 to March 2013 18 consecutive patients with critical limb ischemia were treated with DCA (Turbohawk/Covidien-ev3 Endovascular Inc., North Plymouth, Minnesota, USA) for the treatment of femoro-popliteal obstructive disease. Patients were evaluated at 12 months. Results Technical and procedural success was achieved in every patient. No in-hospital major adverse cardiovascular events occurred. Primary endpoint: freedom from any amputation was obtained in all patients. Secondary endpoints: clinical (Rutherford class improvement) and hemodynamic success (Ankle-brachial index improvement) was achieved in all patients. Conclusion The use of DCA for the treatment of femoro-popliteal obstructive disease is a safe and effective therapeutic strategy for patients with critical limb ischemia. The data included in our study should be considered hypothesis-generating in order to design of a randomized trial comparison with conventional PTA. PMID:27896226

  11. Critical finger ischemia and myocardial fibrosis development after sudden interruption of sildenafil treatment in a systemic sclerosis patient.

    PubMed

    Bruni, C; Bellando-Randone, S; Gargani, L; Picano, E; Pingitore, A; Matucci-Cerinic, M; Guiducci, S

    2016-09-09

    Systemic sclerosis (SSc) is a connective tissue disease frequently associated with Raynaud's Phenomenon (RP). Among possible pharmacological treatments, phosphodiesterase 5 inhibitors are considered in cases of severe non -responsive RP. We present the case of a male SSc patient wh presented with critical finger ischemia and concomitant appearance of myocardial fibrosis after sudden interruption of sildenafil treatment.

  12. Successful carbon dioxide angiography guided endovascular thrombectomy of the superficial femoral artery in a young patient with critical limb ischemia.

    PubMed

    Giusca, Sorin; Eisele, Tom; Raupp, Dorothea; Eisenbach, Christoph; Korosoglou, Grigorios

    2017-03-01

    Currently, the treatment of thromboembolic ischemia of the lower extremities includes percutaneous rotational thrombectomy and aspiration devices. However, the standard approach for endovascular treatment requires the administration of iodine contrast agents, which is problematic in patients with pre-existing renal disease and diabetes. Herein, we describe a case of a CO2 angiography guided endovascular thrombectomy of the superficial femoral artery (SFA) in a young patient with critical limb ischemia. Mechanical thrombectomy using the Rotarex system, catheter aided aspiration and subsequent stent placement in the SFA was entirely guided using CO2 angiography.

  13. Spinal cord stimulation in hemodialysis patients with critical lower-limb ischemia.

    PubMed

    Brümmer, Uwe; Condini, Viviana; Cappelli, Paolo; Di Liberato, Lorenzo; Scesi, Michele; Bonomini, Mario; Costantini, Amedeo

    2006-05-01

    Spinal cord stimulation (SCS) has been proposed for the treatment of ischemic pain and the prevention or delay of amputation in patients with peripheral arterial occlusive disease (PAOD) who are unsuitable for vascular reconstruction. PAOD is common in patients with end-stage renal disease and is associated with substantial morbidity and mortality. Furthermore, many patients are not candidates for limb-sparing procedures and have to undergo primary amputation. We report our experience with SCS in 8 hemodialysis patients with chronic lower-limb ischemia and not suitable for either primary surgical or angioplastic intervention or reintervention. Intensity of ischemic pain, quality of life, use of analgesic medications, limb survival, and outcome of skin ischemic lesions were evaluated before implantation of an SCS device and after 6 and 12 months of follow-up. No complications from SCS device implantation occurred. Both intensity of pain and quality of life significantly improved during follow-up. SCS allowed a decrease in pain medication intake in all patients. Limb survival at 1 year was 75%. Ischemic skin lesions before implantation of an SCS device did not ameliorate during the follow-up period, but the appearance of new lesions was not observed. Implantation of an SCS device in patients with end-stage renal disease with critical limb ischemia dramatically improves quality of life and pain relief. In patients assessed at Leriche-Fontaine stage 2 or 3, the treatment might delay the appearance of ischemic skin lesions and amputation. At these stages, presumed long-term benefits could justify the cost of SCS.

  14. Gastrointestinal ischemia monitoring through impedance spectroscopy as a tool for the management of the critically ill

    PubMed Central

    Sacristan, Emilio

    2015-01-01

    Impedance spectroscopy (IS) has been proposed as a tool for monitoring mucosal tissue ischemia and damage in the gut of critically ill patients resulting from shock and hypoperfusion. A specific device and system have been developed and tested for this specific application over the past 12 years by our research group. This paper reviews previously published studies as well as unpublished experimental results, and puts the whole in context and perspective to help understand this technology. Results presented include summaries of gastric reactance measurement understanding, in vivo measurements in animal models, clinical significance of the measurement, and future perspectives of clinical use of this technology. All of the experimental work done to date has been designed to determine the evolving device prototypes’ performance and limitations from an instrumentation point of view. Although there are still questions to be answered with regard to the IS measurement, we conclude that we have reached enough confidence in the measurement and the device’s performance and safety to begin clinically oriented research to learn how this technology may be useful in the diagnosis and management of different populations of the critically ill. PMID:25711880

  15. Randomized Prospective Controlled Trial of Recombinant Granulocyte Colony-Stimulating Factor as Adjunctive Therapy for Limb-Threatening Diabetic Foot Infection

    PubMed Central

    de Lalla, Fausto; Pellizzer, Giampietro; Strazzabosco, Marco; Martini, Zeno; Du Jardin, Giovanni; Lora, Luciano; Fabris, Paolo; Benedetti, Paolo; Erle, Giuseppe

    2001-01-01

    Adult diabetic patients admitted to our Diabetes Center from September 1996 to January 1998 for severe, limb-threatening foot infection were consecutively enrolled in a prospective, randomized, controlled clinical study aimed at assessing the safety and efficacy of recombinant human granulocyte colony-stimulating factor (G-CSF) (lenograstim) as an adjunctive therapy for the standard treatment of diabetic foot infection. Forty patients, all of whom displayed evidence of osteomyelitis and long-standing ulcer infection, were randomized 1:1 to receive either conventional treatment (i.e., antimicrobial therapy plus local treatment) or conventional therapy plus 263 μg of G-CSF subcutaneously daily for 21 days. The empiric antibiotic treatment (a combination of ciprofloxacin plus clindamycin) was further adjusted, when necessary, according to the results of cultures and sensitivity testing. Microbiologic assessment of foot ulcers was performed by both deep-tissue biopsy and swab cultures, performed at enrollment and on days 7 and 21 thereafter. Patients were monitored for 6 months; the major endpoints (i.e., cure, improvement, failure, and amputation) were blindly assessed at weeks 3 and 9. At enrollment, both patient groups were comparable in terms of both demographic and clinical data. None of the G-CSF-treated patients experienced either local or systemic adverse effects. At the 3- and 9-week assessments, no significant differences between the two groups could be observed concerning the number of patients either cured or improved, the number of patients displaying therapeutic failure, or the species and number of microorganisms previously yielded from cultures at day 7 and day 21. Conversely, among this small series of patients the cumulative number of amputations observed after 9 weeks of treatment appeared to be lower in the G-CSF arm; in fact, only three patients (15%) in this group had required amputation, whereas nine patients (45%) in the other group had

  16. Ischemia/Reperfusion Injury following Acute Myocardial Infarction: A Critical Issue for Clinicians and Forensic Pathologists

    PubMed Central

    Neri, Margherita; Pascale, Natascha; Pomara, Cristoforo

    2017-01-01

    Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality. Reperfusion strategies are the current standard therapy for AMI. However, they may result in paradoxical cardiomyocyte dysfunction, known as ischemic reperfusion injury (IRI). Different forms of IRI are recognized, of which only the first two are reversible: reperfusion-induced arrhythmias, myocardial stunning, microvascular obstruction, and lethal myocardial reperfusion injury. Sudden death is the most common pattern for ischemia-induced lethal ventricular arrhythmias during AMI. The exact mechanisms of IRI are not fully known. Molecular, cellular, and tissue alterations such as cell death, inflammation, neurohumoral activation, and oxidative stress are considered to be of paramount importance in IRI. However, comprehension of the exact pathophysiological mechanisms remains a challenge for clinicians. Furthermore, myocardial IRI is a critical issue also for forensic pathologists since sudden death may occur despite timely reperfusion following AMI, that is one of the most frequently litigated areas of cardiology practice. In this paper we explore the literature regarding the pathophysiology of myocardial IRI, focusing on the possible role of the calpain system, oxidative-nitrosative stress, and matrix metalloproteinases and aiming to foster knowledge of IRI pathophysiology also in terms of medicolegal understanding of sudden deaths following AMI. PMID:28286377

  17. Wound healing and wound location in critical limb ischemia following endovascular treatment.

    PubMed

    Kobayashi, Norihiro; Hirano, Keisuke; Nakano, Masatsugu; Muramatsu, Toshiya; Tsukahara, Reiko; Ito, Yoshiaki; Ishimori, Hiroshi

    2014-01-01

    The differences in wound healing according to wound location remain unclear. Between April 2007 and October 2011, 138 patients (166 limbs) with critical limb ischemia with tissue loss were treated with endovascular treatment. On these limbs, 177 individual wounds were identified on the foot and were evaluated for wound healing rates and time to healing according to their locations. Wound locations were divided into 3 groups: group T (Toe wounds, n=112), group H (Heel wounds, n=25), and group E (Extensive wounds extending onto the fore- or mid-foot along with dorsum or plantar surfaces, n=40). The mean follow-up period was 23±19 months. At 3, 6, 9, and 12 months, wound healing rates were 51%, 64%, 75%, and 75%, respectively, in group T; 12%, 36%, 36%, and 52%, respectively, in group H; and 0%, 5%, 8%, and 13%, respectively, in group E. The median time to healing was 64 days (interquartile range 25-156 days) in group T, 168 days (interquartile range 123-316 days) in group H, and 267 days (interquartile range 177-316 days) in group E (P=0.038). Extensive wounds extending onto the fore- or mid-foot along with dorsum or plantar surfaces were the most difficult type of wound to heal.

  18. Perfusion Angiography of the Foot in Patients with Critical Limb Ischemia: Description of the Technique

    SciTech Connect

    Jens, Sjoerd Marquering, Henk A.; Koelemay, Mark J. W.; Reekers, Jim A.

    2015-02-15

    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 interstitial 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.

  19. Nonrevascularization-based treatments in patients with severe or critical limb ischemia.

    PubMed

    Abu Dabrh, Abd Moain; Steffen, Mark W; Asi, Noor; Undavalli, Chaitanya; Wang, Zhen; Elamin, Mohamed B; Conte, Michael S; Murad, Mohammad Hassan

    2015-11-01

    The aim of this systematic review was to synthesize the existing evidence about various nonrevascularization-based therapies used to treat patients with severe or critical limb ischemia (CLI) who are not candidates for surgical revascularization. We systematically searched multiple databases through November 2014 for controlled randomized and nonrandomized studies comparing the effect of medical therapies (prostaglandin E1 and angiogenic growth factors) and devices (pumps and spinal cord stimulators). We report odds ratios (ORs) and 95% confidence intervals (CIs) of the outcomes of interest pooling data across studies using the random effects model. We included 19 studies that enrolled 2779 patients. None of the nonrevascularization-based treatments were associated with a significant effect on mortality. Intermittent pneumatic compression (OR, 0.14; 95% CI, 0.04-0.55) and spinal cord stimulators (OR, 0.53; 95% CI, 0.36-0.79) were associated with reduced risk of amputation. A priori established subgroup analyses (combined vs single therapy; randomized vs nonrandomized) were not statistically significant. Very low-quality evidence, mainly due to imprecision and increased risk of bias, suggests that intermittent pneumatic compression and spinal cord stimulators may reduce the risk of amputations. Evidence supporting other medical therapies is insufficient. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

  20. Always Contact a Vascular Interventional Specialist Before Amputating a Patient with Critical Limb Ischemia

    SciTech Connect

    Met, Rosemarie; Koelemay, Mark J. W.; Bipat, Shandra; Legemate, Dink A.; Lienden, Krijn P. van; Reekers, Jim A.

    2010-06-15

    Patients with severe critical limb ischemia (CLI) due to long tibial artery occlusions are often poor candidates for surgical revascularization and frequently end up with a lower limb amputation. Subintimal angioplasty (SA) offers a minimally invasive alternative for limb salvage in this severely compromised patient population. The objective of this study was to evaluate the results of SA in patients with CLI caused by long tibial occlusions who have no surgical options for revascularization and are facing amputation. We retrospectively reviewed all consecutive patients with CLI due to long tibial occlusions who were scheduled for amputation because they had no surgical options for revascularization and who were treated by SA. A total of 26 procedures in 25 patients (14 males; mean age, 70 {+-} 15 [SD] years) were evaluated. Technical success rate was 88% (23/26). There were four complications, which were treated conservatively. Finally, in 10 of 26 limbs, no amputation was needed. A major amputation was needed in 10 limbs (7 below-knee amputations and 3 above-knee amputations). Half of the major amputations took place within 3 months after the procedure. Cumulative freedom of major amputation after 12 months was 59% (SE = 11%). In six limbs, amputation was limited to a minor amputation. Seven patients (28%) died during follow-up. In conclusion, SA of the tibial arteries seem to be a valuable treatment option to prevent major amputation in patients with CLI who are facing amputation due to lack of surgical options.

  1. Siglec-5 is a novel marker of critical limb ischemia in patients with diabetes.

    PubMed

    Li, Ju-Yi; Yang, Xiao-Yan; Wang, Xiu-Fang; Jia, Xiong; Wang, Zhong-Jing; Deng, Ai-Ping; Bai, Xiang-Li; Zhu, Lin; Li, Bing-Hui; Feng, Zi-Bo; Li, Ye; Wang, Ling; Jin, Si

    2017-09-12

    Critical Limb Ischemia (CLI) is common but uncommonly diagnosed. Improved recognition and early diagnostic markers for CLI are needed. Therefore, the aim of our study was to identify plasma biomarkers of CLI in patients with type 2 diabetes mellitus (T2DM). In this study, antibody-coated glass slide arrays were used to determine the plasma levels of 274 human cytokines in four matched cases of diabetes with and without CLI. Potential biomarkers were confirmed in an independent cohort by ELISA. After adjusting for confounding risk factors, only plasma level of Siglec-5 remained significantly associated with an increased odds ratio (OR) for diabetes with CLI by binary logistic regression analysis. Receiver operating characteristic (ROC) curve analysis revealed the optimal cut-off points for Siglec-5 was 153.1 ng/ml. After entering Siglec-5, the AUC was 0.99, which was higher than that of confounding risk factors only (AUC = 0.97, P < 0.05). Siglec-5 was expressed in plaques, but not in healthy artery wall in T2DM patients. Elevated plasma Siglec-5 was independently associated with CLI in T2DM. Plasma Siglec-5 levels are implicated as an early diagnostic marker of CLI in T2DM patients and it may become a target for the prevention or treatment of CLI in diabetes.

  2. Functional Imaging of the Foot with Perfusion Angiography in Critical Limb Ischemia

    SciTech Connect

    Reekers, Jim A.; Koelemay, Mark J. W.; Marquering, Henk A. Bavel, Ed T. van

    2016-02-15

    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 of 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.

  3. Characteristics of responders to autologous bone marrow cell therapy for no-option critical limb ischemia.

    PubMed

    Madaric, Juraj; Klepanec, Andrej; Valachovicova, Martina; Mistrik, Martin; Bucova, Maria; Olejarova, Ingrid; Necpal, Roman; Madaricova, Terezia; Paulis, Ludovit; Vulev, Ivan

    2016-08-17

    The present study investigated factors associated with therapeutic benefits after autologous bone marrow cell (BMC) therapy in patients with "no-option" critical limb ischemia (CLI). Sixty-two patients with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were randomized to treatment with 40 ml of autologous BMCs (SmartPreP2) by local intramuscular (n = 32) or intra-arterial (n = 30) application. The primary endpoint was limb salvage and wound healing at 12 months. Seven patients (11 %) died during the follow-up from reasons unrelated to stem cell therapy. The BMC product of patients with limb salvage and wound healing (33/55) was characterized by a higher CD34(+) cell count (p = 0.001), as well as a higher number of total bone marrow mononuclear cells (BM-MNCs) (p = 0.032), than that of nonresponders (22/55). Patients with limb salvage and wound healing were younger (p = 0.028), had lower C-reactive protein levels (p = 0.038), and had higher transcutaneous oxygen pressure (tcpO2) (p = 0.003) before cell application than nonresponders. All patients with major tissue loss at baseline (Rutherford 6 stage of CLI, n = 5) showed progression of limb ischemia and required major limb amputation. In the multiple binary logistic regression model, the number of applied CD34(+) cells (p = 0.046) and baseline tcpO2 (p = 0.031) were independent predictors of limb salvage and wound healing. The number of administrated BM-MNCs strongly correlated with decreased peripheral leukocyte count after 6 months in surviving patients with limb salvage (p = 0.0008). Patients who benefited from autologous BMC therapy for "no-option" CLI were treated with high doses of CD34(+) cells. The absolute number of applied BM-MNCs correlated with the improvement of inflammation. We hypothesize that the therapeutic benefit of cell therapy for peripheral artery disease is the result of synergistic effects mediated by a mixture of

  4. Therapeutic Potential of Adipose-Derived Therapeutic Factor Concentrate for Treating Critical Limb Ischemia.

    PubMed

    Procházka, Václav; Jurčíková, Jana; Laššák, Ondrej; Vítková, Kateřina; Pavliska, Lubomír; Porubová, Ludmila; Buszman, Piotr P; Krauze, Agata; Fernandez, Carlos; Jalůvka, František; Špačková, Iveta; Lochman, Ivo; Jana, Dvořáčková; Merfeld-Clauss, Stephanie; March, Keith L; Traktuev, Dmitry O; Johnstone, Brian H

    2016-01-01

    Transplantation of adipose-derived stem cells (ADSCs) is an emerging therapeutic option for addressing intractable diseases such as critical limb ischemia (CLI). Evidence suggests that therapeutic effects of ADSCs are primarily mediated through paracrine mechanisms rather than transdifferentiation. These secreted factors can be captured in conditioned medium (CM) and concentrated to prepare a therapeutic factor concentrate (TFC) composed of a cocktail of beneficial growth factors and cytokines that individually and in combination demonstrate disease-modifying effects. The ability of a TFC to promote reperfusion in a rabbit model of CLI was evaluated. A total of 27 adult female rabbits underwent surgery to induce ischemia in the left hindlimb. An additional five rabbits served as sham controls. One week after surgery, the ischemic limbs received intramuscular injections of either (1) placebo (control medium), (2) a low dose of TFC, or (3) a high dose of TFC. Limb perfusion was serially assessed with a Doppler probe. Blood samples were analyzed for growth factors and cytokines. Tissue was harvested postmortem on day 35 and assessed for capillary density by immunohistochemistry. At 1 month after treatment, tissue perfusion in ischemic limbs treated with a high dose of TFC was almost double (p < 0.05) that of the placebo group [58.8 ± 23 relative perfusion units (RPU) vs. 30.7 ± 13.6 RPU; mean ± SD]. This effect was correlated with greater capillary density in the affected tissues and with transiently higher serum levels of the angiogenic and prosurvival factors vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conclusions from this study are that a single bolus administration of TFC demonstrated robust effects for promoting tissue reperfusion in a rabbit model of CLI and that a possible mechanism of revascularization was promotion of angiogenesis by TFC. Results of this study demonstrate that TFC represents a potent

  5. A new murine model of sustainable and durable chronic critical limb ischemia fairly mimicking human pathology.

    PubMed

    Lejay, A; Choquet, P; Thaveau, F; Singh, F; Schlagowski, A; Charles, A-L; Laverny, G; Metzger, D; Zoll, J; Chakfe, N; Geny, B

    2015-02-01

    To establish a chronic mouse model of critical limb ischemia (CLI) with in vivo and ex vivo validation, closely mimicking human pathology. Swiss mice (n = 28) were submitted to sequential unilateral femoral (day 0) and iliac (day 4) ligatures. Ischemia was confirmed by clinical scores (tissue and functional damages) and methoxyisobutylisonitrile (MIBI) scintigraphies at days 0, 4, 6, 10, 20, and 30. At days 10, 20, and 30, muscle mitochondrial respiration, calcium retention capacity (CRC), and production of reactive oxygen species (ROS) were investigated, together with transcripts of mitochondrial biogenesis and antioxidant enzymes. Histological analysis was also performed. Clinical and functional damage confirmed CLI. MIBI scintigraphies showed hypoperfusion of the ischemic limb, which remained stable until day 30. Mitochondrial respiration was impaired in ischemic muscles compared with controls (Vmax = 7.93 ± 0.99 vs. 10.09 ± 2.87 mmol/L O2/minute/mg dry weight [dw]; p = .01), together with impaired CRC (7.4 ± 1.6 mmol/L minute/mg dw vs. 11.9 ± 0.9 mmol/L minute/mg dw; p < .001) and biogenesis (41% decrease in peroxisome proliferator-activated receptor gamma coactivator [PGC]-1α, 49% decrease in PGC-1β, and 41% decrease in nuclear respiratory factor-1). Ischemic muscles also demonstrated increased production of ROS under electron paramagnetic resonance (0.084 ± 0.029 vs. 0.051 ± 0.031 mmol/L minute/mg dw; p = .03) and with dihydroethidium staining (3622 ± 604 arbitrary units of fluorescence vs. 1224 ± 324; p < .01), decreased antioxidant enzymes (32% decrease in superoxide dismutase [SOD]1, 41% decrease in SOD2, and 49% decrease in catalase), and myopathic features (wider range in fiber size, rounded shape, centrally located nuclei, and smaller cross-sectional areas). All defects were stable over time. Sequential femoral and iliac ligatures closely mimic human functional, clinical, scintigraphic, and skeletal muscle

  6. Endovascular management of acute limb ischemia.

    PubMed

    Peeters, P; Verbist, J; Keirse, K; Deloose, K; Bosiers, M

    2010-06-01

    Acute limb ischemia (ALI) refers to a rapid worsening of limb perfusion resulting in rest pain, ischemic ulcers or gangrene. With an estimated incidence of 140 million/year, ALI is serious limb-threatening and life-threatening medical emergency demanding prompt action. Three prospective, randomized clinical trials provide data on trombolytic therapy versus surgical intervention in patients with acute lower extremity ischemia. Although they did not give us the final answer, satisfactory results are reported for percutaneous thrombolysis compared with surgery. Moreover, they suggest an important advantage of thrombolysis in acute bypass graft occlusions. Therefore, we believe thrombolytic therapy should be a part of the vascular surgeon's armamentarium to safely and successfully treat ALI patients.

  7. Effects of electrical stimulation therapy on the blood flow in chronic critical limb ischemia patients following regenerative therapy

    PubMed Central

    Yamabata, Shiho; Shiraishi, Hirokazu; Munechika, Mai; Fukushima, Hideki; Fukuoka, Yoshiyuki; Hojo, Tatsuya; Shirayama, Takeshi; Horii, Motoyuki; Matoba, Satoaki; Kubo, Toshikazu

    2016-01-01

    Objectives: We investigated the effects of electrical stimulation therapy on cutaneous and muscle blood flow in critical limb ischemia patients following regenerative therapy. Methods: Three groups were studied: 10 healthy young subjects, 10 elderly subjects, and 7 critical limb ischemia patients after regenerative therapy. After 5 min rest, electrical stimulation was applied at 5 Hz on the tibialis anterior muscle for 10 min. We estimated the relative changes in oxyhemoglobin and total hemoglobin compared to the basal values at rest (Δ[HbO2], Δ[Hbtot]), which reflected the blood flow in the skin and muscle layer, and we simultaneously measured the tissue O2 saturation (StO2) throughout the electrical stimulation and recovery phase by near-infrared spectroscopy. Results: The Δ[HbO2] and Δ[Hbtot] values of the muscle layer in critical limb ischemia patients increased gradually and remained significantly higher at the 5-min and 10-min recovery periods after the electrical stimulation without reducing the StO2, but there is no significant change in the other two groups. Skin blood flow was not influenced by electrical stimulation in three groups. Conclusion: This improvement of the peripheral circulation by electrical stimulation would be beneficial as the adjunctive therapy after regenerative cell therapy. PMID:27504185

  8. Radiological anatomy of upper limb arteries and their anatomical variability: implications for endovascular treatment in critical hand ischemia.

    PubMed

    Mauri, Giovanni; Fresa, Marco; Ferraris, Matteo; Acuña-Valerio, Jorge; Hamade, Meneme; DI Luca, Gabriele; Danzi, Gian B; Ferraresi, Roberto

    2016-12-01

    Critical hand ischemia (CHI) is a quite uncommon but highly disabling condition, generally caused by chronic occlusive arterial disease. For a correct approach to the endovascular treatment of these patients, good knowledge of the normal vascular anatomy and of the most frequently encountered vascular anatomical variations is of paramount importance. In the present paper a description of the normal vascular anatomy of the upper limb and of the most commonly encountered anatomical variations is provided, focusing on the implications for endovascular treatment of patients with CHI. Moreover, data of 151 patients with 172 critically ischemic hands treated at our institution between 2004 and 2016 are presented.

  9. 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.

  10. Balloon angioplasty in tibioperoneal interventions for patients with critical limb ischemia.

    PubMed

    Mustapha, J A; Diaz-Sandoval, Larry J

    2014-09-01

    Tibial arterial disease represents the final frontier in the battle against critical limb ischemia (CLI). Isolated infrapopliteal (IP) disease is mainly seen in the elderly (>80 years old), diabetic, and dialysis-dependent patients with CLI. With the development and evolution of catheter-based technology, endovascular therapy (mainly balloon angioplasty) has become the method of choice for revascularization in these patients. The most common challenges are the severely calcified lesion recalcitrant to dilation (as calcium is heterogeneously distributed in the arterial wall) and the long tibial chronic total occlusions. Percutaneous transluminal angioplasty achieves a technically successful result (<30% residual stenosis) in most cases, but it is limited by high restenosis rates. Although several devices have been used in the IP arena (including orbital and directional atherectomy, laser atherectomy, "contact" atherectomy [CROSSER, Bard], and re-entry devices), percutaneous transluminal angioplasty with plain old balloons has been the subject of most studies with several modified iterations, that is, cryoplasty, cutting balloons, focal force balloons, nitinol-"cage"-constrained balloons, tapered balloons, and most recently drug-coated balloons. In this article, we share our current approach to endovascular IP endovascular interventions. We cover the spectrum from pathophysiology, clinical indications, equipment choices, and procedural steps used in our laboratory when treating patients with CLI (which is synonymous with complex anatomy). Regarding what represents the "gold standard" for the treatment of IP disease, a definite answer is currently not available, as multiple studies looking at new generation drug-coated balloons used alone or in combination with different forms of atherectomy are currently under way. We anxiously wait for these results and in the meantime continue to design newer approaches.

  11. 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.

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

    SciTech Connect

    Jens, Sjoerd; Conijn, Anne P. Frans, Franceline A.; Nieuwenhuis, Marieke B. B. Met, Rosemarie; Koelemay, Mark J. W. Legemate, Dink A.; Bipat, Shandra Reekers, Jim A.

    2015-06-15

    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 months 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.

  13. Long-term outcomes following infrapopliteal angioplasty for critical limb ischemia

    PubMed Central

    Lo, Ruby C.; Darling, Jeremy; Bensley, Rodney P.; Dahlberg, Suzanne E.; Hamdan, Allen D.; Wyers, Mark; Schermerhorn, Marc L.

    2012-01-01

    Objectives Infrapopliteal angioplasty (PTA) is routinely used to treat critical limb ischemia (CLI) despite limited data on long-term outcomes. Methods We reviewed all patients undergoing infrapopliteal PTA for CLI from 2004–2012 stratified by TASC class. Outcomes included restenosis, primary patency, reintervention (w/ PTA or bypass), amputation, procedural complications, wound healing, and survival. Results Infrapopliteal PTA (stenting 14%, multilevel intervention 50%) was performed in 459 limbs of 413 patients (59% male) with technical success of 93% and perioperative complications in 11%. TASC class was 16% A, 22% B, 27% C, and 34% D. Multilevel interventions were performed in 50% of limbs and were evenly distributed among all TASC classes. All technical failures were TASC D lesions. Mean follow-up was 15 months. 5-year survival was 49%. One- and 5-year primary patency was 57% & 38% and limb salvage was 84% & 81%. Restenosis was associated with TASC C (HR 2.2, 95% CI 1.2–3.9, P=.010) and TASC D (HR 2.4, 95% CI 1.3–4.4, P=.004) lesions. Amputation rates were higher in patients who were not candidates for bypass (HR 4.4, 95% CI 2.6–7.5, P<.001) and with TASC D lesions (HR 3.8, 95% CI 1.1–12.5, P=.03). Unsuitability for bypass was also predictive of repeat PTA (HR 1.8, 95% CI 1.0–3.4, P=.047). Postoperative clopidogrel use was associated with lower rates of any revascularization (HR .46, 95% CI .25–.83, P=.011). Conclusions Infrapopliteal PTA is effective primary therapy for TASC A, B, and C lesions. Surgical bypass should be offered to patients with TASC D disease who are suitable candidates. Multilevel intervention does not adversely affect outcome. PMID:23375610

  14. Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia

    PubMed Central

    Li, Yaqian; Liu, Wei; Liu, Fei; Zeng, Yang; Zuo, Simin; Feng, Siyu; Qi, Chunxiao; Wang, Bingjie; Yan, Xiaojun; Khademhosseini, Ali; Bai, Jing; Du, Yanan

    2014-01-01

    The promise of cell therapy for repair and restoration of damaged tissues or organs relies on administration of large dose of cells whose healing benefits are still limited and sometimes irreproducible due to uncontrollable cell loss and death at lesion sites. Using a large amount of therapeutic cells increases the costs for cell processing and the risks of side effects. Optimal cell delivery strategies are therefore in urgent need to enhance the specificity, efficacy, and reproducibility of cell therapy leading to minimized cell dosage and side effects. Here, we addressed this unmet need by developing injectable 3D microscale cellular niches (microniches) based on biodegradable gelatin microcryogels (GMs). The microniches are constituted by in vitro priming human adipose-derived mesenchymal stem cells (hMSCs) seeded within GMs resulting in tissue-like ensembles with enriched extracellular matrices and enhanced cell–cell interactions. The primed 3D microniches facilitated cell protection from mechanical insults during injection and in vivo cell retention, survival, and ultimate therapeutic functions in treatment of critical limb ischemia (CLI) in mouse models compared with free cell-based therapy. In particular, 3D microniche-based therapy with 105 hMSCs realized better ischemic limb salvage than treatment with 106 free-injected hMSCs, the minimum dosage with therapeutic effects for treating CLI in literature. To the best of our knowledge, this is the first convincing demonstration of injectable and primed cell delivery strategy realizing superior therapeutic efficacy for treating CLI with the lowest cell dosage in mouse models. This study offers a widely applicable cell delivery platform technology to boost the healing power of cell regenerative therapy. PMID:25197069

  15. Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia.

    PubMed

    Li, Yaqian; Liu, Wei; Liu, Fei; Zeng, Yang; Zuo, Simin; Feng, Siyu; Qi, Chunxiao; Wang, Bingjie; Yan, Xiaojun; Khademhosseini, Ali; Bai, Jing; Du, Yanan

    2014-09-16

    The promise of cell therapy for repair and restoration of damaged tissues or organs relies on administration of large dose of cells whose healing benefits are still limited and sometimes irreproducible due to uncontrollable cell loss and death at lesion sites. Using a large amount of therapeutic cells increases the costs for cell processing and the risks of side effects. Optimal cell delivery strategies are therefore in urgent need to enhance the specificity, efficacy, and reproducibility of cell therapy leading to minimized cell dosage and side effects. Here, we addressed this unmet need by developing injectable 3D microscale cellular niches (microniches) based on biodegradable gelatin microcryogels (GMs). The microniches are constituted by in vitro priming human adipose-derived mesenchymal stem cells (hMSCs) seeded within GMs resulting in tissue-like ensembles with enriched extracellular matrices and enhanced cell-cell interactions. The primed 3D microniches facilitated cell protection from mechanical insults during injection and in vivo cell retention, survival, and ultimate therapeutic functions in treatment of critical limb ischemia (CLI) in mouse models compared with free cell-based therapy. In particular, 3D microniche-based therapy with 10(5) hMSCs realized better ischemic limb salvage than treatment with 10(6) free-injected hMSCs, the minimum dosage with therapeutic effects for treating CLI in literature. To the best of our knowledge, this is the first convincing demonstration of injectable and primed cell delivery strategy realizing superior therapeutic efficacy for treating CLI with the lowest cell dosage in mouse models. This study offers a widely applicable cell delivery platform technology to boost the healing power of cell regenerative therapy.

  16. Sarcopenia is a prognostic factor for overall survival in patients with critical limb ischemia.

    PubMed

    Matsubara, Yutaka; Matsumoto, Takuya; Aoyagi, Yukihiko; Tanaka, Shinichi; Okadome, Jun; Morisaki, Koichi; Shirabe, Ken; Maehara, Yoshihiko

    2015-04-01

    Sarcopenia has been proposed as a prognostic factor for various diseases. Patients with critical limb ischemia (CLI) have a very poor prognosis, but sarcopenia has not been reported as a prognostic factor for CLI patients. If sarcopenia is associated with the prognosis of CLI patients, it could help select the treatment plan. Therefore, we examined whether sarcopenia is a prognostic factor for CLI patients. We performed a retrospective study of CLI patients diagnosed with Fontaine III or IV peripheral artery disease who underwent preoperative computed tomography imaging and revascularization between January 2002 and December 2009. The presence of sarcopenia was defined as skeletal muscle area of <114.0 cm(2) for men or <89.8 cm(2) for women using transverse computed tomography scans at the third lumbar vertebra. We compared the 5-year survival rate and clinical characteristics between patients with or without sarcopenia. We also screened possible prognostic factors for overall survival using hazard ratios (HRs) with 95% confidence intervals (CIs). Of 64 eligible patients, 28 patients had sarcopenia and 36 did not. There were significant differences in age, skeletal muscle area, body mass index, and the presence of smoking, cerebrovascular disease, and hemodialysis between patients with and without sarcopenia (all P < .05). The 5-year survival rate was significantly lower in patients with sarcopenia (23.5% vs 77.5%, P = .001). Prognostic factors for overall survival were the presence of sarcopenia (HR, 3.22; 95% CI, 1.24-9.11; P = .02), requirement for hemodialysis (HR, 4.30; 95% CI, 1.60-12.2; P = .004), and postoperative complications (HR, 5.02; 95% CI, 1.90-13.7; P = .001). Our results suggest that sarcopenia is a prognostic factor for CLI patients. Exercise and nutritional interventions focusing on improving sarcopenia might be useful treatment options for CLI patients. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights

  17. Long-Term Prognosis of Diabetic Patients With Critical Limb Ischemia

    PubMed Central

    Faglia, Ezio; Clerici, Giacomo; Clerissi, Jacques; Gabrielli, Livio; Losa, Sergio; Mantero, Manuela; Caminiti, Maurizio; Curci, Vincenzo; Quarantiello, Antonella; Luppattelli, Tommaso; Morabito, Alberto

    2009-01-01

    OBJECTIVE To evaluate the long-term prognosis of critical limb ischemia (CLI) in diabetic patients. RESEARCH DESIGN AND METHODS A total of 564 consecutive diabetic patients were hospitalized for CLI from January 1999 to December 2003; 554 were followed until December 2007. RESULTS The mean follow-up was 5.93 ± 1.28 years. Peripheral angioplasty (PTA) was performed in 420 (74.5%) and bypass graft (BPG) in 117 (20.6%) patients. Neither PTA nor BPG were possible in 27 (4.9%) patients. Major amputations were performed in 74 (13.4%) patients: 34 (8.2%) in PTA, 24 (21.1%) in BPG, and 16 (59.2%) in a group that received no revascularization. Restenosis occurred in 94 patients, bypass failures in 36 patients, and recurrent ulcers in 71 patients. CLI was observed in the contralateral limb of 225 (39.9%) patients; of these, 15 (6.7%) required major amputations (rate in contralateral compared with initial limb, P = 0.007). At total of 276 (49.82%) patients died. The Cox model showed significant hazard ratios (HRs) for mortality with age (1.05 for 1 year [95% CI 1.03–1.07]), unfeasible revascularization (3.06 [1.40–6.70]), dialysis (3.00 [1.63–5.53]), cardiac disease history (1.37 [1.05–1.79]), and impaired ejection fraction (1.08 for 1% point [1.05–1.09]). CONCLUSIONS Diabetic patients with CLI have high risks of amputation and death. In a dedicated diabetic foot center, the major amputation, ulcer recurrence, and major contralateral limb amputation rates were low. Coronary artery disease (CAD) is the leading cause of death, and in patients with CAD history the impaired ejection fraction is the major independent prognostic factor. PMID:19223609

  18. Moderate Exercise Allows for shorter Recovery Time in Critical Limb Ischemia.

    PubMed

    Lejay, Anne; Laverny, Gilles; Paradis, Stéphanie; Schlagowski, Anna-Isabel; Charles, Anne-Laure; Singh, François; Zoll, Joffrey; Thaveau, Fabien; Lonsdorfer, Evelyne; Dufour, Stéphane; Favret, Fabrice; Wolff, Valérie; Metzger, Daniel; Chakfe, Nabil; Geny, Bernard

    2017-01-01

    Whether and how moderate exercise might allow for accelerated limb recovery in chronic critical limb ischemia (CLI) remains to be determined. Chronic CLI was surgically induced in mice, and the effect of moderate exercise (training five times per week over a 3-week period) was investigated. Tissue damages and functional scores were assessed on the 4th, 6th, 10th, 20th, and 30th day after surgery. Mice were sacrificed 48 h after the last exercise session in order to assess muscle structure, mitochondrial respiration, calcium retention capacity, oxidative stress and transcript levels of genes encoding proteins controlling mitochondrial functions (PGC1α, PGC1β, NRF1) and anti-oxidant defenses markers (SOD1, SOD2, catalase). CLI resulted in tissue damages and impaired functional scores. Mitochondrial respiration and calcium retention capacity were decreased in the ischemic limb of the non-exercised group (Vmax = 7.11 ± 1.14 vs. 9.86 ± 0.86 mmol 02/min/g dw, p < 0.001; CRC = 7.01 ± 0.97 vs. 11.96 ± 0.92 microM/mg dw, p < 0.001, respectively). Moderate exercise reduced tissue damages, improved functional scores, and restored mitochondrial respiration and calcium retention capacity in the ischemic limb (Vmax = 9.75 ± 1.00 vs. 9.82 ± 0.68 mmol 02/min/g dw; CRC = 11.36 ± 1.33 vs. 12.01 ± 1.24 microM/mg dw, respectively). Exercise also enhanced the transcript levels of PGC1α, PGC1β, NRF1, as well as SOD1, SOD2, and catalase. Moderate exercise restores mitochondrial respiration and calcium retention capacity, and it has beneficial functional effects in chronic CLI, likely by stimulating reactive oxygen species-induced biogenesis and anti-oxidant defenses. These data support further development of exercise therapy even in advanced peripheral arterial disease.

  19. 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.

  20. Predictive ability of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system following infrapopliteal endovascular interventions for critical limb ischemia.

    PubMed

    Darling, Jeremy D; McCallum, John C; Soden, Peter A; Meng, Yifan; Wyers, Mark C; Hamdan, Allen D; Verhagen, Hence J; Schermerhorn, Marc L

    2016-09-01

    The Society for Vascular Surgery (SVS) Lower Extremity Guidelines Committee has composed a new threatened lower extremity classification system that reflects the three major factors that impact amputation risk and clinical management: Wound, Ischemia, and foot Infection (WIfI). Our goal was to evaluate the predictive ability of this scale following any infrapopliteal endovascular intervention for critical limb ischemia (CLI). From 2004 to 2014, a single institution, retrospective chart review was performed at the Beth Israel Deaconess Medical Center for all patients undergoing an infrapopliteal angioplasty for CLI. Throughout these years, 673 limbs underwent an infrapopliteal endovascular intervention for tissue loss (77%), rest pain (13%), stenosis of a previously treated vessel (5%), acute limb ischemia (3%), or claudication (2%). Limbs missing a grade in any WIfI component were excluded. Limbs were stratified into clinical stages 1 to 4 based on the SVS WIfI classification for 1-year amputation risk, as well as a novel WIfI composite score from 0 to 9. Outcomes included patient functional capacity, living status, wound healing, major amputation, major adverse limb events, reintervention, major amputation, or stenosis (RAS) events (> ×3.5 step-up by duplex), amputation-free survival, and mortality. Predictors were identified using Kaplan-Meier survival estimates and Cox regression models. Of the 596 limbs with CLI, 551 were classified in all three WIfI domains on a scale of 0 (least severe) to 3 (most severe). Of these 551, 84% were treated for tissue loss and 16% for rest pain. A Cox regression model illustrated that an increase in clinical stage increases the rate of major amputation (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.1-2.3). Separate regression models showed that a one-unit increase in the WIfI composite score is associated with a decrease in wound healing (HR, 1.2; 95% CI, 1.1-1.4) and an increase in the rate of RAS events (HR, 1

  1. 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).

  2. Endovascular recanalization of infrapopliteal occlusions in patients with critical limb ischemia

    PubMed Central

    Singh, Gagan D.; Armstrong, Ehrin J.; Yeo, Khung-Keong; Singh, Satinder; Westin, Gregory G.; Pevec, William C.; Dawson, David L.; Laird, John R.

    2014-01-01

    Background Endovascular therapies are increasingly used for treatment of critical limb ischemia (CLI). Infrapopliteal (IP) occlusions are common in CLI, and successful limb salvage may require restoration of arterial flow in the distribution of a chronically occluded vessel. We sought to describe the procedural characteristics and outcomes of patients with IP occlusions who underwent endovascular intervention for treatment of CLI. Methods All patients with IP interventions for treatment of CLI from 2006 to 2012 were included. Angiographic and procedural data were compared between patients who underwent intervention for IP occlusions vs IP stenosis. Restenosis was determined by Doppler ultrasound imaging. Limb salvage was the primary end point of the study. Additional end points included primary patency, primary assisted patency, secondary patency, occlusion crossing success, procedural success, and amputation-free survival. Results A total of 187 patients with CLI underwent interventions for 356 IP lesions, and 77 patients (41%) had interventions for an IP occlusion. Patients with an intervention for IP occlusion were more likely to have zero to one vessel runoff (83% vs 56%; P < .001) compared with interventions for stenosis. Compared with IP stenoses, IP occlusions were longer (118 ± 86 vs 73 ± 67 mm; P < .001) and had a smaller vessel diameter (2.5 ± 0.8 vs 2.7 ± 0.5 mm; P =.02). Wire crossing was achieved in 83% of IP occlusions, and the overall procedural success for IP occlusions was 79%. The overall 1-year limb salvage rate was 84%. Limb salvage was highest in the stenosis group, slightly lower in the successful occlusion group, and lowest in the failed occlusion group (92% vs 75% vs 58%, respectively; P = .02). Unsuccessfully treated IP occlusions were associated with a significantly higher likelihood of major amputation (hazard ratio, 5.79; 95% confidence interval, 1.89–17.7) and major amputation or death (hazard ratio, 2.69; 95% confidence interval

  3. Sarcopenia is a risk factor for cardiovascular events experienced by patients with critical limb ischemia.

    PubMed

    Matsubara, Yutaka; Matsumoto, Takuya; Inoue, Kentaro; Matsuda, Daisuke; Yoshiga, Ryosuke; Yoshiya, Keiji; Furuyama, Tadashi; Maehara, Yoshihiko

    2017-05-01

    Prognosis is poor for patients with critical limb ischemia (CLI), and the most frequent cause of death is cardiovascular disease. Low grip strength is a risk factor for cardiovascular events, and sarcopenia may be associated as well. Thus, we hypothesized that sarcopenia is a risk factor for cardiovascular events experienced by patients with CLI. If this is true and appropriate therapy becomes available, the prognosis of patients with CLI will improve with appropriate risk management strategies to prevent cardiovascular events. Therefore, the aim of this study was to verify this hypothesis. We studied 114 patients who underwent revascularization and computed tomography between January 2002 and December 2012 in the Department of Surgery and Sciences at Kyushu University in Japan. Sarcopenia was defined as skeletal muscle area measured by L3-level computed tomography scan <114.0 cm(2) and <89.8 cm(2) for men and women, respectively. Clinical characteristics, cardiovascular event-free survival, <2-year death, causes of death, and effective treatments for sarcopenia were investigated. We identified 53 (46.5%) patients with sarcopenia. Three-year cardiovascular event-free survival rates were 43.1% and 91.2% for patients with and without sarcopenia, respectively (P < .01). During follow-up, cardiovascular disease caused the deaths of 4 and 15 patients without and with sarcopenia (P < .01), respectively, and in particular, ischemic heart disease caused the deaths of 0 and 5 patients without or with sarcopenia (P < .05), respectively. Single antiplatelet therapy (SAPT; hazard ratio, 0.46; 95% confidence interval, 0.24-0.82; P < .01) and statin therapy (hazard ratio, 0.38; 95% confidence interval, 0.16-0.78; P < .01) were independent factors associated with improved cardiovascular event-free survival. Three-year cardiovascular event-free survival rates for patients with sarcopenia who received SAPT, dual antiplatelet therapies, and no antiplatelet therapy were 75

  4. Alternative conduit for infrageniculate bypass in patients with critical limb ischemia.

    PubMed

    Moreira, Carla C; Leung, Alexander D; Farber, Alik; Rybin, Denis; Doros, Gheorghe; Siracuse, Jeffrey J; Kalish, Jeffrey; Eslami, Mohammad H

    2016-07-01

    Autologous great saphenous vein (GSV) has always been considered the gold standard conduit for infrainguinal revascularization. When GSV is inadequate or unavailable, alternative conduits have been used. In this study, we compared modern outcomes of different conduit types used in lower extremity bypass (LEB) for patients with critical limb ischemia (CLI). The Vascular Study Group of New England database (2003-2014) was queried for patients who underwent infrageniculate bypass originating from the femoral arteries. Conduit types were categorized as single-segment GSV, alternative autologous conduit (AAC), and nonautologous conduit (NAC). Primary outcomes were 1-year freedom from major adverse limb event (MALE), MALE-free survival, and primary graft patency. Multivariable Cox regression was used to adjust for demographics and comorbidities. LEB was performed in 2148 patients, of which 1125 were to below-knee popliteal (BK-Pop) and 1023 to infrapopliteal artery (IPA) targets. The baseline characteristics differed among the conduit groups: Patients in the GSV group were younger and had fewer comorbidities than in the AAC groups. Patients undergoing BK-Pop bypass with NAC had higher rates of postoperative myocardial infarction (7.1%) and postoperative (5.8%) and 1-year death (40.8%) than in those with GSV (3.1%, 2%, and 31.7%, respectively) and AAC (0%, 0%, and 25%, respectively). In multivariable analysis, conduit type did not make a difference in 1-year MALE, MALE-free survival, or primary graft patency for BK-Pop bypasses. For IPA bypasses, NAC use was associated with higher rates of postoperative (6.4%) and in-hospital death (4.5%) compared with GSV (2.5% and 1.4%, respectively) and AAC (2.9% and 1.9%, respectively). In adjusted analysis, NAC was associated with higher risk of MALE (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.03-2.20; P = .036) and primary patency loss (HR, 1.3; 95% CI, 0.91-1.89), and lower MALE-free survival (HR, 1.47; 95% CI, 1

  5. Moderate Exercise Allows for shorter Recovery Time in Critical Limb Ischemia

    PubMed Central

    Lejay, Anne; Laverny, Gilles; Paradis, Stéphanie; Schlagowski, Anna-Isabel; Charles, Anne-Laure; Singh, François; Zoll, Joffrey; Thaveau, Fabien; Lonsdorfer, Evelyne; Dufour, Stéphane; Favret, Fabrice; Wolff, Valérie; Metzger, Daniel; Chakfe, Nabil; Geny, Bernard

    2017-01-01

    Whether and how moderate exercise might allow for accelerated limb recovery in chronic critical limb ischemia (CLI) remains to be determined. Chronic CLI was surgically induced in mice, and the effect of moderate exercise (training five times per week over a 3-week period) was investigated. Tissue damages and functional scores were assessed on the 4th, 6th, 10th, 20th, and 30th day after surgery. Mice were sacrificed 48 h after the last exercise session in order to assess muscle structure, mitochondrial respiration, calcium retention capacity, oxidative stress and transcript levels of genes encoding proteins controlling mitochondrial functions (PGC1α, PGC1β, NRF1) and anti-oxidant defenses markers (SOD1, SOD2, catalase). CLI resulted in tissue damages and impaired functional scores. Mitochondrial respiration and calcium retention capacity were decreased in the ischemic limb of the non-exercised group (Vmax = 7.11 ± 1.14 vs. 9.86 ± 0.86 mmol 02/min/g dw, p < 0.001; CRC = 7.01 ± 0.97 vs. 11.96 ± 0.92 microM/mg dw, p < 0.001, respectively). Moderate exercise reduced tissue damages, improved functional scores, and restored mitochondrial respiration and calcium retention capacity in the ischemic limb (Vmax = 9.75 ± 1.00 vs. 9.82 ± 0.68 mmol 02/min/g dw; CRC = 11.36 ± 1.33 vs. 12.01 ± 1.24 microM/mg dw, respectively). Exercise also enhanced the transcript levels of PGC1α, PGC1β, NRF1, as well as SOD1, SOD2, and catalase. Moderate exercise restores mitochondrial respiration and calcium retention capacity, and it has beneficial functional effects in chronic CLI, likely by stimulating reactive oxygen species-induced biogenesis and anti-oxidant defenses. These data support further development of exercise therapy even in advanced peripheral arterial disease. PMID:28790926

  6. Early endothelial progenitor cells in bone marrow are a biomarker of cell therapy success in patients with critical limb ischemia.

    PubMed

    Smadja, David M; Duong-van-Huyen, Jean-Paul; Dal Cortivo, Liliane; Blanchard, Anne; Bruneval, Patrick; Emmerich, Joseph; Gaussem, Pascale

    2012-02-01

    Endothelial progenitor cells (EPC) have been proposed for autologous angiogenic therapy. The objectives of this study were to quantify EPC in the peripheral blood and bone marrow mononuclear cells (BM-MNC) of patients with critical limb ischemia that had received BM-MNC as a cell therapy product, and to study the putative relationship between the presence of EPC and the process of neovascularization in toe or transmetatarsal amputation specimens. Early and late endothelial progenitor cells (CFU-EC and ECFC) were cultivated and quantified according to published methods in peripheral blood and BM-MNC from patients with critical limb ischemia (CLI; n = 11) enrolled in the OPTIPEC trial ( http://clinicaltrials.gov/ct2/show/NCT00377897 ) to receive BM-MNC as a cell therapy product. Eight out of the 11 patients had undergone amputations. Three of the patients displayed a neoangiogenic process that was associated with a higher number of CFU-EC in BM-MNC, while CD3+ , CFU-GM and CD34+ in BM-MNC, and EPC in peripheral blood, did not correlate with the appearance of newly formed vessels. As expected, circulating CFU-EC and ECFC counts were significantly lower in CLI patients compared with age-matched controls. In patients with critical limb ischemia, EPC in peripheral blood were decreased compared with healthy individuals. However, in BM-MNC we found that relative numbers of CFU-EC could be used as an indicator to discriminate patients with neoangiogenic processes. These results need to be confirmed in a randomized study.

  7. Use of the AngioSculpt scoring balloon for infrapopliteal lesions in patients with critical limb ischemia: 1-year outcome.

    PubMed

    Bosiers, Marc; Deloose, Koen; Cagiannos, Catherine; Verbist, Jürgen; Peeters, Patrick

    2009-01-01

    The AngioSculpt Scoring Balloon Catheter (AngioScore, Inc., Fremont, CA) is composed of a semicompliant balloon encircled by three nitinol spiral struts providing targeted lesion scoring on balloon inflation. Between April 2005 and April 2006, procedural and follow-up data on 31 patients (mean age 76 years; 54.8% males) endovascularly treated for severe infrapopliteal disease were collected. The AngioSculpt catheter was used to treat 36 complex, tibioperoneal, atherosclerotic lesions. All patients had symptomatic critical limb ischemia (Rutherford 4-5) and single-vessel runoff to the ankle. Complication-free survival at 1 month was the safety end point, whereas primary patency and limb salvage were the efficacy end points evaluated at 1 year. The AngioSculpt balloon was successfully inflated in all 36 target lesions. Eleven patients (35.5%) required additional stenting for minor dissections or suboptimal stenosis reduction. The 1-month complication-free survival was 96.8%. One-year survival, primary patency, and limb salvage rates were 83.9 +/- 6.6%, 61.0 +/- 9.3%, and 86.3 +/- 6.4%, respectively. The 1-year data show the AngioSculpt Scoring Balloon Catheter to be an effective and safe treatment for infrapopliteal, atherosclerotic lesions in patients with critical limb ischemia. However, more patients, a longer follow-up, and randomized studies comparing it with conventional balloon angioplasty and stenting in the infrapopliteal region are required.

  8. Determinants of survival and major amputation after peripheral endovascular intervention for critical limb ischemia.

    PubMed

    Vierthaler, Luke; Callas, Peter W; Goodney, Philip P; Schanzer, Andres; Patel, Virenda I; Cronenwett, Jack; Bertges, Daniel J

    2015-09-01

    Our objective was to analyze periprocedural and 1-year outcomes of peripheral endovascular intervention (PVI) for critical limb ischemia (CLI). We reviewed 1244 patients undergoing 1414 PVIs for CLI (rest pain, 29%; tissue loss, 71%) within the Vascular Study Group of New England (VSGNE) from January 2010 to December 2011. Overall survival (OS), amputation-free survival (AFS), and freedom from major amputation at 1 year were analyzed using the Kaplan-Meier method. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). The number of arteries treated during each procedure were 1 (49%), 2 (35%), 3 (12%), and ≥4 (5%). Target arterial segments and TransAtlantic Inter-Society Consensus classifications were aortoiliac, 27% (A, 48%; B, 28%; C, 12%; and D, 12%); femoral-popliteal, 48% (A, 29%; B, 34%; C, 20%; and D, 17%); and infrapopliteal, 25% (A, 17%; B, 14%; C, 25%; D, 44%). Technical success was 92%. Complications included access site hematoma (5.0%), occlusion (0.3%), and distal embolization (2.4%). Mortality and major amputation rates were 2.8% and 2.2% at 30 days, respectively. Overall percutaneous or open reintervention rate was 8.0% during the first year. At 1-year, OS, AFS, and freedom from major amputation were 87%, 87%, and 94% for patients with rest pain and 80%, 71%, and 81% for patients with tissue loss. Independent predictors of reduced 1-year OS (C index = .74) included dialysis (HR, 3.8; 95% CI, 2.8-5.1; P < .01), emergency procedure (HR, 2.5; 95% CI, 1.0-6.2; P = .05), age >80 years (HR, 2.2; 95% CI, 1.7-2.8; P < .01), not living at home preoperatively (HR, 2.0; 95% CI, 1.4-2.8; P < .01), creatinine >1.8 mg/dL (HR, 1.9; 95% CI, 1.3-2.8; P < .01), congestive heart failure (HR, 1.7; 95% CI, 1.3-2.2; P < .01), and chronic β-blocker use (HR, 1.4; 95% CI, 1.0-1.9; P = .03), whereas independent preoperative ambulation (HR, 0.7; 95% CI, 0.6-0.9; P = .014) was protective. Independent predictors of major

  9. Determinants of survival and major amputation after peripheral endovascular intervention for critical limb ischemia

    PubMed Central

    Vierthaler, Luke; Callas, Peter W.; Goodney, Philip P.; Schanzer, Andres; Patel, Virenda I.; Cronenwett, Jack; Bertges, Daniel J.

    2017-01-01

    Objective Our objective was to analyze periprocedural and 1-year outcomes of peripheral endovascular intervention (PVI) for critical limb ischemia (CLI). Methods We reviewed 1244 patients undergoing 1414 PVIs for CLI (rest pain, 29%; tissue loss, 71%) within the Vascular Study Group of New England (VSGNE) from January 2010 to December 2011. Overall survival (OS), amputation-free survival (AFS), and freedom from major amputation at 1 year were analyzed using the Kaplan-Meier method. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results The number of arteries treated during each procedure were 1 (49%), 2 (35%), 3 (12%), and ≥4 (5%). Target arterial segments and TransAtlantic Inter-Society Consensus classifications were aortoiliac, 27% (A, 48%; B, 28%; C, 12%; and D, 12%); femoral-popliteal, 48% (A, 29%; B, 34%; C, 20%; and D, 17%); and infrapopliteal, 25% (A, 17%; B, 14%; C, 25%; D, 44%). Technical success was 92%. Complications included access site hematoma (5.0%), occlusion (0.3%), and distal embolization (2.4%). Mortality and major amputation rates were 2.8% and 2.2% at 30 days, respectively. Overall percutaneous or open reintervention rate was 8.0% during the first year. At 1-year, OS, AFS, and freedom from major amputation were 87%, 87%, and 94% for patients with rest pain and 80%, 71%, and 81% for patients with tissue loss. Independent predictors of reduced 1-year OS (C index = .74) included dialysis (HR, 3.8; 95% CI, 2.8–5.1; P < .01), emergency procedure (HR, 2.5; 95% CI, 1.0–6.2; P = .05), age >80 years (HR, 2.2; 95% CI, 1.7–2.8; P < .01), not living at home preoperatively (HR, 2.0; 95% CI, 1.4–2.8; P < .01), creatinine >1.8 mg/dL (HR, 1.9; 95% CI, 1.3–2.8; P < .01), congestive heart failure (HR, 1.7; 95% CI, 1.3–2.2; P < .01), and chronic β-blocker use (HR, 1.4; 95% CI, 1.0–1.9; P = .03), whereas independent preoperative ambulation (HR, 0.7; 95% CI, 0.6–0.9; P = .014) was

  10. 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

  11. Endovascular therapy as the primary approach for limb salvage in patients with critical limb ischemia: experience with 443 infrapopliteal procedures.

    PubMed

    Bosiers, Marc; Hart, Joseph P; Deloose, Koen; Verbist, Jurgen; Peeters, Patrick

    2006-01-01

    Endovascular strategies for the treatment of critical infrageniculate peripheral arterial occlusive disease exist and are becoming the primary methodology for such lesions at many centers. Although technically feasible for experienced operators, the evidence to support this strategy for below the knee (BTK) interventions is still evolving. We studied the 6-month and 1-year outcomes of percutaneous transluminal angioplasty (PTA) alone, PTA with stenting, and excimer laser recanalization for BTK lesions in patients with critical limb ischemia. Between September 2002 and June 2005, 443 patients (355 Rutherford category 4, 82 category 5, 6 category 6) underwent intervention for 681 BTK lesions. Follow-up was performed at 6-month intervals after index intervention: limb salvage data were recorded and duplex ultrasonography was performed to measure the patency of treated areas. The primary patency and limb salvage rates of the entire population were 85.2% and 97.0% and 74.2% and 96.6% at 6 months and 1 year, respectively. Stratified for the treatment strategy (PTA alone in 79, PTA with stenting in 300 patients, and excimer laser in 64), 1-year primary patency rates were 68.6%, 75.5%, and 75.4%, whereas the limb salvage rates were 96.7%, 98.6%, and 87.9% for each modality, respectively. Endovascular intervention will become the primary treatment for BTK lesions in patients with critical limb ischemia, with 1-year primary patency and limb salvage rates that compare favorably with published surgical data. Prospective, randomized, multicenter trials will be needed to further establish the role of endovascular intervention in this challenging patient group.

  12. Why critical limb ischemia criteria are not applicable to diabetic foot and what the consequences are.

    PubMed

    Jörneskog, G

    2012-01-01

    Neuropathy, peripheral arterial occlusive disease and microvascular disturbances are important factors contributing to foot problems in diabetic patients. In the diabetic foot with ischemia, the alterations in skin microvascular function are pronounced including severely reduced capillary circulation and abolished hyperaemic responses. These microvascular disturbances, which are superimposed on the already existing structural diabetic microangiopathy, are compatible with a state of "chronic capillary ischemia" and an increased shunting of blood through arteriovenous channels. This maldistribution of blood in skin microcirculation is not detected by measurement of peripheral blood pressure (systolic ankle blood pressure, systolic toe blood pressure). As indicated in several studies toe blood pressure is a poor predictor of local tissue perfusion, tissue survival and healing of chronic foot ulcers. Consequently, the disturbances in peripheral tissue perfusion of the diabetic foot may be underestimated leading to delayed vascular interventions and/or medical treatment. Thus, measurements of peripheral blood pressure, e.g. toe blood pressure, should be combined with investigations of local tissue perfusion in order to get an adequate estimation of peripheral tissue perfusion in diabetic patients. For this purpose local skin microcirculation can be investigated by transcutaneous oxygen tension of the forefoot. Also, due to these reasons, the threshold for revascularization should be lower in diabetic patients with foot ulcer.

  13. Intravenous iloprost for treatment of critical limb ischemia in patients unsuitable for revascularization.

    PubMed

    Çevirme, Deniz; Aksoy, Eray; Gül, Yaşar Gökhan; Erdem, Hasan; Adademir, Taylan; Köksal, Cengiz; Bozkurt, Kürşat

    2015-10-01

    Whether medical therapy alone may reduce the amputation rates in patients with chronic limb ischemia and who are unsuitable for revascularization is a controversial topic. In this study, we aimed to investigate the effects of 1 week infusion of iloprost in the treatment of patients with chronic limb ischemia. Twenty-seven consecutive patients were included in the study. There were 23 men (85.2%) and 4 women (14.8%) with a mean age of 68.93 ± 14.84 years. Patients were considered eligible if they were unsuitable for surgical and endovascular revascularization. Follow-up was made on 10th day and 6th month and included ankle brachial index and clinical assessment. Minor side effects occurred in four patients (16.0%), but the treatment was continued. In-hospital mortality occurred in one patient (4.0%). Another two patients died and four patients received amputation until follow-up (overall mortality 11.1%). There was significant increase in mean ankle-brachial index values between 1st day and 10th day (p < 0.001), between 1st day and 6th month (p < 0.001), and between 10th day and 6th month (p < 0.001). One-week treatment with iloprost may provide both long lasting symptomatic benefit and may improve hemodynamic parameters, which were shown to predict future amputation. © The Author(s) 2014.

  14. Role of contrast-enhanced ultrasound arterial mapping in surgical planning for patients with critical limb ischemia.

    PubMed

    Mestre, Xavier Martí; Coll, Ramon Vila; Villegas, Antoni Romera; Rico, Carlos Martínez

    2015-06-01

    The goal of the study described here was to evaluate the role of contrast-enhanced ultrasound (CEUS) arterial mapping in surgical planning in cases of critical limb ischemia. From March 2007 to December 2012, 565 consecutive patients with critical limb ischemia of the lower limbs were treated and initially examined with only ultrasound (US) arterial mapping. For 479 of the 565 patients, basic US examination results were deemed sufficient for surgical planning (group A). That is, US examination provided sufficient information to decide a surgical plan to treat those patients. In the remaining 86 patients, basic US examination was insufficient for revascularization planning, and CEUS examination was performed (group B). In 5 cases, CEUS results were also insufficient for surgical planning, as a suitable outflow vessel was not visualized. In these cases, a pre-operative arteriogram was performed. To assess the usefulness of CEUS, we compared results of examinations with and without contrast administration, surgical findings and angiographic findings when available. Data were collected prospectively. Examinations were compared by establishing the degree of agreement between results of paired examinations and degree of agreement between CEUS results and surgical findings. Clinical, hemodynamic (ankle-brachial index) and duplex follow-up was performed at 1 and 3 mo to evaluate cumulative patency of the procedures in each group. Within group B, degree of agreement between basic US and CEUS was 46.5%. CEUS resulted in a change in the surgical plan in 46 of 86 patients. Among all 565 patients, degree of agreement between surgical decision based on basic ultrasound arterial mapping and final decision based on surgical findings was 87.1%, and improved to 95.2% with CEUS (p = 0.00001, κ index = 0.823). Degree of agreement between the ultrasound-based decision and surgical findings was 97.5% in group A (κ index = 0.818) and 94.2% in group B (κ = 0.848). There was no

  15. Early results from an angiosome-directed open surgical technique for venous arterialization in patients with critical lower limb ischemia

    PubMed Central

    Houlind, Kim; Christensen, Johnny; Hallenberg, Christian; Jepsen, Jørn M.

    2013-01-01

    Background Patients with critical lower limb ischemia without patent pedal arteries cannot be treated by the conventional arterial reconstruction. Venous arterialization has been suggested to improve limb salvage in this subgroup of patients but has not gained wide acceptance. We report our early experience after implementing deep and superficial venous arterialization of the lower limb. Materials and methods Ten patients with critical ischemia and without crural or pedal arteries available for conventional bypass surgery or angioplasty were treated with distal venous arterialization. Inflow was from the most distal unobstructed segment. Run-off was the dorsal pedal venous arch (n=5), the dorsal pedal venous arch and a concomitant vein of the posterior tibial artery (n=3), or the dorsal pedal venous arch and a concomitant vein of the common plantar artery (n=2) depending on the location of the ischemic lesion. Venous valves were destroyed using antegrade valvulotomes, guide wires, knob needles, or retrograde valvulotomes via an extra incision. Results Seven of the operated limbs were amputated after 23 (1–256) days (median [range]). The main reasons for amputation were lack of healing of either the original wound, of incisional wounds on the foot, or persisting pain at rest. In three cases, the bypass was open at the time of amputation. Two patients experienced complete wound healing after 231 and 342 days, respectively. By the end of follow-up, the last patient was ambulating with slow wound healing but without pain 309 days after surgery. Conclusion Venous arterialization may be used as a treatment of otherwise unsalveable limbs. The success rate is, however, limited. Technical optimization of the technique is warranted. PMID:24358432

  16. Microcirculatory investigations to determine the effect of spinal cord stimulation for critical leg ischemia: the Dutch multicenter randomized controlled trial.

    PubMed

    Ubbink, D T; Spincemaille, G H; Prins, M H; Reneman, R S; Jacobs, M J

    1999-08-01

    Patients with non-reconstructable critical limb ischemia generally undergo medical treatment only to prevent or postpone amputation. There is some evidence that spinal cord stimulation (SCS) stimulates ischemic wound healing. Thus, this could benefit limb survival through improved skin perfusion. We investigated the effect of SCS versus conservative treatment on skin microcirculation in relation to treatment outcome in patients with non-reconstructable critical limb ischemia. Standard medical treatment plus SCS was compared with only standard medical treatment in a multicenter randomized controlled trial comprised of 120 patients with surgically non-reconstructable chronic rest pain or ulceration. We investigated skin microcirculation by means of capillary microscopy, laser Doppler perfusion, and transcutaneous oxygen measurements in the foot. The microcirculatory status just before treatment was classified in three categories (poor, intermediate, and good) and was related to limb survival after a minimum follow-up period of 18 months. Clinical parameters, peripheral blood pressures, and limb survival rates showed no significant differences between the SCS and standard groups during the follow-up period. In both treatment groups, amputation frequency after 18 months was high in patients with an initially poor microcirculatory skin perfusion (SCS 80% vs standard treatment 71%; NS) and low in those with a good skin perfusion (29% vs 11 %, respectively; NS). In patients with an intermediate skin microcirculation amputation, frequency was twice as low in patients additionally treated with SCS as in the standard treatment group (48% vs 24%; P =.08). In these patients, microcirculatory reactive hyperemia during the follow-up period reduced in the standard group but not in the SCS group (P <.01). Selection on the basis of the initial microcirculatory skin perfusion identifies patients in whom SCS can improve local skin perfusion and limb survival.

  17. Early results from an angiosome-directed open surgical technique for venous arterialization in patients with critical lower limb ischemia.

    PubMed

    Houlind, Kim; Christensen, Johnny; Hallenberg, Christian; Jepsen, Jørn M

    2013-01-01

    Patients with critical lower limb ischemia without patent pedal arteries cannot be treated by the conventional arterial reconstruction. Venous arterialization has been suggested to improve limb salvage in this subgroup of patients but has not gained wide acceptance. We report our early experience after implementing deep and superficial venous arterialization of the lower limb. Ten patients with critical ischemia and without crural or pedal arteries available for conventional bypass surgery or angioplasty were treated with distal venous arterialization. Inflow was from the most distal unobstructed segment. Run-off was the dorsal pedal venous arch (n=5), the dorsal pedal venous arch and a concomitant vein of the posterior tibial artery (n=3), or the dorsal pedal venous arch and a concomitant vein of the common plantar artery (n=2) depending on the location of the ischemic lesion. Venous valves were destroyed using antegrade valvulotomes, guide wires, knob needles, or retrograde valvulotomes via an extra incision. Seven of the operated limbs were amputated after 23 (1-256) days (median [range]). The main reasons for amputation were lack of healing of either the original wound, of incisional wounds on the foot, or persisting pain at rest. In three cases, the bypass was open at the time of amputation. Two patients experienced complete wound healing after 231 and 342 days, respectively. By the end of follow-up, the last patient was ambulating with slow wound healing but without pain 309 days after surgery. Venous arterialization may be used as a treatment of otherwise unsalveable limbs. The success rate is, however, limited. Technical optimization of the technique is warranted.

  18. Critical peripheral ischemia precipitated by severe episode of Raynaud's phenomenon in a patient with aPL-positive systemic lupus erythematosus, upon high titer anti-RNP seroconversion.

    PubMed

    Levy, O; Maslakov, I; Vosco, S; Markov, A; Amit-Vazina, M; Tishler, M

    2015-03-01

    A 35-year-old female with long standing aPL-positive lupus without history of thromboembolic events, who has developed critical peripheral ischemia (CPI) is described. An episode of severe Raynaud's phenomenon rapidly progressed to an extensive digit-threatening ischemia, involving bilateral hands and feet. She was successfully treated with corticosteroids, anticoagulation, iloprost, sildenafil, and nifedipine. Her serological studies were remarkable for the emergence of high titer anti-RNP seroconversion and an increase in aPL titer, suggesting that these autoantibodies played a role in the pathogenesis of CPI. It is important to note that such observation should herald this potentially devastating complication of systemic lupus erythematosus.

  19. Long-Term Outcomes of Diabetic Patients With Critical Limb Ischemia Followed in a Tertiary Referral Diabetic Foot Clinic

    PubMed Central

    Uccioli, Luigi; Gandini, Roberto; Giurato, Laura; Fabiano, Sebastiano; Pampana, Enrico; Spallone, Vincenza; Vainieri, Erika; Simonetti, Giovanni

    2010-01-01

    OBJECTIVE We describe the long-term outcomes of 510 diabetic patients with critical limb ischemia (CLI) and an active foot ulcer or gangrene, seen at the University Hospital of Rome Tor Vergata, a tertiary care clinic. RESEARCH DESIGN AND METHODS These patients were seen between November 2002 and November 2007 (mean follow-up 20 ± 13 months [range 1–66 months]). The Texas Wound Classification was used to grade these wounds that were either class C (ischemia) and D (ischemia+infection) and grade 2–3 (deep–very deep). This comprehensive treatment protocol includes rapid and extensive initial debridement, aggressive use of peripheral percutaneous angioplasty, empirical intravenous antibiotic therapy, and strict follow-up. RESULTS The protocol was totally applied (with percutaneous angioplasty [PA+]) in 456 (89.4%) patients and partially (without percutaneous angioplasty [PA−]) in 54 (10.6%) patients. Outcomes for the whole group and PA+ and PA− patients are, respectively: healing, n = 310 (60.8%), n = 284 (62.3%), and n = 26 (48.1%); major amputation, n = 80 (15.7%), n = 67 (14.7%), and n = 13 (24.1%); death, n = 83 (16.25%), n = 68 (14.9%), and n = 15 (27.8%); and nonhealing, n = 37 (7.25%), n = 37 (8.1%), and n = 0 (0%) (χ2 <0.0009). Predicting variables at multivariate analysis were the following: for healing, ulcer dimension, infection, and ischemic heart disease; and for major amputation, ulcer dimension, number of minor amputations, and age. Additional predicting variables for PA+ patients were the following: for healing, transcutaneous oxygen tension [ΔTcPo2]; and for major amputation, basal TcPo2, basal A1C, ΔTcPo2, and percutaneous angioplasty technical failure. CONCLUSIONS Early diagnosis of CLI, aggressive treatment of infection, and extensive use of percutaneous angioplasty in ischemic affected ulcers offers improved outcome for many previously at-risk limbs. Ulcer size >5 cm2 indicates a reduced chance of healing and increased risk of major

  20. Critical Roles of Reactive Oxygen Species in Age-Related Impairment in Ischemia-Induced Neovascularization by Regulating Stem and Progenitor Cell Function

    PubMed Central

    Lam, Yuen Ting

    2016-01-01

    Reactive oxygen species (ROS) regulate bone marrow microenvironment for stem and progenitor cells functions including self-renewal, differentiation, and cell senescence. In response to ischemia, ROS also play a critical role in mediating the mobilization of endothelial progenitor cells (EPCs) from the bone marrow to the sites of ischemic injury, which contributes to postnatal neovascularization. Aging is an unavoidable biological deteriorative process with a progressive decline in physiological functions. It is associated with increased oxidative stress and impaired ischemia-induced neovascularization. This review discusses the roles of ROS in regulating stem and progenitor cell function, highlighting the impact of unbalanced ROS levels on EPC dysfunction and the association with age-related impairment in ischemia-induced neovascularization. Furthermore, it discusses strategies that modulate the oxidative levels of stem and progenitor cells to enhance the therapeutic potential for elderly patients with cardiovascular disease. PMID:26697140

  1. The Importance of Patency in Patients with Critical Limb Ischemia Undergoing Endovascular Revascularization for Infrapopliteal Arterial Disease

    PubMed Central

    Baumann, Frederic; Ozdoba, Christoph; Gröchenig, Ernst; Diehm, Nicolas

    2015-01-01

    Critical limb ischemia (CLI) represents the most severe form of peripheral arterial disease (PAD) and frequently occurs in medically frail patients. CLI patients frequently exhibit multi-segmental PAD commonly including the tibial arterial segment. Endovascular therapy has been established as first-line revascularization strategy for most CLI patients. Restenosis was reported to occur in up to more than two-thirds of CLI patients undergoing angioplasty of complex tibial arterial obstructions. Nevertheless, favorable clinical outcomes were observed for infrapopliteal angioplasty when compared with bypass surgery, despite higher patency rates for the latter. Based on these observations, infrapopliteal patency was considered to be only of secondary importance upon clinical outcomes in CLI patients. In contrast to these earlier observations, however, recent findings from two randomized clinical trials indicate that infrapopliteal patency does impact on clinical outcomes in CLI patients. The purpose of the present manuscript is to provide a critical reappraisal of the present literature on the clinical importance of tibial arterial patency in CLI patients undergoing endovascular revascularization and to discuss utility and limitations of currently available anti-restenosis technologies. PMID:26664867

  2. Recurrent Lower-Extremity Compartment Syndrome after Four-Compartment Fasciotomy Secondary to Acute Limb Ischemia.

    PubMed

    Kerkar, Ashwini P; Farber, Alik; Kalish, Jeffrey A; Siracuse, Jeffrey J

    2016-01-01

    Lower-extremity compartment syndrome is a limb-threatening event necessitating emergent treatment using fasciotomy. Recurrent compartment syndrome is rare and has only been reported after trauma and in conjunction with underlying connective tissue disorders. In this report, we present a case of recurrent lower-extremity compartment syndrome caused by ischemia-reperfusion injury, in a patient previously treated with adequate 4-compartment fasciotomies. As such, this is the first reported case of recurrent compartment syndrome in the setting of ischemia-reperfusion injury that required treatment with 4-compartment fasciotomies on both occasions. This case demonstrates that fasciotomy is not protective against the development of recurrent compartment syndrome due to ischemia-reperfusion injury and that patients at high risk require monitoring. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. 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

  4. Myocardial ischemia during cardiopulmonary bypass. The hazards of ventricular fibrillation in the presence of a critical coronary stenosis.

    PubMed

    Ciardullo, R C; Schaff, H V; Flaherty, J T; Gott, V L

    1977-05-01

    The effect of a critical coronary artery stenosis on myocardial blood flow and metabolism in the fibrillating heart was assessed by placing 10 dogs on cardiopulmonary bypass, venting the ventricle, inducing ventricular fibrillation, and applying critical stenosis to the left anterior descending coronary artery (LAD). Endocardial and epicardial blood flows were measured by the radioactive microsphere technique prior to the application of the stenosis and after one hour and 2 hours of fibrillation. Intramyocardial oxygen tension (PO2) and carbon dioxide tension (PCO2) were continuously monitored in the LAD-supplied myocardium by a mass spectrometer probe inserted at midmyocardial depth. Selective arterial-coronary venous lactate differences were determined at control, one hour, and 2 hours. At the end of the 2 hour period, vital dye injection defined the distribution of the LAD. Endocardial flow to the myocardium of the stenosed LAD was reduced by 50 per cent after one hour and by 70 per cent after 2 hours (p less than 0.05). Epicardial flow fell 40 per cent after one hour and 50 per cent after 2 hours (p less than 0.05). Endocardial and epicardial flow in the distribution of the unstenosed circumflex coronary artery remained unchanged. Changes in myocardial PO2 and PCO2 in the LAD-supplied myocardium indicated the development of severe ischemia in all 10 dogs and suggested myocardial infarction in 5. There was a conversion from lactate extraction to lactate production during the 2 hour period of ventricular fibrillation. From this study, it is concluded that the myocardium distal to a critical stenosis suffers a progressive reduction in flow during ventricular fibrillation which does not occur in regions supplied by unstenosed coronary arteries. Thus prolonged fibrillation in the presence of a flow-limiting coronary stenosis may play a role in the pathogenesis of myocardial infarction during coronary bypass surgery.

  5. An experimental model of ischemia in rabbit hindlimb.

    PubMed Central

    Hong, J. H.; Bahk, Y. W.; Suh, J. S.; Kwak, B. K.; Shim, H. J.; Kim, J. S.; Kim, H. S.; Moon, Y. H.; Kim, S. J.; Chung, J. W.; Park, J. H.

    2001-01-01

    This study was performed to establish an experimental model of ischemia for the investigation of new treatment modality of limb-threatening ischemia. We produced ischemia in the hindlimbs of 8 New Zealand white rabbits. Under general anesthesia, the left femoral artery was exposed, freed, and excised from distal external iliac artery to proximal popliteal and saphenous arteries. And then both hindlimbs were serially examined to assess the ischemia according to the time table until postoperative 6 weeks. We assessed clinical observation, blood pressure, radioisotopic perfusion scan, and angiography. Clinical ischemic changes of the operated feet were observed in 63%. The blood pressure of left calves was measurable on postoperative day 3 (p<0.05, vs preoperative day 2) and then gradually increased to reach a plateau in postoperative week 6. Radioisotopic arterial perfusion showed similar profiles as in blood pressure. Angiography of ischemic hindlimbs demonstrated a few collateral vessels arising from the internal iliac artery with the reconstitution of the posterior tibial artery in postoperative week 2. In postoperative week 6, collaterals remained the same in number. However, these became dilated and tortuous and showed reconstitution in distal hindleg. In conclusion, this is a reproducible, measurable, and economical animal model of hind limb ischemia. PMID:11641535

  6. Effects of shock waves on the microcirculation in critical limb ischemia (CLI) (8-week study).

    PubMed

    De Sanctis, M T; Belcaro, G; Nicolaides, A N; Cesarone, M R; Incandela, L; Marlinghaus, E; Griffin, M; Capodanno, S; Ciccarelli, R

    2000-08-01

    Shock waves (SWs) are used to control and decrease pain in several clinical conditions (e.g., painful elbow and shoulder, etc). This clinical effect may be due to cellular stunning of the tissues (particularly nervous components) in the area treated with SW. It may also be the consequence of unknown metabolic actions on tissues, which may include changes in cellular permeability and the liberation of proteins and mediators locally acting on pain and nerve endings. The aim of this study was to evaluate the reduction in pain and the microcirculation improvement induced by SWs treatment in an 8-week study in patients with chronic limb ischemia (CLI). Patients with CLI (15 with rest pain only and 15 with rest pain and limited distal necrosis) were included. The treatment was based on a 30-minute SWs session, three times weekly for 2 weeks. Clinical and microcirculatory evaluation were performed with laser Doppler Po2 and Pco2 measurements. Pain was measured with an analogue scale line. A Minilith SL1 (Storz Medical, Switzerland) litotriptor was used. The parabolic reflector is coupled to the skin with a silicon water cushion. Focal pressure was adjusted between 6 and 70 Mpa in eight steps. The energy flux density was variable from 0.03 to 0.5 mJ/mm2. Focal diameter and distance were defined (depth of target within the patient's foot of about 70 mm). The coded intensity used in this study was between 6 and 8 and the application time was 20 min (at four impulses per second). Twenty-eight of the 30 patients with CLI (15 with rest pain only and 13 with necrosis) completed the study. The treatment was well tolerated. Blood pressure was unchanged after 8 weeks while the increase in laser Doppler flux was significant (p<0.05) (at all measurements after treatment). The ORACLE score at 1 and 8 weeks was decreased (p<0.05). The same trend was observed with the analogue scale line for pain (p<0.05). PO2 increased (p<0.05) and Pco2 decreased (p<0.05). Tibial pressure did not

  7. Phase Ib Safety, Two-Dose Study of MultiGeneAngio in Patients with Chronic Critical Limb Ischemia.

    PubMed

    Flugelman, Moshe Y; Halak, Moshe; Yoffe, Boris; Schneiderman, Jacob; Rubinstein, Chen; Bloom, Allan-Isaac; Weinmann, Eran; Goldin, Ilya; Ginzburg, Victor; Mayzler, Olga; Hoffman, Aaron; Koren, Belly; Gershtein, Diana; Inbar, Michal; Hutoran, Marina; Tsaba, Adili

    2017-03-01

    Critical limb ischemia (CLI) is the most severe presentation of peripheral arterial disease. We developed cell-based therapy entailing intra-arterial injection of autologous venous endothelial cells (ECs) modified to express angiopoietin 1, combined with autologous venous smooth muscle cells (SMCs) modified to express vascular endothelial growth factor. This combination promoted arteriogenesis in animal models and was safe in patients with limiting claudication. In an open-label, phase Ib study, we assessed the safety and efficacy of this therapy in CLI patients who failed or were unsuitable for surgery or intravascular intervention. Of 23 patients enrolled, 18 with rest pain or non-healing ulcers (Rutherford categories 4 and 5) were treated according to protocol, and 5 with significant tissue loss (Rutherford 6) were treated under compassionate treatment. Patients were assigned randomly to receive 1 × 10(7) or 5 × 10(7) (EC-to-SMC ratio, 1:1) of the cell combination. One-year amputation-free survival rate was 72% (13/18) for Rutherford 4 and 5 patients; all 5 patients with Rutherford 6 underwent amputation. Of the 12 with unhealing ulcers at dosing, 6 had complete healing and 2 others had >66% reduction in ulcer size. Outcomes did not differ between the dose groups. No severe adverse events were observed related to the therapy. Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

  8. Two-year outcome after Xpert stent implantation for treating below the knee lesions in critical limb ischemia.

    PubMed

    Bosiers, Marc; Lioupis, Christos; Deloose, Koen; Verbist, Jürgen; Peeters, Patrick

    2009-01-01

    We investigated the efficacy of Xpert (Abbott Vascular, Abbott Park, IL) nitinol stents for the treatment of infrapopliteal lesions in patients with Critical Limb Ischemia (CLI). Between May 2005 and November 2007, 94 CLI patients (70 male, mean age 73.5 years) received 134 Xpert stents in 102 limbs. Seventy-nine patients (71.2%) were scored as Rutherford Category 4, 31 patients (27.9%) as Category 5 and 1 patient (0.9%) as Category 6. Primary endpoint of this study was defined as 2-year duplex derived primary patency. Secondary endpoints were 2-year limb salvage rate and the absence of reintervention after the index procedure. Kaplan Meier analysis reported 2-year primary patency and limb salvage rates of 54.4% and 90.8%, respectively. Stratification by lesion location did not reveal any significant differences in 2-year primary patency rates in proximal and distal below the knee lesions. Our results suggest that treatment with nitinol Xpert stents can be considered effective for treating CLI patients, with satisfying patency outcome.

  9. The Use of Below-Knee Percutaneous Transluminal Angioplasty in Arterial Occlusive Disease Causing Chronic Critical Limb Ischemia

    SciTech Connect

    Loefberg, Ann-Marie; Loerelius, Lars-Erik; Karacagil, Sadettin; Westman, Bo; Almgren, Bo; Berqgvist, David

    1996-09-15

    Purpose: To determine the efficacy, safety and long-term results of crural artery percutaneous transluminal angioplasty (PTA) in limbs with chronic critical limb ischemia (CLI). Methods: Patients undergoing crural artery PTA due to CLI were followed at regular clinic visits with ankle brachial pressure index (ABPI) measurements. PTA of the crural arteries was attempted either alone (n= 39) or in combination with PTA of the superficial and/or popliteal artery (n= 55) in 86 limbs (82 patients and 94 procedures) presenting with CLI. The ages of patients ranged from 37 to 94 years (mean 72 years). The indications for PTA were rest pain in 10 and ulcer/gangrene in 84 limbs.Results: A technically successful PTA with at least one crural level was achieved in 88% of cases (n= 83). Cumulative primary clinical success rates at 6, 12, 24, and 36 months were 55%, 51%, 36%, and 36%, respectively. Cumulative secondary clinical success and limb salvage rates at 36 months were 44% and 72%, respectively. Conclusion: PTA of the crural arteries might be considered the primary choice of treatment in patients with CLI and distal lesions with localized stenosis or segmental short occlusions.

  10. Angiographic study of upper limb vascularization in a large cohort of hemodialysis patients with critical hand ischemia.

    PubMed

    Ferraresi, Roberto; Acuña-Valerio, Jorge; Ferraris, Matteo; Fresa, Marco; Hamade, Meneme; Danzi, Gian B; Gandini, Roberto; Mauri, Giovanni

    2016-12-01

    Critical hand ischemia (CHI) is a not rare condition in patients with end-stage-renal-disease on hemodialysis (HD), and presents devastating consequences due to its impact on life quality. In HD patients CHI may be related to three main conditions: obstruction of the big upper limb arteries, obstruction of the small hand and finger arteries, and the steal effect of a hemodialysis access. The aim of this study was to describe the angiographic pattern of upper limb vascularization and associated cardiovascular risk factors, in a large cohort of consecutive HD patients with CHI studied in our center. In our center 114 HD consecutive patients (age 64±10 years) with a total of 132 upper limbs affected by CHI (21 with rest pain and 93 with tissue loss) underwent angiography in our center. The majority of them were diabetic males. We computed the prevalence of obstructive disease for each vascular segment of the upper limb. Above-the-elbow arteries were mostly spared, while below-the-elbow and hand arteries were extensively affected. We found a stenosis or occlusion in humeral artery (2.3%), radial (61.4%) or ulnar (90.1%) arteries, deep palmar arch (51.5%), superficial palmar arch (58.3%) and digital arteries (72.4%). In 42.4% of cases an ipsilateral functioning arteriovenous fistula was present. CHI in HD patients is a result of below-the-elbow and hand vessel obstruction and is not primarily related to dialysis access.

  11. Prevalence and Impact of Critical Limb Ischemia on In-Hospital Outcome in Transcatheter Aortic Valve Implantation in Germany.

    PubMed

    Malyar, Nasser M; Kaier, Klaus; Freisinger, Eva; Lüders, Florian; Kaleschke, Gerrit; Baumgartner, Helmut; Frankenstein, Lutz; Reinecke, Holger; Reinöhl, Jochen

    2017-09-05

    Peripheral artery disease (PAD) is common in patients with aortic valve stenosis (AS). We assessed the prevalence of critical limb ischemia (CLI) and its impact on in-hospital outcome in patients undergoing transcatheter aortic valve implantation (TAVI) for severe AS. All isolated TAVI in Germany between 2007 and 2013 for AS were analysed regarding stage specific prevalence of PAD, comorbidities, in-hospital complications and mortality using diagnostic and procedural codes. Among 32,044 patients with TAVI, 3,375 (10.5%) had PAD and 654 (2.0%) CLI. TAVI patients with PAD, particularly those with CLI, had higher incidence of periprocedural stroke, bleeding and acute kidney injury (P<0.001). The overall in-hospital mortality among TAVI without PAD, non-CLI PAD and CLI was 6.1%, 8.4% and 14.7%, respectively (P<0.001). In a multivariate logistic regression analysis CLI was an independent predictor of in-hospital mortality (odds ratio 1.96; 95% confidence interval 1.56-2.47; P<0.001). In patients undergoing TAVI, presence of PAD is associated with an increased risk of periprocedural complications, while only CLI predicts independently increased in-hospital mortality. Whether CLI represents a marker of general poor health status resulting in the poor outcome or a modifiable risk factor whose treatment prior to TAVI can improve the outcome requires prospective studies.

  12. The BEST-CLI trial: a multidisciplinary effort to assess which therapy is best for patients with critical limb ischemia.

    PubMed

    Farber, Alik; Rosenfield, Kenneth; Menard, Matthew

    2014-09-01

    Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease and is associated with a significant risk of limb loss. It is currently treated with limb revascularization by a variety of specialists. Although both open vascular bypass and endovascular therapy are offered to patients with infrainguinal peripheral arterial disease and CLI, significant disagreement exists as to which therapy works best in candidates for both types of intervention. Persistent clinical equipoise in combination with a paucity of comparative effectiveness data to guide treatment of CLI has led to a multidisciplinary effort to organize the Best Endovascular versus Best Surgical Therapy in patients with CLI (BEST-CLI) trial. The BEST-CLI trial is a pragmatic, multicenter, open label, randomized trial that compares best endovascular therapy with best open surgical treatment in patients eligible for both treatments. This trial is highly innovative in both its design and its collaborative nature. BEST-CLI aims to provide urgently needed clinical guidance for CLI management by using (1) a pragmatic design comparing the effectiveness of established techniques while allowing for the introduction of newer therapies as they become available; (2) a novel primary end point that includes limb amputation rates, repeat intervention, and mortality; (3) a multidisciplinary structure that fosters cooperation among interventional cardiologists, interventional radiologists, vascular surgeons, and vascular medicine specialists; and (4) novel techniques to evaluate the cost-effectiveness and quality-of-life outcomes of the 2 treatment strategies being tested. Copyright © 2014 Elsevier Inc. All rights reserved.

  13. Prediction of Limb Salvage after Therapeutic Angiogenesis by Autologous Bone Marrow Cell Implantation in Patients with Critical Limb Ischemia

    PubMed Central

    Tara, Shuhei; Miyamoto, Masaaki; Takagi, Gen; Fukushima, Yoshimitsu; Kirinoki-ichikawa, Sonoko; Takano, Hitoshi; Takagi, Ikuyo; Mizuno, Hiroshi; Yasutake, Masahiro; Kumita, Shinichiro; Mizuno, Kyoichi

    2011-01-01

    Purpose: Despite advances in therapeutic angiogenesis by bone marrow cell implantation (BMCI), limb amputation remains a major unfavorable outcome in patients with critical limb ischemia (CLI). We sought to identify predictor(s) of limb salvage in CLI patients who received BMCI. Materials and Methods: Nineteen patients with CLI who treated by BMCI were divided into two groups; four patients with above-the-ankle amputation by 12 weeks after BMCI (amputation group) and the remaining 15 patients without (salvage group). We performed several blood-flow examinations before BMCI. Ankle-brachial index (ABI) was measured with the standard method. Transcutaneous oxygen tension (TcPO2) was measured at the dorsum of the foot, in the absence (baseline) and presence (maximum TcPO2) of oxygen inhalation. 99mtechnetium-tetrofosmin (99mTc-TF) perfusion index was determined at the foot and lower leg as the ratio of brain. Results: Maximum TcPO2 (p = 0.031) and 99mTc-TF perfusion index in the foot (p = 0.0068) was significantly higher in the salvage group than in the amputation group. Receiver operating characteristic (ROC) curve analysis identified maximum TcPO2 and 99mTc-TF perfusion index in the foot as having high predictive accuracy for limb salvage. Conclusion: Maximum TcPO2 and 99mTc-TF perfusion index in the foot are promising predictors of limb salvage after BMCI in CLI. PMID:23555423

  14. Heparin-bonded expanded polytetrafluoroethylene grafts for infragenicular bypass in patients with critical limb ischemia: 2-year results.

    PubMed

    Dorrucci, V; Griselli, F; Petralia, G; Spinamano, L; Adornetto, R

    2008-04-01

    The use of prosthetic grafts in below-knee (BK) bypasses may be necessary in patients with no available autologous vein and critical limb ischemia not amenable to angioplasty. Such conduits, however, have generally yielded disappointing results. A new heparin-bonded expanded polytetrafluoroethylene graft (Gore-Tex Propaten Vascular Graft) designed to provide resistance to thrombosis may be associated with decreased early graft failure and increased patency. This graft was implanted in 27 limbs (26 patients; 18 men; mean age 71 years; Rutherford class 4 to 6 disease) in a BK femoropopliteal and femorodistal location, without perioperative complications and with immediate graft patency. During a mean follow-up time of 24 months, 4 cases of thrombosis occurred, all at least 6 months postoperatively: 2 cases resolved after fibrinolytic treatment, 1 required surgical revision and in 1 case, amputation was required because of a delay in seeking treatment for thrombosis. Two patients died of cardiac disease during follow-up. The 2-year primary and secondary patency rates for the BK bypasses were 85% and 93%, respectively; the limb-salvage rate was 96%. These results are encouraging for a prosthetic graft, especially in the light of the severity of the vascular disease in the limbs treated.

  15. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study.

    PubMed

    Lee, Han Cheol; An, Sung Gyu; Lee, Hye Won; Park, Jin-Sup; Cha, Kwang Soo; Hong, Taek Jong; Park, Jong Ha; Lee, Sun Young; Kim, Sang-Pil; Kim, Yeong Dae; Chung, Sung Woon; Bae, Yong Chan; Shin, Yong Beom; Kim, Jeung Il; Jung, Jin Sup

    2012-01-01

    Treatment of critical limb ischemia (CLI) by bypass operation or percutaneous vascular intervention is occasionally difficult. The safety and efficacy of multiple intramuscular adipose tissue-derived mesenchymal stem cells (ATMSC) injections in CLI patients was determined in the study. The study included 15 male CLI patients with ischemic resting pain in 1 limb with/without non-healing ulcers and necrotic foot. ATMSC were isolated from adipose tissue of thromboangiitis obliterans (TAO) patients (B-ATMSC), diabetes patients (D-ATMSC), and healthy donors (control ATMSC). In a colony-forming unit assay, the stromal vascular fraction of TAO and diabetic patients yielded lesser colonies than that of healthy donors. D-ATMSC showed lower proliferation abilitythan B-ATMSC and control ATMSC, but they showed similar angiogenic factor expression with control ATMSC and B-ATMSC. Multiple intramuscular ATMSC injections cause no complications during the follow-up period (mean follow-up time: 6 months). Clinical improvement occurred in 66.7% of patients. Five patients required minor amputation during follow-up, and all amputation sites healed completely. At 6 months, significant improvement was noted on pain rating scales and in claudication walking distance. Digital subtraction angiography before and 6 months after ATMSC implantation showed formation of numerous vascular collateral networks across affected arteries. Multiple intramuscular ATMSC injections might be a safe alternative to achieve therapeutic angiogenesis in patients with CLI who are refractory to other treatment modalities.

  16. FDA perspective on objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia.

    PubMed

    Kumar, Allison; Brooks, Steven S; Cavanaugh, Kenneth; Zuckerman, Bram

    2009-12-01

    The article by Conte et al.(1) on behalf of the Society for Vascular Surgery (SVS) in this issue of the Journal of Vascular Surgery provides guidelines for improving the consistency and interpretability of clinical trials intended to evaluate treatment options for patients with critical limb ischemia (CLI). This article identifies a number of key challenges with conducting and comparing CLI trials, including the wide spectrum of clinical presentations that CLI encompasses, the use of disparate eligibility criteria and endpoint measurements, and logistical and economic considerations that can limit study initiation and completion. The authors propose definitions for a number of performance goals derived from historical surgical literature as a means of reducing the negative impact of these factors. The current editorial reviews aspects of this proposal from the perspective of the authors in terms of their understanding of the statutory obligations of the U.S. Food and Drug Administration (FDA) to regulate the marketing of cardiovascular devices based on valid scientific evidence.

  17. [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

    2016-01-23

    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.

  18. Sulodexide as Adjunctive Therapy in Diabetic Foot Patients With Critical Limb Ischemia Treated With Percutaneous Transluminal Angioplasty.

    PubMed

    Piaggesi, Alberto; Abbruzzese, Lorenza; Mattaliano, Chiara; Bargellini, Irene; Cicorelli, Antonello; Iacopi, Elisabetta; Lunardi, Alessandro; Coppelli, Alberto; Goretti, Chiara; Cioni, Roberto

    2014-06-01

    We evaluated the safety and efficacy of sulodexide, a biocompound of glycosamin-glicans, as adjunct medical therapy to percutaneous transluminal angioplasty (PTA) in diabetes mellitus (DM) patients with critical limb ischemia (CLI). We studied 27 consecutive DM patients with CLI successfully subjected to PTA who, on top of standard antiplatelet therapy, received sulodexide 25 mg bid, and were followed-up for 24 weeks, monitoring adverse events, transcutaneous oxygen tension (TcPO2), ankle-brachial pressure index, pain, and ulcer dimension. At the end of follow-up, ulcer healing, amputation rates, and cardiovascular risk profile of patients were evaluated. Patients were compared with a historical superimposable control group that was treated for the same indications in the same way as the study group, except for sulodexide inception. No differences in ulcer healing and amputation rates were found at the end of follow-up between the groups. In the study group, TcPO2 was significantly (P < .05) higher at the end of follow-up, and pain intensity was reduced more rapidly. Plasma fibrinogen and plasma creatinine concentration were significantly (P < .05) reduced in study group at the end of follow-up. No differences in adverse events were observed between the groups during follow-up. Our data suggest that sulodexide administration after PTA, on top of antiplatelet therapy, may improve the outcome of PTA in DM patients with CLI by improving microcirculatory function.

  19. Pedal-plantar loop technique for a challenging below-the-knee chronic total occlusion: a novel approach to percutaneous revascularization in critical lower limb ischemia.

    PubMed

    Fusaro, Massimiliano; Dalla Paola, Luca; Biondi-Zoccai, Giuseppe

    2007-02-01

    Arterial revascularization by means of percutaneous transluminal angioplasty (PTA) is a mainstay in the management of patients with peripheral artery disease and critical limb ischemia (CLI). However, when employing standard approaches, percutaneous transluminal angioplasty (PTA) of below-the-knee arteries may fail in up to 20% of cases. In the present article, we report on a novel interventional strategy, the pedal-plantar loop technique, which we successfully employed in a patient with critical lower limb ischemia. This technique may sensibly increase success rates of PTA in very challenging total occlusions of below-the-knee arteries (e.g., those lacking a proximal occlusion stump). Technical points pertinent to this case are clearly illustrated, including the need to accurately choose guidewires and balloons of appropriate length, and the extensive use of the subintimal angioplasty technique.

  20. 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

  1. 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

  2. Infrapopliteal calcification patterns in critical limb ischemia: diagnostic, pathologic and therapeutic implications in the search for the endovascular holy grail.

    PubMed

    Mustapha, Jihad A; Diaz-Sandoval, Larry J; Saab, Fadi

    2017-06-01

    Critical limb ischemia (CLI) represents the terminal stage of peripheral arterial disease (PAD) and is characterized by multilevel and multivessel disease. Amongst patients with infrainguinal disease, approximately one third have predominantly isolated infrapopliteal disease and the remaining two thirds, a combination of femoropopliteal and infrapopliteal disease. Isolated infrapopliteal disease is mainly seen in the elderly, diabetic, or dialysis-dependent patients. These patients have higher risk of amputation and shorter amputation-free survival. Infrapopliteal disease presents with either complex high-grade calcified tandem lesions in multiple vessels or with long chronic total occlusion (CTO) segments with plaques characterized by higher calcium and lower fibro-fatty content than the inflow vessels, as arterial calcium deposition increases as we progress distally in the arterial tree. Vascular calcification occurs in both intima and media. Intimal calcification leads to development of calcified atheroma and occlusive lesions. Medial calcification leads to stiffening and decrease in arterial wall elasticity and compliance leading to atherosclerosis, reduced perfusion, and PAD, increasing cardiovascular mortality among patients with end-stage renal disease. This article attempts to review the implications of the diverse pathologic patterns of calcium distribution in infrapopliteal vessels of CLI patients, on the diagnostic modalities, technological developments, and the evolution of therapeutic approaches to improve outcomes among these patients. A critical analysis of the currently available data is provided, pointing to the surprising omission on the role of calcium on outcomes, and future directions are discussed. Is infrapopliteal calcium a roadblock or the avenue towards new paths? Necessity remains the mother of invention.

  3. Results of distal revascularization in elderly patients for critical ischemia of the lower limbs.

    PubMed

    Illuminati, G; Calio, F G; Bertagni, A; Piermattei, A; Vietri, F; Martinelli, V

    1999-04-01

    Thirty eight patients over 75 years of age were operated upon of 40 distal arterial revascularizations for critical ischaemia of the lower limbs. Arterial reconstruction was proposed to ambulatory, self sufficient patients, with a patent artery of the leg or the foot in continuity with pedal arch, at arteriography. The revascularized artery was the peroneal in 14 cases, the anterior tibial in 11, the posterior tibial in 9, the dorsalis pedis in 5, and the external plantar artery in 1 case. Postoperative mortality was 2.6%. No postoperative arterial occlusion occurred and no postoperative amputation needed to be performed. The mean follow-up of 37 patients surviving operation was 21 months (ext. 2-52 months). At 36 months interval, patients' survival was 43%, primary patency rate was 57%, and limb salvage rate was 76%, at life-table analysis. Distal revascularization enables a good number of elderly patients in critical ischaemia of the lower limb, to enjoy an active, independent life, with a viable limb.

  4. The significance of regional hemoglobin oxygen saturation values and limb-to-arm ratios of near-infrared spectroscopy to detect critical limb ischemia.

    PubMed

    Boezeman, Reinout Pe; Boersma, Doeke; Wille, Jan; Kelder, Johannes C; Visscher, Mareije I; Waanders, Frans Gj; Moll, Frans L; de Vries, Jean-Paul Pm

    2016-10-01

    This study examines the application of near-infrared spectroscopy to noninvasively detect critical limb ischemia using regional hemoglobin oxygen saturation in percentage values and regional hemoglobin oxygen saturation limb-to-arm ratios. The regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios were calculated in 61 patients with critical limb ischemia (group A). Measurements were performed in rest at four fixed spots at the most affected lower limb and at a reference spot at both upper arms. Similar measurements were performed in the left lower limb of 30 age-matched control patients without peripheral arterial disease (group B). The regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios were significantly different at all measured spots between the groups (all p < 0.001), except for the regional hemoglobin oxygen saturation limb-to-arm ratios of the distal vastus lateralis (p = 0.056). However, a broad overlap of individual regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios was found in both groups, which resulted in poor discriminative predictive value of single measurements. Single measurements of regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios at all measured spots have poor discriminative predictive value in detection of critical limb ischemia. Measurement of regional hemoglobin oxygen saturation values and regional hemoglobin oxygen saturation limb-to-arm ratios at any of the measurement spots has no added value in detecting lower limb ischemia in individuals compared with current diagnostic modalities. © The Author(s) 2015.

  5. Monitoring of cerebral blood flow and ischemia in the critically ill.

    PubMed

    Miller, Chad; Armonda, Rocco

    2014-12-01

    Secondary ischemic injury is common after acute brain injury and can be evaluated with the use of neuromonitoring devices. This manuscript provides guidelines for the use of devices to monitor cerebral blood flow (CBF) in critically ill patients. A Medline search was conducted to address essential pre-specified questions related to the utility of CBF monitoring. Peer-reviewed recommendations were constructed according to the GRADE criteria based upon the available supporting literature. Transcranial Doppler ultrasonography (TCD) and transcranial color-coded duplex sonography (TCCS) are predictive of angiographic vasospasm and delayed ischemic neurological deficits after aneurysmal subarachnoid hemorrhage. TCD and TCCS may be beneficial in identifying vasospasm after traumatic brain injury. TCD and TCCS have shortcomings in identifying some secondary ischemic risks. Implantable thermal diffusion flowmetry (TDF) probes may provide real-time continuous quantitative assessment of ischemic risks. Data are lacking regarding ischemic thresholds for TDF or their correlation with ischemic injury and clinical outcomes.TCD and TCCS can be used to monitor CBF in the neurocritical care unit. Better and more developed methods of continuous CBF monitoring are needed to limit secondary ischemic injury in the neurocritical care unit.

  6. 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

    2017-08-11

    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.

  7. Combined autologous bone marrow mononuclear cell and gene therapy as the last resort for patients with critical limb ischemia

    PubMed Central

    Skóra, Jan; Pupka, Artur; Janczak, Dariusz; Barć, Piotr; Dawiskiba, Tomasz; Korta, Krzysztof; Baczyńska, Dagmara; Garcarek, Jerzy

    2014-01-01

    Introduction Our study was designed to investigate the safety and efficacy of combined autologous bone marrow mononuclear cell (MNC) and gene therapy in comparison to conventional drug therapy in patients with critical limb ischemia (CLI). Material and methods Thirty-two patients with CLI persisting for 12–48 months (average time 27.5 months) were randomized into 2 groups, each group consisting of 16 patients. In the first group, administration of autologous bone marrow MNC and vascular endothelial growth factor (VEGF) plasmid was performed. The patients from the second group were treated pharmacologically with pentoxifylline. Ankle-brachial index (ABI) was measured and angiography was performed before and finally 3 months after treatment. The pain was evaluated using the Visual Analog Scale (VAS) before and after 3 months. Results Ankle-brachial index improved significantly from 0.29 ±0.21 to 0.52 ±0.23 (p < 0.001) in 12 patients (75.0%) 3 months after the experimental therapy in group 1. In this group angiography showed the development of collateral vessels. Ischemic ulcers healed completely in 11 patients (68.75%). In group 2 the ABI did not improve in any patient; moreover the complete healing of skin ulcers was not found in any of the patients of this group. Amputation was performed in 4 (25.0%) patients in group 1, and in 8 patients (50%) from group 2. Conclusions These data after 3-month follow-up indicate that intramuscular injection of MNC combined with gene therapy in patients with chronic CLI is safe, and a more feasible and effective method of treatment than the conventional therapy. However, both therapies are limited by the degree of microcirculation damage. PMID:25995748

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

    SciTech Connect

    Torres-Blanco, Álvaro Edo-Fleta, Gemma; Gómez-Palonés, Francisco; Molina-Nácher, Vicente; Ortiz-Monzón, Eduardo

    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 underwent 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.

  9. Intraoperative adjunctive stem cell treatment in patients with critical limb ischemia using a novel point-of-care device.

    PubMed

    Kolvenbach, R; Kreissig, Carla; Cagiannos, Catherine; Afifi, Rana; Schmaltz, Eva

    2010-04-01

    In a prospective trial we tested whether adjunctive intraoperative stem cell treatment in patients with critical limb ischemia (CLI) can be performed safely in combination with bypass surgery and/or interventional treatment. The end point of our study was the safety and integrity of a novel point-of-care system used in patients with CLI. We included only patients with CLI and tissue loss according to Rutherford categories 4-6. The Harvest Bone Marrow Aspirate Concentrate System consists of an automated, microprocessor-controlled dedicated centrifuge with decanting capability and the accessory BMAC Pack for processing a patient's bone marrow aspirate (BMA). The centrifuge is portable and enables BMA to be rapidly processed in the operating room to provide an autologous concentrate of nucleated cells for immediate injection. The surgeon aspirated 120 ml BMA from the iliac crest. Eight consecutive patients were treated according to the study protocol. The mean follow-up period was 9.2 months (range 2-18). Stem cells were always injected during the final revascularization attempt. One minor amputation and two major amputations were required. In five of eight patients there was a discrete increase in the ankle-brachial index post-stem cell treatment. The dose of stem cells after centrifugation was 17.2 (range 13.8-54.2)x10E6 CD34-positive cells and 7.8 (range 1.8-35.9)x10E6 CD133-positive cells. The injected dose of VEGFR-2-coexpressing stem cells was 0.5-5.7x10E4. We were able to show that the buffy coat preparation using a point-of-care system is a simple and fast method to enrich stem cells from BMAs. This automated system gives high recovery rates and good reproducibility. Copyright (c) 2010 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.

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

    SciTech Connect

    Gandini, Roberto; Uccioli, Luigi; Spinelli, Alessio; Del Giudice, Costantino Ros, Valerio Da; Volpi, Tommaso; Meloni, Marco; Simonetti, Giovanni

    2013-02-15

    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 56 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.

  11. Preliminary study of laser doppler perfusion signal by wavelet transform in patients with critical limb ischemia before and after revascularization.

    PubMed

    Ticcinelli, Valentina; Martini, Romeo; Bagno, Andrea

    2014-01-01

    The haemodynamics of skin microcirculation can be quantitatively evaluated by Laser Doppler Fluxmetry (LDF). LDF signal in human skin shows periodic oscillations. Spectral analysis by wavelet transform displays six characteristic frequency intervals (FI) from 0.005 to 2 Hz, related to distinct vascular structures activities: heart (0.6-2 Hz), sympathetic respiratory (0.145-0.6 Hz), myogenic (0.052-0.145 Hz), local sympathetic nerve (0.021-0.052 Hz) and endothelial cells NO dependent (0.0095-0.021 Hz) and NO independent (0.005-0.0095 Hz). The most advanced stage of peripheral arterial obstructive disease is the critical limb ischemia (CLI), which causes the reduction of blood perfusion threatening limb viability. Besides macrocirculatory alterations, many studies have shown microvascular misdistribution of skin blood flow as the main factor that leads patients to CLI. Revascularization can save limb and patient's life, too. In the present study, LDF signals have been recorded on the skin of the foot dorsum in 15 patients suffering from CLI. LDF signals have been analyzed before and after limb revascularization by means of the wavelet analysis. Significant changes in frequency distribution before and after limb revascularization have been detected: the median normalized values of spectral power increases for 49.8% (p = 0.0341) in the frequency range 0.050328-0.053707 Hz, whereas spectral power decreases for 77.1% (p = 0.0179) in the frequency range 0.018988-0.029284 Hz. We can conclude that changes in the frequency intervals occur after revascularization, shifting from a prevailing endothelial activity toward a prevailing sympathetic activity.

  12. Therapeutic potential of sustained-release sodium nitrite for critical limb ischemia in the setting of metabolic syndrome

    PubMed Central

    Polhemus, David J.; Bradley, Jessica M.; Islam, Kazi N.; Brewster, Luke P.; Calvert, John W.; Tao, Ya-Xiong; Chang, Carlos C.; Pipinos, Iraklis I.; Goodchild, Traci T.

    2015-01-01

    Nitrite is a storage reservoir of nitric oxide that is readily reduced to nitric oxide under pathological conditions. Previous studies have demonstrated that nitrite levels are significantly reduced in cardiovascular disease states, including peripheral vascular disease. We investigated the cytoprotective and proangiogenic actions of a novel, sustained-release formulation of nitrite (SR-nitrite) in a clinically relevant in vivo swine model of critical limb ischemia (CLI) involving central obesity and metabolic syndrome. CLI was induced in obese Ossabaw swine (n = 18) by unilateral external iliac artery deployment of a full cross-sectional vessel occlusion device positioned within an endovascular expanded polytetrafluoroethylene-lined nitinol stent-graft. At post-CLI day 14, pigs were randomized to placebo (n = 9) or SR-nitrite (80 mg, n = 9) twice daily by mouth for 21 days. SR-nitrite therapy increased nitrite, nitrate, and S-nitrosothiol in plasma and ischemic skeletal muscle. Oxidative stress was reduced in ischemic limb tissue of SR-nitrite- compared with placebo-treated pigs. Ischemic limb tissue levels of proangiogenic growth factors were increased following SR-nitrite therapy compared with placebo. Despite the increases in cytoprotective and angiogenic signals with SR-nitrite therapy, new arterial vessel formation and enhancement of blood flow to the ischemic limb were not different from placebo. Our data clearly demonstrate cytoprotective and proangiogenic signaling in ischemic tissues following SR-nitrite therapy in a very severe model of CLI. Further studies evaluating longer-duration nitrite therapy and/or additional nitrite dosing strategies are warranted to more fully evaluate the therapeutic potential of nitrite therapy in peripheral vascular disease. PMID:25910804

  13. Ultrasound-Guided Arterial Access: Outcomes Among Patients With Peripheral Artery Disease and Critical Limb Ischemia Undergoing Peripheral Interventions.

    PubMed

    Mustapha, J A; Diaz-Sandoval, Larry J; Jaff, Michael R; Adams, George; Beasley, Robert; Finton, Sara; McGoff, Theresa; Miller, Larry E; Ansari, Mohammad; Saab, Fadi

    2016-06-01

    Arterial cannulation is a vital component of endovascular interventions and often unconventional access approaches are required due to disease complexity. Historically, varying maneuvers have been utilized to obtain arterial access. Lack of consensus exists regarding the safest and most effective method. This study examined the feasibility and immediate outcomes of ultrasound-guided access in traditional and advanced access approaches. Data were analyzed from a cohort of 407 patients enrolled in the Peripheral RegIstry of Endovascular Clinical OutcoMEs (PRIME). The 407 patients underwent 649 procedures with 896 access sites utilized. Access success, immediate outcomes, complications, and length of hospital stay were analyzed. Mean age was 70 years, and 67% were male. The majority of patients had critical limb ischemia (58%), 39% were Rutherford classification III. Most commonly utilized access sites were common femoral retrograde, common femoral antegrade, posterior tibial, and anterior tibial arteries (34.6%, 33.0%, 12.1%, and 12.1%, respectively). Mean number of attempts was 1.2, 1.2, 1.5, and 1.4, respectively; median time to access was 39, 45, 41, and 59 seconds, respectively; and access success rate was 99.4%, 97.3%, 90.7%, and 92.6%; respectively. Access-site combinations utilized were femoral antegrade (n = 188), femoral retrograde (n = 185), dual femoral/ tibio-pedal (n = 130), dual femoral retrograde (n = 44), retrograde tibio-pedal (n = 73), and other (n = 29). Access-related complications were low overall: hematoma (1.2%), bleeding requiring transfusion/intervention (1.7%), pseudoaneurysm (1.7%), arteriovenous fistula (0.3%), aneurysm (0%), compartment syndrome (0%), and death (0%). Utilization of ultrasound-guided arterial access in this complex cohort was shown to be safe and effective regardless of arterial bed and approach.

  14. Lack of Association Between Limb Hemodynamics and Response to Infrapopliteal Endovascular Therapy in Patients With Critical Limb Ischemia.

    PubMed

    Mustapha, J A; Diaz-Sandoval, Larry J; Adams, George; Jaff, Michael R; Beasley, Robert; McGoff, Theresa; Finton, Sara; Miller, Larry E; Ansari, Mohammad; Saab, Fadi

    2017-05-01

    Non-invasive limb hemodynamics may aid in diagnosis of critical limb ischemia (CLI), although the relationship with disease severity and response to endovascular therapy is unclear. This prospective, single-center study enrolled 100 CLI patients (Rutherford class 4-6) who underwent infrapopliteal endovascular revascularization (175 lesions) in the Peripheral RegIstry of Endovascular Clinical OutcoMEs (PRIME) registry. Hemodynamic measures included ankle-brachial index (ABI), toe-brachial index (TBI), and toe pressure (TP). Procedure success following revascularization was defined as stenosis ≤30%. Hemodynamic success was defined as an increase >0.15 in ABI or TBI relative to baseline. Freedom from amputation was defined as no major or minor amputation during follow-up. Clinical success was defined as a decrease of at least one Rutherford class during follow-up. Treatment success was defined as procedure success, freedom from amputation, and clinical improvement. Median baseline hemodynamic values were 0.90 for ABI, 0.39 for TBI, and 54 mm Hg for TP. Twenty-nine patients (29%) did not meet the common hemodynamic diagnostic criterion for eligibility in CLI trials (ABI ≤0.5, TBI ≤0.5, or TP <50 mm Hg). Main outcomes included 96% procedure success, 95% freedom from amputation, 64% clinical success, and 62% treatment success. There was no relationship between baseline (or with the pretreatment to posttreatment change) limb hemodynamic values and the response to infrapopliteal endovascular therapy. Non-invasive hemodynamic studies may have limited clinical usefulness in patients with CLI. The usefulness of these parameters to confirm eligibility and to assess response to therapy in interventional CLI clinical trials should be re-evaluated.

  15. What is the evidence on efficacy of spinal cord stimulation in (subgroups of) patients with critical limb ischemia?

    PubMed

    Klomp, H M; Steyerberg, E W; Habbema, J D F; van Urk, H

    2009-01-01

    The use of spinal cord stimulation (SCS) has been advocated for the management of ischemic pain and the prevention of amputations in patients with inoperable critical limb ischemia (CLI), although data on benefit are conflicting. Several reports described apparently differential treatment effects in subgroups. The purpose of this study was to analyze the data on the efficacy of SCS and to clarify preselection issues. Five randomized trials have been performed with a total number of 332 patients. Primary outcome measures were mortality and limb survival. In the largest multicenter randomized trial (n = 120), which compared SCS treatment and best medical treatment alone in patients with inoperable CLI, we determined the incidence of amputation and its relation to various predefined risk factors. We used Kaplan-Meier and Cox regression analyses to quantify prognostic effects and differential treatment effects. Meta-analysis yielded a relative risk for amputation of 0.79 and a risk difference of -0.07 (p = 0.15). The risk factor analysis clearly showed that patients with ischemic skin lesions (ulcerations or gangrene) had a worse prognosis (i.e., higher risk of amputation) (relative risk 2.30, p = 0.01). We did not observe significant interactions between this prognostic factor (or any other) and the effect of SCS. The analysis did not indicate a subgroup of patients who might specifically be helped by SCS. Meta-analysis including all randomized data shows insufficient evidence for higher efficacy of SCS treatment compared with best medical treatment alone. Although some factors provide prognostic information as to the risk of amputation in patients with CLI, there are no data supporting a more favorable treatment effect in any group.

  16. Phospholipase A2 of Peroxiredoxin 6 Plays a Critical Role in Cerebral Ischemia/Reperfusion Inflammatory Injury.

    PubMed

    Shanshan, Yu; Beibei, Jiang; Li, Tan; Minna, Gao; Shipeng, Lei; Li, Peng; Yong, Zhao

    2017-01-01

    Microglia-mediated inflammation is an important step in the progression of cerebral ischemia/reperfusion injury and the associated production of receptors of immunomoudulation, including Toll-like receptors (TLRs). Peroxiredoxin 6 (Prdx6) has been demonstrated as the endogenous antioxidant protein for its peroxidase properties. However, the role of the independent phospholipase A2 (iPLA2) activity of Prdx6 in stroke has not been well studied. In this study, we evaluated whether blocking the calcium-iPLA2 activity of Prdx6 using siRNA and inhibitors (1-hexadecyl-3-(trifluoroethgl)-sn-glycerol-2 phosphomethanol, MJ33) would have a critical effect on inflammatory brain damage. We conducted oxygen-glucose deprivation (OGD)/recovery (R) in vitro and middle cerebral artery occlusion (MCAO) in vivo in a microglia/neuron co-culture system and in rats. In vitro, we found that Prdx6-iPLA2 activity was associated with the secretion of neurotoxic inflammatory mediators interleukin1β (IL-1β), interleukin-17 (IL-17) and interleukin-23 (IL-23) and elevated expression of Toll-like receptor 2/4 (TLR2/4), leading to the formation of nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in microglial cells. In vivo, combined treatment with Prdx6-iPLA2 activity inhibitor MJ33 showed a greater diminution in neurologic deficits, cerebral infarction, brain water content and inflammatory molecules than Prdx6-siRNA treatment alone. Our findings provide new insight into Prdx6-iPLA2 function in the brain. Inhibition of Prdx6-iPLA2 activity by gene therapy and/or pharmacology may constitute a promising new therapeutic approach to the treatment of stroke.

  17. Three-Dimensional Rotational Angiography of the Foot in Critical Limb Ischemia: A New Dimension in Revascularization Strategy

    SciTech Connect

    Jens, Sjoerd; Lucatelli, Pierleone; Koelemay, Mark J. W.; Marquering, Henk A. Reekers, Jim A.

    2013-06-15

    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. 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.

  18. Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound.

    PubMed

    Tebebi, Pamela A; Kim, Saejeong J; Williams, Rashida A; Milo, Blerta; Frenkel, Victor; Burks, Scott R; Frank, Joseph A

    2017-02-07

    Mesenchymal stem cells (MSC) are promising therapeutics for critical limb ischemia (CLI). Mechanotransduction from pulsed focused ultrasound (pFUS) upregulates local chemoattractants to enhance homing of intravenously (IV)-infused MSC and improve outcomes. This study investigated whether pFUS exposures to skeletal muscle would improve local homing of iv-infused MSCs and their therapeutic efficacy compared to iv-infused MSCs alone. CLI was induced by external iliac arterial cauterization in 10-12-month-old mice. pFUS/MSC treatments were delayed 14 days, when surgical inflammation subsided. Mice were treated with iv-saline, pFUS alone, IV-MSC, or pFUS and IV-MSC. Proteomic analyses revealed pFUS upregulated local chemoattractants and increased MSC tropism to CLI muscle. By 7 weeks post-treatment, pFUS + MSC significantly increased perfusion and CD31 expression, while reducing fibrosis compared to saline. pFUS or MSC alone reduced fibrosis, but did not increase perfusion or CD31. Furthermore, MSCs homing to pFUS-treated CLI muscle expressed more vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) than MSCs homing to non-pFUS-treated muscle. pFUS + MSC improved perfusion and vascular density in this clinically-relevant CLI model. The molecular effects of pFUS increased both MSC homing and MSC production of VEGF and IL-10, suggesting microenvironmental changes from pFUS also increased potency of MSCs in situ to further enhance their efficacy.

  19. Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound

    PubMed Central

    Tebebi, Pamela A.; Kim, Saejeong J.; Williams, Rashida A.; Milo, Blerta; Frenkel, Victor; Burks, Scott R.; Frank, Joseph A.

    2017-01-01

    Mesenchymal stem cells (MSC) are promising therapeutics for critical limb ischemia (CLI). Mechanotransduction from pulsed focused ultrasound (pFUS) upregulates local chemoattractants to enhance homing of intravenously (IV)-infused MSC and improve outcomes. This study investigated whether pFUS exposures to skeletal muscle would improve local homing of iv-infused MSCs and their therapeutic efficacy compared to iv-infused MSCs alone. CLI was induced by external iliac arterial cauterization in 10–12-month-old mice. pFUS/MSC treatments were delayed 14 days, when surgical inflammation subsided. Mice were treated with iv-saline, pFUS alone, IV-MSC, or pFUS and IV-MSC. Proteomic analyses revealed pFUS upregulated local chemoattractants and increased MSC tropism to CLI muscle. By 7 weeks post-treatment, pFUS + MSC significantly increased perfusion and CD31 expression, while reducing fibrosis compared to saline. pFUS or MSC alone reduced fibrosis, but did not increase perfusion or CD31. Furthermore, MSCs homing to pFUS-treated CLI muscle expressed more vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) than MSCs homing to non-pFUS-treated muscle. pFUS + MSC improved perfusion and vascular density in this clinically-relevant CLI model. The molecular effects of pFUS increased both MSC homing and MSC production of VEGF and IL-10, suggesting microenvironmental changes from pFUS also increased potency of MSCs in situ to further enhance their efficacy. PMID:28169278

  20. Therapeutic angiogenesis with intramuscular NV1FGF improves amputation-free survival in patients with critical limb ischemia.

    PubMed

    Nikol, Sigrid; Baumgartner, Iris; Van Belle, Eric; Diehm, Curt; Visoná, Adriana; Capogrossi, Maurizio C; Ferreira-Maldent, Nicole; Gallino, Augusto; Wyatt, Michael Graham; Wijesinghe, Lasantha Dinesh; Fusari, Melissa; Stephan, Dominique; Emmerich, Joseph; Pompilio, Giulio; Vermassen, Frank; Pham, Emmanuel; Grek, Vincent; Coleman, Michael; Meyer, François

    2008-05-01

    This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.

  1. Characterization of the Cellular Output of a Point-of-Care Device and the Implications for Addressing Critical Limb Ischemia.

    PubMed

    Woodell-May, Jennifer E; Tan, Matthew L; King, William J; Swift, Matthew J; Welch, Zachary R; Murphy, Michael P; McKale, James M

    2015-01-01

    Critical limb ischemia (CLI) is a terminal disease with high morbidity and healthcare costs due to limb loss. There are no effective medical therapies for patients with CLI to prevent amputation. Cell-based therapies are currently being investigated to address this unmet clinical need and have shown promising preliminary results. The purpose of this study was to characterize the output of a point-of-care cell separator (MarrowStim P.A.D. Kit), currently under investigation for the treatment of CLI, and compare its output with Ficoll-based separation. The outputs of the MarrowStim P.A.D. Kit and Ficoll separation were characterized using an automated hematology analyzer, colony-forming unit (CFU) assays, and tubulogenesis assays. Hematology analysis indicated that the MarrowStim P.A.D. Kit concentrated the total nucleated cells, mononuclear cells, and granulocytes compared with baseline bone marrow aspirate. Cells collected were positive for VEGFR-2, CD3, CD14, CD34, CD45, CD56, CD105, CD117, CD133, and Stro-1 antigen. CFU assays demonstrated that the MarrowStim P.A.D. Kit output a significantly greater number of mesenchymal stem cells and hematopoietic stem cells compared with cells output by Ficoll separation. There was no significant difference in the number of endothelial progenitor cells output by the two separation techniques. Isolated cells from both techniques formed interconnected nodes and microtubules in a three-dimensional cell culture assay. This information, along with data currently being collected in large-scale clinical trials, will help instruct how different cellular fractions may affect the outcomes for CLI patients.

  2. Hypertensive extracorporeal limb perfusion (HELP): a new technique for managing critical lower limb ischemia.

    PubMed

    Lane, Rodney J; Phillips, Mark; McMillan, Darryl; Huckson, Matt; Liang, Samuel Wei-Unn; Cuzzilla, Michael

    2008-11-01

    The concept of repeatedly connecting an extracorporeal blood pump to produce pancycle suprasystolic inflow pressures to ischemic limbs is introduced. Balloon catheters allow for limb isolation from the systemic circulation. In the acute phase, it is assumed that pressure is proportion to flow (Poiseuille's Law) and in the chronic phase that collateral growth is related to endothelial shear stress and wall tension. The primary objective was to establish that increased flow could be achieved through collateral circulation in animals and in man with extracorporeal limb hyperperfusion. The second objective was to develop and test an arterial access system capable of intermittent regional hyperperfusion similar in concept to intermittent hemodialysis. Finally, to demonstrate the translocation of these concepts into humans facing major limb amputation where all standard treatment options had been exhausted. Twelve sheep (6 hyperperfusion and 6 controls) were attached to a cardiac vortex pump and perfused at 200 mm Hg pancycle with the superficial femoral artery doubly ligated and isolated from the systemic circulation with a balloon catheter. Pressure transducers measured carotid and distal femoral pressures and the carotid-femoral index was calculated. To allow hyperperfusion to be repeated transcutaneously, a peripheral access system (PAS [Allvascular, St Leonards, New South Wales, Australia]) was constructed. This device was implanted in the common carotid artery in 8 sheep and opened approximately 3 days a week for continuous arterial access up to 37 days for 67 openings. To demonstrate these principles in humans, 3 patients with critically ischemic limbs were hyperperfused intermittently. Digital thermography compared the other limb as controls and provided objective evidence of the vascular changes. The mean carotid-femoral index was 0.6 +/- 0.01 for controls compared with 1.1 +/- 0.28 for the hyperperfusion group (P < .001). The collateral flow was superior to

  3. The mucus layer is critical in protecting against ischemia-reperfusion-mediated gut injury and in the restitution of gut barrier function.

    PubMed

    Qin, Xiaofa; Sheth, Sharvil U; Sharpe, Susan M; Dong, Wei; Lu, Qi; Xu, Dazhong; Deitch, Edwin A

    2011-03-01

    It is well documented that the gut injury plays a critical role in the development of systemic inflammation and distant organ injury in conditions associated with splanchnic ischemia. Consequently, understanding the mechanisms leading to gut injury is important. In this context, recent work suggests a protective role for the intestinal mucus layer and an injury-inducing role for luminal pancreatic proteases. Thus, we explored the role of the mucus layer in gut barrier function by observing how the removal of the mucus layer affects ischemia-reperfusion-mediated gut injury in rats as well as the potential role of luminal pancreatic proteases in the pathogenesis of gut injury. Ischemia was induced by the ligation of blood vessels to segments of the ileum for 45 min, followed by up to 3 h of reperfusion. The ileal segments were divided into five groups. These included a nonischemic control, ischemic segments exposed to saline, the mucolytic N-acetylcysteine (NAC), pancreatic proteases, or NAC + pancreatic proteases. Changes in gut barrier function were assessed by the permeation of fluorescein isothiocyanate dextran (molecular weight, 4,000 d) in ileal everted sacs. Gut injury was measured morphologically and by the luminal content of protein, DNA, and hemoglobin. The mucus layer was assessed functionally by measuring its hydrophobicity and morphologically. Gut barrier function was promptly and effectively reestablished during reperfusion, which was accompanied by the restoration of the mucus layer. In contrast, treatment of the gut with the mucolytic NAC for 10 min during ischemia resulted in a failure of mucus restitution and further increases in gut permeability and injury. The presence of digestive proteases by themselves did not exacerbate gut injury, but in combination with NAC, they caused an even greater increase in gut injury and permeability. These results suggest that the mucus layer not only serves as a barrier between the luminal contents and gut surface

  4. Successful bone marrow transplantation reveals the lack of endothelial progenitor cells mobilization in a patient with critical limb ischemia: a case report.

    PubMed

    Cobellis, G; Botti, C; Taddeo, A; Silvestroni, A; Lillo, S; Da Ponte, A; Villa, M L; Sica, V; Della Bella, S

    2010-09-01

    Restoring blood flow to ischemic tissue is a prerequisite for treatment of ischemic diseases. Cell-based therapy based on bone marrow transplantation is a promising option for patients with critical limb ischemia (CLI). The efficacy of cell therapies to augment neovascularization seems to involve endothelial progenitor cells (EPCs); however, the mechanisms underlying the efficacy have not been fully elucidated. Herein we have described the case of a young patient with severe CLI, who experienced a 24-month beneficial clinical response to autologous bone marrow transplantation. The exceptional amelioration enabled him to perform standardized maximal treadmill exercise test that demonstrated lack of exercise-induced EPC mobilization, despite adequate stromal-derived factor 1 and vascular endothelial growth factor responses. Therefore, tissue ischemia is not sufficient to promote the recruitment of EPCs that have been demonstrated to be involved in the recovery from ischemia. The local implantation of marrow-derived elements may provide cells and/or trophic factors, which have the capacity to augment angiogenesis, opening new approaches to the etiopathogenesis of the disease. 2010 Elsevier Inc. All rights reserved.

  5. Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia.

    PubMed

    Kumagai, Motoyuki; Marui, Akira; Tabata, Yasuhiko; Takeda, Takahide; Yamamoto, Masaya; Yonezawa, Atsushi; Tanaka, Shiro; Yanagi, Shigeki; Ito-Ihara, Toshiko; Ikeda, Takafumi; Murayama, Toshinori; Teramukai, Satoshi; Katsura, Toshiya; Matsubara, Kazuo; Kawakami, Koji; Yokode, Masayuki; Shimizu, Akira; Sakata, Ryuzo

    2016-05-01

    As a form of therapeutic angiogenesis, we sought to investigate the safety and efficacy of a sustained-release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel in patients with critical limb ischemia (CLI). We conducted a phase I-IIa study that analyzed 10 CLI patients following a 200-μg intramuscular injection of bFGF-incorporated gelatin hydrogel microspheres into the ischemic limb. Primary endpoints were safety and transcutaneous oxygen pressure (TcO2) at 4 and 24 weeks after treatment. During the follow-up, there was no death or serious procedure-related adverse event. After 24 weeks, TcO2 (28.4 ± 8.4 vs. 46.2 ± 13.0 mmHg for pretreatment vs after 24 weeks, p < 0.01) showed significant improvement. Regarding secondary endpoints, the distance walked in 6 min (255 ± 105 vs. 318 ± 127 m, p = 0.02), the Rutherford classification (4.4 ± 0.5 vs. 3.1 ± 1.4, p = 0.02), the rest pain scale (1.7 ± 1.0 vs. 1.2 ± 1.3, p = 0.03), and the cyanotic scale (2.0 ± 1.1 vs. 0.9 ± 0.9, p < 0.01) also showed improvement. The blood levels of bFGF were within the normal range in all patients. A subanalysis of patients with arteriosclerosis obliterans (n = 7) or thromboangiitis obliterans (Buerger's disease) (n = 3) revealed that TcO2 had significantly improved in both subgroups. TcO2 did not differ between patients with or without chronic kidney disease. The sustained release of bFGF from biodegradable gelatin hydrogel may offer a safe and effective form of angiogenesis for patients with CLI.

  6. Increased Pre-operative Pulse Pressure Predicts Procedural Complications and Mortality in Patients Undergoing Tibial Interventions for Critical Limb Ischemia

    PubMed Central

    Darling, Jeremy D.; Lee, Vanessa; Schermerhorn, Marc L.; Guzman, Raul J.

    2015-01-01

    Introduction Pulse pressure is a non-invasive measure of arterial stiffness. Elevated pulse pressure is associated with an increased risk of cardiovascular events and death. The effects of pulse pressure on outcomes after endovascular interventions for critical limb ischemia (CLI), however, are unknown. We thus evaluated whether increased pre-operative pulse pressure was associated with adverse outcomes and mortality in patients undergoing endovascular tibial artery intervention. Methods All patients undergoing endovascular tibial intervention for CLI at a single institution from 2004 to 2014 were included in this study. Pre-operative pulse pressure was derived from measurements obtained in the holding area prior to the procedure. Patients were divided into 2 groups based on pulse pressure, < 80 or ≥ 80. Patient demographics and co-morbidities were documented, and outcomes including procedural complications, repeat intervention, amputation, and mortality were recorded. Multivariable logistic regression was utilized to account for patient demographics and comorbidities. Results Of 371 patients, 186 patients had a pre-operative pulse pressure <80 and 185 had a pre-operative pulse pressure ≥80. No significant differences in patient demographics or comorbidities were identified; however there was a trend toward older age in patients with elevated pulse pressure (70 vs. 72, P = 0.07). On univariate analysis, procedural complications (21% vs. 13%, P = 0.02), reinterventions (26% vs. 17%, P < 0.01), and restenosis (32% vs. 23%, P = 0.03) were more common among patients with pulse pressure ≥ 80. Procedural complications remained significant on multivariate analysis (OR 1.8, 95% CI 1.0-3.1, P = 0.04). There was no difference in 30-day mortality; however increased mortality was seen at 5 years of follow-up (OR: 1.6, 95% CI: 1.0-2.5, P = 0.04) following multivariable analysis. Conclusions Increased pre-operative pulse pressure is associated with procedural complications

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

    PubMed Central

    2011-01-01

    Background 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. Methods 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. Results 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. Conclusions BMAC shows promise in improving AMP-free survival if the

  8. Lower extremity autologous vein bypass for critical limb ischemia is not adversely affected by prior endovascular procedure.

    PubMed

    Santo, Vincent J; Dargon, Phong; Azarbal, Amir F; Liem, Timothy K; Mitchell, Erica L; Landry, Gregory J; Moneta, Gregory L

    2014-07-01

    It has been reported that a failed endovascular intervention adversely affects results of lower extremity bypass (LEB). We reviewed rates of prior endovascular intervention (PEI) in patients undergoing LEB with autologous vein for critical limb ischemia (CLI) to determine effects on graft patency, limb salvage, and amputation-free survival. Retrospective review was conducted of consecutive autologous vein LEBs performed for CLI between 2005 and 2012 at a tertiary care academic medical center. Overall, 314 autologous vein LEBs were performed for CLI, 71% for tissue loss. TransAtlantic Inter-Society Consensus II type D or type C lesions were present in 62% and 25%, respectively. The great saphenous vein was used as a conduit in 83%, and the distal target was infrapopliteal in 60%. The 30-day mortality rate was 3.5%. Primary patency rates at 1 year and 5 years were 61% and 45%. Secondary patency rates at 1 year and 5 years were 88% and 64%, with 23% requiring an intervention to maintain patency. The 5-year limb salvage rate was 89%, and the 5-year amputation-free survival was 49%. There were 61 patients (19%) who had undergone a PEI and 253 (81%) who underwent bypass with no prior endovascular intervention (NPEI). There were 19 iliac stents, 29 femoral interventions, 13 popliteal interventions, 9 crural interventions, 9 infrainguinal thrombectomies, and 13 infrainguinal thrombolyses. PEI and NPEI patients had similar demographics and prevalence of atherosclerotic risk factors. The 1-year primary patency rate was 62% for NPEI patients vs 59% for PEI patients (P = .759). The 1-year and 2-year secondary patency rates were 87% and 79% for NPEI patients vs 89% and 78% for PEI patients (P = .947). The 3-year limb salvage rate was 89% for NPEI patients vs 92% for PEI patients (P = .445). The 3-year amputation-free survival was 59% for NPEI patients vs 52% for PEI patients (P = .399). Median follow-up time was 323 days for NPEI patients (interquartile range, 83

  9. 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

  10. Prevalence of Tibial Artery and Pedal Arch Patency by Angiography in Patients With Critical Limb Ischemia and Noncompressible Ankle Brachial Index.

    PubMed

    Randhawa, Mandeep Singh; Reed, Grant W; Grafmiller, Kevin; Gornik, Heather L; Shishehbor, Mehdi H

    2017-05-01

    Approximately 20% of patients undergoing ankle brachial index testing for critical limb ischemia have noncompressible vessels because of tibial artery calcification. This represents a clinical challenge in determining tibial artery patency. We sought to identify the prevalence of tibial artery and pedal arch patency by angiography in these patients. One hundred twenty-five limbs (of 89 patients) with critical limb ischemia and ankle brachial index ≥1.4 who underwent lower extremity angiograms within 1 year were included. Reviewers of angiography were blinded to results of physiological testing. Tibial artery vessels were classified as completely occluded, significantly stenosed (≥50%), or patent (<50% stenosis). The sensitivity of toe brachial index and pulse volume recording to predict tibial artery disease was also determined. Of 125 limbs with noncompressible ankle brachial index, 72 (57.6%) anterior tibial and 80 (64%) posterior tibial arteries were occluded. Another 23 (18.4%) anterior tibial and 13 (10.4%) posterior tibial arteries had ≥50% stenosis. Pulse volume recording was moderate to severely dampened in 54 of 119 (45.4%) limbs. Toe brachial index <0.7 was found in 75 of 83 (90.4%) limbs. Moderate to severe pulse volume recording dampening was 43.6% sensitive, whereas toe brachial index <0.7 was 89.7% sensitive in diagnosing occluded or significantly stenotic tibial artery disease. The pedal arch was absent or incomplete in 86 of 103 (83.5%) limbs. Among patients with critical limb ischemia and noncompressible ankle brachial index results, the prevalence of occlusive tibial and pedal arch disease is very high. Toe brachial index <0.7 is more sensitive in diagnosing occluded and significantly stenotic tibial artery disease in these patients compared with ankle pulse volume recording. © 2017 American Heart Association, Inc.

  11. Myocardial Ischemia

    MedlinePlus

    ... pectoris: Chest pain caused by myocardial ischemia. www.uptodate.com/home. Accessed June 1, 2015. Deedwania PC. Silent myocardial ischemia: Epidemiology and pathogenesis. www.uptodate.com/home. Accessed June 1, 2015. Mann DL, ...

  12. 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.

  13. The effectiveness of percutaneous transluminal angioplasty for the treatment of critical limb ischemia: a 10-year experience.

    PubMed

    Kudo, Toshifumi; Chandra, Fiona A; Ahn, Samuel S

    2005-03-01

    To determine the efficacy, safety, and long-term results, including continued clinical improvement and limb salvage, of percutaneous transluminal angioplasty (PTA) in patients with critical limb ischemia (CLI). From August 1993 to March 2004, 138 limbs in 111 patients with CLI (rest pain in 62 [45%] and ulcer/gangrene in 76 [55%]) were treated by PTA. In iliac lesions, stents were placed selectively for primary PTA failure: residual stenosis (>30%) or pressure gradient (>5 mm Hg). Stent placement was limited in infrainguinal lesions. The most distal affected arteries treated with angioplasty were the iliac artery in 45 limbs (33%; iliac group), the femoropopliteal artery in 41 limbs (30%; FP group), and tibial arteries in 52 limbs (37%; BK group). All analysis was performed according to an intent-to-treat basis. Reporting standards of the Society for Vascular Surgery and the International Society for Cardiovascular Surgery were followed to evaluate initial success, and late follow-up status was evaluated with the Kaplan-Meier method. Patency was evaluated by using ultrasound scanning and ankle-brachial pressure index measurement. There was one (0.9%) perioperative death. Twenty stents were placed selectively in 14 iliac arteries. Mean follow-up was 14.7 months (range, 1-75 months). Overall, initial technical and clinical success rates were 96.4% and 92.8%, respectively. The cumulative primary, assisted primary, and secondary patency; continued clinical improvement; and limb salvage rates +/- SE at 5 years were 31.4% +/- 10.4%, 75.5% +/- 5.7%, 79.6% +/- 5.5%, 36.1% +/- 10.0%, and 89.1% +/- 4.0%, respectively. In each subgroup, the primary, assisted primary, and secondary patency; continued clinical improvement; and limb salvage rates at 3 years were 51.6%, 94.7%, 97.8%, 65.1%, and 95.0%, respectively, in the iliac group; 49.4%, 72.2%, 76.4%, 57.4%, and 92.7%, respectively, in the FP group; and 23.5%, 41.8%, 46.1%, 51.1%, and 77.3%, respectively, in the BK group. Of

  14. Comparison of open and endovascular treatment of patients with critical limb ischemia in the Vascular Quality Initiative.

    PubMed

    Siracuse, Jeffrey J; Menard, Matthew T; Eslami, Mohammad H; Kalish, Jeffrey A; Robinson, William P; Eberhardt, Robert T; Hamburg, Naomi M; Farber, Alik

    2016-04-01

    There is significant controversy in the management of critical limb ischemia (CLI) arising from infrainguinal peripheral arterial disease. We sought to compare practice patterns and perioperative and long-term outcomes for patients undergoing lower extremity bypass (LEB) and percutaneous vascular interventions (PVIs) for CLI in the Vascular Quality Initiative (VQI). The prospectively collected VQI (2010-2013) LEB and PVI databases were retrospectively queried. Demographics, comorbidities, and perioperative outcomes were recorded. We evaluated all patients (cohort 1), those without comorbidities known to increase surgical risk (cohort 2) to control for patient factors, and patients with treatment anatomically limited to the superficial femoral artery (cohort 3) to control for anatomic factors. Multivariable analyses were performed to identify predictors of outcomes. There were 7897 patients with CLI and infrainguinal peripheral arterial disease, 4838 treated with PVI and 3059 with LEB. PVI patients had more comorbidities across all cohorts, whereas those undergoing LEB were more likely to have had a previous revascularization procedure. Follow-up at 1 year was 45.8% for PVI and 53.5% for LEB. After adjustment for comorbidities, cohort 1 patients treated with PVI vs LEB had lower odds of in-hospital or 30-day mortality (odds ratio [OR], 0.59; 95% confidence interval [CI], 0.43-0.81; P = .001). This difference was not seen for the lower risk (cohort 2) patients (OR, 0.66; 95% CI, 0.39-1.14; P = .134) or the superficial femoral artery-only (cohort 3) patients (OR, 1.25; 95% CI, 0.53-2.96; P = .604). The 3-year mortality was higher with PVI in cohort 1 (HR, 1.23; 95% CI, 1.07-1.42; P = .003) and cohort 2 (HR, 1.63; 95% CI, 1.32-2.02; P < .001) but not cohort 3 (HR, 1.18; 95% CI, 0.82-1.71; P = .368). Amputation or death at 1 year was similar for PVI vs LEB in cohort 1 (HR, 0.98; 95% CI, 0.82-1.16; P = .816), cohort 2 (HR, 0.89; 95% CI, 0.7-1.15; P = .37), and

  15. 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

  16. Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia.

    PubMed

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

    2011-06-01

    The purpose of this Phase I open label nonrandomized 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). Between September 2005 and March 2009, 29 patients (30 limbs), with a median age of 66 years (range, 23-84 years; 14 male, 15 female) with CLI were enrolled. Twenty-one 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 × 10(9) ABMNC injected intramuscularly in the index limb distal to the anterior tibial tuberosity. The primary safety end point was accumulation of serious adverse events, and the primary efficacy end point was AFS at 1 year. Secondary end points at 12 weeks posttreatment were changes in first toe pressure (FTP), toe-brachial index (TBI), ankle-brachial index (ABI), and transcutaneous oxygen measurements (TcPO(2)). Perfusion of the index limb was measured with positron emission tomography-computed tomography (PET-CT) with intra-arterial infusion of H(2)O(15). RP, using a 10-cm visual analogue 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. There were two serious adverse events; however, there were no procedure-related deaths. Amputation-free survival at 1 year was 86.3%. There was a significant increase in FTP (10.2 ± 6.2 mm Hg; 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 H(2)O(15

  17. The mucus layer is critical in protecting against ischemia/reperfusion-mediated gut injury and in the restitution of gut barrier function

    PubMed Central

    Qin, Xiaofa; Sheth, Sharvil U.; Sharpe, Susan M.; Dong, Wei; Lu, Qi; Xu, Dazhong; Deitch, Edwin A.

    2011-01-01

    It is well documented that the gut injury plays a critical role in the development of systemic inflammation and distant organ injury in conditions associated with splanchnic ischemia. Consequently understanding the mechanisms leading to gut injury is important. In this context, recent work suggests a protective role for the intestinal mucus layer and an injury-inducing role for luminal pancreatic proteases. Thus, we explored the role of the mucus layer in gut barrier function by observing how the removal of the mucus layer affects ischemia/reperfusion-mediated gut injury in rats as well as the potential role of luminal pancreatic proteases in the pathogenesis of gut injury. Ischemia was induced by the ligation of blood vessels to segments of the ileum for 45 min, followed by up to three hours of reperfusion. The ileal segments were divided into 5 groups. These included a non-ischemic control, ischemic segments exposed to saline, the mucolytic N-acetylcholine (NAC), pancreatic proteases or NAC plus pancreatic proteases. Changes in gut barrier function were assessed by the permeation of fluorescein isothiocyanate dextran (MW 4000 Da; FD4) in ileal everted sacs. Gut injury was measured morphologically and by the luminal content of protein, DNA and hemoglobin. The mucus layer was assessed functionally by measuring its hydrophobicity and morphologically. Gut barrier function was promptly and effectively re-established during reperfusion, which was accompanied by the restoration of the mucus layer. In contrast, treatment of the gut with the mucolytic NAC for 10 min during ischemia resulted in a failure of mucus restitution and further increases in gut permeability and injury. The presence of digestive proteases by themselves did not exacerbate gut injury but in combination with NAC, they caused an even greater increase in gut injury and permeability. These results suggest that the mucus layer not only serves as a barrier between the luminal contents and gut surface

  18. 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.

  19. Femorofemoral grafts for lower limb ischemia caused by intra-aortic balloon pump.

    PubMed

    Friedell, M L; Alpert, J; Parsonnet, V; Brief, D K; Brener, B J; Goldenkranz, R J; Nozick, J

    1987-01-01

    From January 1975 to December 1985, 1454 patients had an intra-aortic balloon inserted for cardiac assistance. Eighty balloon-dependent patients had severe limb ischemia and required a femorofemoral graft (FFG) (5% of the total group of patients). Twenty-nine of the 80 patients with grafts (or 36%) left the hospital and 28 were followed up for an average of 40 months to determine late complications associated with the crossover grafts. All grafts remained patent. The 28 patients were classified into five groups according to the degree and type of lower limb ischemia. Group I consisted of 13 asymptomatic patients (46%); group II had four (14%) patients with mild claudication caused by preexisting peripheral arteriosclerosis; group III comprised four patients (14%) without preexisting disease but claudication subsequent to the FFG; group IV had five patients with irreversible ischemic sequelae before grafting ending in amputation, foot drop, or persistent paresthesia; and group V consisted of two patients with graft infection (7%). The perioperative mortality rate of the balloon-dependent patients with an FFG (64%) reflects the gravity of the cardiac condition. Placement of an FFG to relieve limb ischemia in these patients is followed by few immediate or late complications in the survivors and any persistent limb changes were related to the prolonged ischemia present before revascularization. Our data suggest that in balloon-dependent patients with limb-threatening ischemia, aggressive use of the FFG is limb-saving, durable, and allows continuation of balloon support.

  20. Non-contrast-enhanced MR angiography in critical limb ischemia: performance of quiescent-interval single-shot (QISS) and TSE-based subtraction techniques.

    PubMed

    Altaha, Mustafa A; Jaskolka, Jeffrey D; Tan, Kongteng; Rick, Manuela; Schmitt, Peter; Menezes, Ravi J; Wintersperger, Bernd J

    2017-03-01

    The aim of this study was to evaluate diagnostic performance of non-contrast-enhanced 2D quiescent-interval single-shot (QISS) and 3D turbo spin-echo (TSE)-based subtraction magnetic resonance angiography (MRA) in the assessment of peripheral arteries in patients with critical limb ischemia (CLI). Nineteen consecutive patients (74 % male, 72.8 ± 9.9 years) with CLI underwent 2D QISS and 3D TSE-based subtraction MRA at 1.5 T. Axial-overlapping QISS MRA (3 mm/2 mm; 1 × 1 mm(2)) covered from the toes to the aortic bifurcation while coronal 3D TSE-based subtraction MRA (1.3 × 1.2 × 1.3 mm(3)) was restricted to the calf only. MRA data sets (two readers) were evaluated for stenosis (≥50 %) and image quality. Results were compared with digital subtraction angiography (DSA). Two hundred and sixty-seven (267) segments were available for MRA-DSA comparison, with a prevalence of stenosis ≥50 % of 41.9 %. QISS MRA was rated as good to excellent in 79.5-96.0 % of segments without any nondiagnostic segments; 89.8-96.1 % of segments in 3D TSE-based subtraction MRA were rated as nondiagnostic or poor. QISS MRA sensitivities and specificities (segmental) were 92 % and 95 %, respectively, for reader one and 81-97 % for reader two. Due to poor image quality of 3D TSE-based subtraction MRA, diagnostic performance measures were not calculated. QISS MRA demonstrates excellent diagnostic performance and higher robustness than 3D TSE-based subtraction MRA in the challenging patient population with CLI. • QISS MRA allows reliable diagnosis of peripheral artery stenosis in critical limb ischemia. • Robustness of TSE-based subtraction MRA is limited in critical limb ischemia. • QISS MRA allows robust therapy planning in PAD patients with resting leg pain.

  1. TNF-α is Critical for Ischemia-induced Leukostasis, But Not Retinal Neovascularization nor VEGF-induced Leakage

    PubMed Central

    Vinores, Stanley A.; Xiao, Wei-Hong; Shen, JiKui; Campochiaro, Peter.A.

    2007-01-01

    Vascular endothelial growth factor (VEGF) and tumor necrosis factor-α (TNF-α) show significant overlap with regard to their effects in the eye. It has been postulated that VEGF-induced leukostasis, breakdown of the blood-retinal barrier, and ischemia-induced retinal neovascularization may be mediated, at least in part, through TNF-α. In this study, we used mice deficient in TNF-α to test our hypothesis. Compared to wild type mice, TNF-α-deficient mice showed an 80% reduction in leukocyte accumulation in retinal vessels after intravitreous injection of VEGF, and 100% reductions after intravitreous injections of interleukin-1β (IL-1β) or platelet-activating factor (PAF). The increase in retinal vascular permeability induced by injection of PAF was significantly reduced in mice lacking TNF-α, but VEGF- and IL-1β-induced leakage was unaffected. Compared to wild type mice with oxygen-induced ischemic retinopathy, TNF-α-deficient mice with ischemic retinopathy showed significantly reduced leukostasis and mild reduction in vascular leakage, but no significant difference in retinal neovascularization. These data suggest that TNF-α mediates VEGF-, IL-1β-, and PAF-induced leukostasis and vascular leakage mediated by PAF, but not leakage caused by VEGF or IL-1β. Ischemia-induced retinal neovascularization, which has previously been shown to require VEGF, does not require TNF-α and is unaffected by attenuation of leukostasis. PMID:17107717

  2. Design and Rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial.

    PubMed

    Menard, Matthew T; Farber, Alik; Assmann, Susan F; Choudhry, Niteesh K; Conte, Michael S; Creager, Mark A; Dake, Michael D; Jaff, Michael R; Kaufman, John A; Powell, Richard J; Reid, Diane M; Siami, Flora Sandra; Sopko, George; White, Christopher J; Rosenfield, Kenneth

    2016-07-08

    Critical limb ischemia (CLI) is increasing in prevalence, and remains a significant source of mortality and limb loss. The decision to recommend surgical or endovascular revascularization for patients who are candidates for both varies significantly among providers and is driven more by individual preference than scientific evidence. The Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial is a prospective, randomized, multidisciplinary, controlled, superiority trial designed to compare treatment efficacy, functional outcomes, quality of life, and cost in patients undergoing best endovascular or best open surgical revascularization. Approximately 140 clinical sites in the United States and Canada will enroll 2100 patients with CLI who are candidates for both treatment options. A pragmatic trial design requires consensus on patient eligibility by at least 2 investigators, but leaves the choice of specific procedural strategy within the assigned revascularization approach to the individual treating investigator. Patients with suitable single-segment of saphenous vein available for potential bypass will be randomized within Cohort 1 (n=1620), while patients without will be randomized within Cohort 2 (n=480). The primary efficacy end point of the trial is Major Adverse Limb Event-Free Survival. Key secondary end points include Re-intervention and Amputation-Free-Survival and Amputation Free-Survival. The BEST-CLI trial is the first randomized controlled trial comparing endovascular therapy to open surgical bypass in patients with CLI to be carried out in North America. This landmark comparative effectiveness trial aims to provide Level I data to clarify the appropriate role for both treatment strategies and help define an evidence-based standard of care for this challenging patient population. URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02060630. © 2016 The Authors. Published on behalf of the American

  3. Topical Therapy As Adjuvant Treatment to Save a Limb With Critical Ischemia From Extensive and Deep Diabetic Foot Infection When Revascularization Is Not Feasible.

    PubMed

    Shen, Jen-Hsiang; Liu, Chin-Jui; Lo, Shun-Chun; Chen, Yu-Tsung; Chang, Chang-Cheng

    2016-01-01

    Patients with diabetes mellitus are susceptible to foot ulcerations associated with the complex triad of peripheral sensory neuropathy, vasculopathy, and trauma. Local infection of a diabetic foot ulcer (DFU) acts a significant deterrent to healing because the response to aggressive debridement antimicrobial therapy is limited when peripheral circulation is poor. We share an experience of using silver-impregnated hydrofiber wound dressing as an alternative to amputation in an 85-year-old female patient with an infected, ischemic DFU. This patient had a long-standing history of diabetes mellitus and hypertension for more than 30 years; both conditions were managed with oral medications. Penetrative injury caused by toothpicks resulted in 2 ulcers over the right lateral and medial plantar areas of her right foot. The DFUs were present within a period of 6 months. Due to the deep wound and progressively worsening infection, she was admitted for systemic antibiotics, debridement, and plantar fasciotomy. Percutaneous transluminal angioplasty was indicated, but the patient refused due to concerns related to potential nephrotoxicity associated with contrast use. Amputation was proposed as the final resort if the critical ischemia showed no improvement. Before undertaking amputation, silver-impregnated hydrofiber dressings were applied to the DFUs, along with antiplatelet medications. Following 4 months of treatment, the right medial plantar ulcer healed completely and the DFU over the lateral plantar ulcer was 75% smaller in surface area. Both DFUs remained healed when evaluated at 8 months. We found that a silver-impregnated hydrofiber dressing, combined with antiplatelet medications, allowed the patient to avoid amputation despite 2 deep and extensively infected DFUs with critical limb ischemia when revascularization was not feasible.

  4. 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 (TcPO2), 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 TcPO2 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 TcPO2 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

  5. Rationale and Design of Randomized Clinical Trial for the Assessment of Macitentan Efficiency as Coadjuvant Treatment to Open and Endovascular Revascularization in Critical Limb Ischemia

    PubMed Central

    Michel, Ignacio; De Haro, Joaquin; Bleda, Silvia; Laime, Ilsem V.; Uyaguari, Jhenifer; Acin, Francisco

    2016-01-01

    INTRODUCTION Critical limb ischemia (CLI) is defined by ischemic rest pain, tissue loss, or both, secondary to arterial insufficiency, and its prevalence is increasing mainly as a result of the worldwide high prevalence of diabetes. Currently, there are no available conclusive data on the efficacy of any coadjuvant therapy after revascularization procedure benefiting amputation and patency rates. Macitentan is an orally active dual endothelin (ET) receptor antagonist that may contribute to reduce the amputation rate and improve revascularization patency in CLI. METHODS/DESIGN REVASC is a proposed pilot, open-label, controlled, randomized, single-center clinical double-blind trial to be conducted in Spain on a study population of European patients with CLI, which will compare the clinical outcomes and cost-effectiveness of macitentan coadjuvant treatment after limb revascularization with the standard antiplatelet treatment strategy for severe limb ischemia. Patients are randomized 1:1 to receive macitentan or placebo for 12 weeks. The primary clinical end point will be amputation-free survival rate at 12 months, defined as the time to major (above the ankle) amputation for the index (trial) limb or death from any cause, whichever comes first. Secondary outcomes include overall survival, quality of life, in-hospital mortality and morbidity, repeat interventions, healing of tissue loss, and hemodynamic changes following revascularization. Sample size is estimated as 120 patients. The economic analysis will consist of two components: a “within-study” analysis, which will be based on study end points; and a “model-based” analysis, which will extrapolate and compare costs and effects likely to accrue beyond the study follow-up period. DISCUSSION The REVASC trial is designed to be pragmatic and represents current practice of the real-world population management after limb revascularization for CLI due to atherosclerosis. Current evidence does not support any

  6. AG490 suppresses EPO-mediated activation of JAK2-STAT but enhances blood flow recovery in rats with critical limb ischemia.

    PubMed

    Chai, Han-Tan; Yip, Hon-Kan; Sun, Cheuk-Kwan; Hsu, Shu-Yuan; Leu, Steve

    2016-01-01

    Erythropoietin (EPO) has been demonstrated to enhance recovery in ischemic organs through enhancing angiogenesis. In this study, we used an experimental critical limb ischemia (CLI) rat model to reveal the underlying mechanisms and directly examine the benefits of the anti-apoptotic capacity of EPO in the acute phase of limb ischemia and following blood flow recovery. To determine the role of the JAK2/STAT pathway in EPO-enhanced recovery after CLI, male Sprague-Dawley rats (n = 8 for each group) were divided into group 1 (normal control), group 2 (CLI treated with normal saline), group 3 (CLI treated with EPO), group 4 (CLI treated with AG490, a JAK2 inhibitor), and group 5 (CLI treated with EPO and AG490). Animals were sacrificed either at day 1 or day 14 and biochemical and histopathological examination of ischemic quadriceps were conducted. At day 1, EPO administration reduced expression levels of apoptotic indices and activated the JAK2/STAT pathway; this activation was inhibited by additional AG490 treatment. Furthermore, the decrease in the size of the infarcted area, as well as activation of ERK1/2 and JNK showed similar regulatory trends with EPO or AG490 treatment. Of Interest, EPO and AG490 in combination showed a synergistic effect, increasing expression levels of antioxidants (GR, GPx, NQO-1) and decreasing transcriptional levels of pro-inflammatory factors (TNF-α, NF-kB). At day 14, laser Doppler analysis showed that the blood flow recovery was enhanced by EPO, AG490, or combined treatment. Although inhibition of the JAK2/STAT pathways reduces the anti-apoptotic effects of EPO in the early phase of CLI, the benefits of AG490 in anti-inflammation and anti-oxidation still play a positive role in enhancing blood flow recovery after CLI.

  7. Hepatic ischemia

    MedlinePlus

    ... blood or oxygen, causing injury to liver cells. Causes Low blood pressure from any condition can lead to hepatic ischemia. ... liver's blood vessels Treatment Treatment depends on the cause. Low blood pressure and blood clots must be treated right away. ...

  8. Intestinal Ischemia

    MedlinePlus

    ... and hormone medications, such as estrogen Cocaine or methamphetamine use Vigorous exercise, such as long-distance running ... anti-phospholipid syndrome. Illegal drug use. Cocaine and methamphetamine use have been linked to intestinal ischemia. Complications ...

  9. Silent Ischemia

    MedlinePlus

    ... can be used to diagnose silent ischemia: An exercise stress test can show blood flow through your coronary arteries in response to exercise. Holter monitoring records your heart rate and rhythm ...

  10. 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.

  11. Comparison of Graft Patency, Limb Salvage, and Antithrombotic Therapy Between Prosthetic and Autogenous Below-Knee Bypass for Critical Limb Ischemia

    PubMed Central

    Suckow, Bjoern D.; Kraiss, Larry W.; Stone, David H.; Schanzer, Andres; Bertges, Daniel J.; Baril, Donald T.; Cronenwett, Jack L.; Goodney, Philip P.

    2014-01-01

    Background The autogenous vein is the preferred conduit in below-knee vascular reconstructions. However, many argue that prosthetic grafts can perform well in crural bypass with adjunctive antithrombotic therapy. We therefore compared outcomes of below-knee prosthetic versus autologous vein bypass grafts for critical limb ischemia and the use of adjunctive antithrombotic therapy in both settings. Methods Utilizing the registry of the Vascular Study Group of New England (2003–2009), we studied 1227 patients who underwent below-knee bypass for critical limb ischemia, 223 of whom received a prosthetic graft to the below-knee popliteal artery (70%) or more distal target (30%). We used propensity matching to identify a patient cohort receiving single-segment saphenous vein yet had remained similar to the prosthetic cohort in terms of characteristics, graft origin/target, and antithrombotic regimen. Main outcome measures were graft patency and major limb amputation within 1 year. Secondary outcomes were bleeding complications (reoperation or transfusion) and mortality. We performed comparisons by conduit type and by antithrombotic therapy. Results Patients receiving prosthetic conduit were more likely to be treated with warfarin than those with greater saphenous vein (57% vs. 24%, P < 0.001). After propensity score matching, we found no significant difference in primary graft patency (72% vs. 73%, P = 0.81) or major amputation rates (17% vs. 13%, P = 0.31) between prosthetic and single-segment saphenous vein grafts. In a subanalysis of grafts to tibial versus popliteal targets, we noted equivalent primary patency and amputation rates between prosthetic and venous conduits. Whereas overall 1-year prosthetic graft patency rates varied from 51% (aspirin + clopidogrel) to 78% (aspirin + warfarin), no significant differences were seen in primary patency or major amputation rates by antithrombotic therapy (P = 0.32 and 0.17, respectively). Further, the incidence of bleeding

  12. Long-term survival of patients with critical limb ischemia treated with iloprost: response rate and predictive criteria. A retrospective analysis of 102 patients.

    PubMed

    Melillo, E; Lucaccini, E; Berchiolli, R; Adami, D; Nuti, M; Dell'Omo, G; Farina, A; Panigada, G; Roberts, A T; Meini, S

    2016-12-01

    Critical limb ischemia (CLI) patients have poor long-term prognosis. We showed that iloprost improves outcomes (major amputation and survival) up a 5-year follow-up, but it is not known if in this length of time the survival curves, of clinical responders and non-responders, differ. A retrospective study enrolling 102 consecutive patients between 2004-2008, with clinical and instrumental (ultrasound, angiography, transcutaneous tensiometry of oxygen TcpO2 and carbon dioxide TcpCO2 in the affected and contralateral limbs) diagnosis of critical ischemia. All patients received the best medical therapy. Iloprost was administered (0.5-2 ng/kg/min 6 hours/day for 2-4 weeks) in all patients initially considered unsuitable for revascularization, repeating it regularly in time every six-twelve months in the case of positive response. The minimum expected follow-up was 4 years. 71.5% of patients were treated with iloprost and the responder rate was 71.2%. Most of the patients were regularly retreated with repeated cycles. Initial median supine TcpCO2 in symptomatic limb was higher in untreated patients than those treated (58 vs. 49 mmHg; p < 0.05) and in non-responders compared to responders (60 vs. 49 mmHg; p < 0.05). TcpCO2 directly and significantly correlated with the highest risk of mortality and seems to represent a new accurate prognostic criterion of unfavourable short and long-term response to prostanoid. In iloprost group, major amputations were significantly reduced. Revascularization was significantly higher in non-responders (57.1% vs. 11.5%; p < 0.05). There was a significantly higher prevalence of subsequent myocardial infarction in the non-iloprost group (27.6% vs. 9.6%; p < 0.05). The survival rate of non-responders was higher than untreated up until the second year (76.2% vs. 62%; p < 0.05). At 4 years we found higher survival in patients treated with iloprost (64.3% vs. 41% in untreated; p < 0.05) and in responders (75% vs. 38.1% in non-responders; p < 0

  13. Impact of deteriorated calcium-phosphate homeostasis on amputation-free survival after endovascular revascularization in patients with critical limb ischemia on hemodialysis.

    PubMed

    Hioki, Hirofumi; Miyashita, Yusuke; Shiraki, Tatsuya; Iida, Osamu; Uematsu, Masaaki; Miura, Takashi; Ebisawa, Souichirou; Ikeda, Uichi

    2016-04-01

    Patients on hemodialysis (HD) have abnormalities of calcium-phosphate (CaP) homeostasis and high CaP product contributes to atherosclerosis pathogenesis and adverse events. Patients on HD with critical limb ischemia (CLI) are at risk for major amputation and death because of advanced systemic atherosclerotic disease. The aim of this study was to evaluate the relationship between CaP product and amputation-free survival (AFS) in CLI after endovascular treatment (EVT). We retrospectively analyzed 221 CLI patients on HD. In Kaplan-Meier analysis, AFS was significantly lower in patients with CaP product ⩾ 55 mg(2)/dL(2) compared to those with CaP product <55 mg(2)/dL(2) (54.3% vs 78.5%, p = 0.002). However, neither serum phosphate nor calcium levels were individually associated with AFS. In multivariate analysis, CaP product ⩾ 55 mg(2)/dL(2) was an independent predictor for AFS in CLI patients on HD (hazard ratio, 3.03; 95% confidence interval, 1.78-5.15; p-value < 0.001). We concluded abnormal CaP homeostasis was associated with lower AFS after EVT in CLI patients on HD, and can serve for their risk stratification. © The Author(s) 2015.

  14. A Phase II Trial of Autologous Transplantation of Bone Marrow Stem Cells for Critical Limb Ischemia: Results of the Naples and Pietra Ligure Evaluation of Stem Cells Study

    PubMed Central

    Maione, Ciro; Botti, Chiara; Marino, Gennaro; Lillo, Stefano; Garrone, Alberto; Lanza, Lorella; Pagliari, Stefano; Silvestroni, Andrea; Signoriello, Giuseppe

    2012-01-01

    Critical limb ischemia (CLI) is a vascular disease affecting lower limbs, which is going to become a demanding challenge because of the aging of the population. Despite advances in endovascular therapies, CLI is associated with high morbidity and mortality. Patients without direct revascularization options have the worst outcomes. To date, 25%–40% of CLI patients are not candidates for surgical or endovascular approaches, ultimately facing the possibility of a major amputation. This study aimed to assess the safety and efficacy of autologous bone marrow (BM) transplantation performed in “no-option” patients, in terms of restoring blood perfusion by collateral flow and limb salvage. A multicenter, prospective, not-controlled phase II study for no-option CLI patients was performed. Patients were subjected to intra-arterial infusion of autologous bone marrow and followed for 12 months after the treatment. Variation of blood perfusion parameters, evaluated by laser Doppler flowmetry or transcutaneous oximetry, was set as the primary endpoint at 12 months after treatment and amputation-free survival as the secondary endpoint. Sixty patients were enrolled and treated with BM transplantation, showing improvement in objective and subjective measures of perfusion. Furthermore, survival analysis demonstrated improved amputation-free survival rates (75.2%) at 12 months after the treatment. This study provides further evidence that autologous bone marrow transplantation is well tolerated by CLI patients without adverse effects, demonstrating trends toward improvement in perfusion and reduced amputation rate, confirming the feasibility and safety of the procedure. PMID:23197862

  15. Safety and Effectiveness of Bone Marrow Cell Concentrate in the Treatment of Chronic Critical Limb Ischemia Utilizing a Rapid Point-of-Care System

    PubMed Central

    Gupta, Saniya; Sethi, Dalip; Powell, Richard J.; Harris, Kenneth Lee; Jungla, Nungshi; Arambam, Priyadarshini; Kaul, Upendra; Seth, Ashok; Bukhari, Suhail

    2017-01-01

    Critical limb ischemia (CLI) is the end stage of lower extremity peripheral vascular disease (PVD) in which severe obstruction of blood flow results in ischemic rest pain, ulcers and/or gangrene, and a significant risk of limb loss. This open-label, single-arm feasibility study evaluated the safety and therapeutic effectiveness of autologous bone marrow cell (aBMC) concentrate in revascularization of CLI patients utilizing a rapid point-of-care device. Seventeen (17) no-option CLI patients with ischemic rest pain were enrolled in the study. Single dose of aBMC, prepared utilizing an intraoperative point-of-care device, the Res-Q™ 60 BMC system, was injected intramuscularly into the afflicted limb and patients were followed up at regular intervals for 12 months. A statistically significant improvement in Ankle Brachial Index (ABI), Transcutaneous Oxygen Pressure (TcPO2), mean rest pain and intermittent claudication pain scores, wound/ ulcer healing, and 6-minute walking distance was observed following aBMC treatment. Major amputation-free survival (mAFS) rate and amputation-free rates (AFR) at 12 months were 70.6% and 82.3%, respectively. In conclusion, aBMC injections were well tolerated with improved tissue perfusion, confirming the safety, feasibility, and preliminary effectiveness of aBMC treatment in CLI patients. PMID:28194186

  16. 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.

  17. 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.

  18. Results of infrapopliteal endovascular procedures performed in diabetic patients with critical limb ischemia and tissue loss from the perspective of an angiosome-oriented revascularization strategy.

    PubMed

    Acín, Francisco; Varela, César; López de Maturana, Ignacio; de Haro, Joaquín; Bleda, Silvia; Rodriguez-Padilla, Javier

    2014-01-01

    Our aim was to describe our experience with infrapopliteal endovascular procedures performed in diabetic patients with ischemic ulcers and critical ischemia (CLI). A retrospective study of 101 procedures was performed. Our cohort was divided into groups according to the number of tibial vessels attempted and the number of patent tibial vessels achieved to the foot. An angiosome anatomical classification of ulcers were used to describe the local perfusion obtained after revascularization. Ischemic ulcer healing and limb salvage rates were measured. Ischemic ulcer healing at 12 months and limb salvage at 24 months was similar between a single revascularization and multiple revascularization attempts. The group in whom none patent tibial vessel to the foot was obtained presented lower healing and limb salvage rates. No differences were observed between obtaining a single patent tibial vessel versus more than one tibial vessel. Indirect revascularization of the ulcer through arterial-arterial connections provided similar results than those obtained after direct revascularization via its specific angiosome tibial artery. Our results suggest that, in CLI diabetic patients with ischemic ulcers that undergo infrapopliteal endovascular procedures, better results are expected if at least one patent vessel is obtained and flow is restored to the local ischemic area of the foot.

  19. The BEST-CLI trial: a multidisciplinary effort to assess whether surgical or endovascular therapy is better for patients with critical limb ischemia.

    PubMed

    Menard, Matthew T; Farber, Alik

    2014-03-01

    Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease and is associated with a risk of limb loss. This vascular condition is currently treated with limb revascularization by surgery or endovascular intervention performed by a variety of specialists. Because both open vascular bypass and the less invasive endovascular therapy can be performed in selected patients with CLI, there exists significant disagreement as to which therapy should be performed first and which is more successful. The paucity of comparative effectiveness data to guide treatment of CLI has prompted a multidisciplinary effort to organize the Best Endovascular Versus Best Surgical Therapy in Patients With CLI (BEST-CLI) trial. The BEST-CLI trial is a pragmatic, multicenter, open-label, randomized trial that compares best endovascular therapy with best open surgical treatment in patients eligible for both treatments. BEST-CLI aims to provide urgently needed clinical guidance for CLI management by using a pragmatic design comparing the effectiveness of established techniques while allowing for the introduction of newer therapies as they become available; a novel primary endpoint that includes limb amputation rates, repeat intervention, and mortality; a multidisciplinary structure that fosters cooperation among interventional cardiologists, interventional radiologists, vascular surgeons, and vascular medicine specialists; and novel techniques to evaluate the cost-effectiveness and quality-of-life outcomes of the two treatment strategies being tested.

  20. Safety and Effectiveness of Bone Marrow Cell Concentrate in the Treatment of Chronic Critical Limb Ischemia Utilizing a Rapid Point-of-Care System.

    PubMed

    Ponemone, Venkatesh; Gupta, Saniya; Sethi, Dalip; Suthar, Manish; Sharma, Monika; Powell, Richard J; Harris, Kenneth Lee; Jungla, Nungshi; Arambam, Priyadarshini; Kaul, Upendra; Seth, Ashok; Bukhari, Suhail

    2017-01-01

    Critical limb ischemia (CLI) is the end stage of lower extremity peripheral vascular disease (PVD) in which severe obstruction of blood flow results in ischemic rest pain, ulcers and/or gangrene, and a significant risk of limb loss. This open-label, single-arm feasibility study evaluated the safety and therapeutic effectiveness of autologous bone marrow cell (aBMC) concentrate in revascularization of CLI patients utilizing a rapid point-of-care device. Seventeen (17) no-option CLI patients with ischemic rest pain were enrolled in the study. Single dose of aBMC, prepared utilizing an intraoperative point-of-care device, the Res-Q™ 60 BMC system, was injected intramuscularly into the afflicted limb and patients were followed up at regular intervals for 12 months. A statistically significant improvement in Ankle Brachial Index (ABI), Transcutaneous Oxygen Pressure (TcPO2), mean rest pain and intermittent claudication pain scores, wound/ ulcer healing, and 6-minute walking distance was observed following aBMC treatment. Major amputation-free survival (mAFS) rate and amputation-free rates (AFR) at 12 months were 70.6% and 82.3%, respectively. In conclusion, aBMC injections were well tolerated with improved tissue perfusion, confirming the safety, feasibility, and preliminary effectiveness of aBMC treatment in CLI patients.

  1. Hydrogen Sulfide Levels and Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Activity Are Attenuated in the Setting of Critical Limb Ischemia (CLI)

    PubMed Central

    Islam, Kazi N; Polhemus, David J; Donnarumma, Erminia; Brewster, Luke P; Lefer, David J

    2015-01-01

    Background Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are endogenous enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythroid 2-related factor 2 is responsible for the expression of antioxidant response element–regulated genes and is known to be upregulated by H2S. We examined the levels of H2S, H2S-producing enzymes, and nuclear factor-erythroid 2-related factor 2 activation status in skeletal muscle obtained from critical limb ischemia (CLI) patients. Methods and Results Gastrocnemius tissues were attained postamputation from human CLI and healthy control patients. We found mRNA and protein levels of cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase were significantly decreased in skeletal muscle of CLI patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in nuclear factor-erythroid 2-related factor 2 activation as well as antioxidant proteins, such as Cu, Zn-superoxide dismutase, catalase, and glutathione peroxidase in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation, were significantly increased in skeletal muscle of CLI patients as compared to healthy controls. Conclusions The data demonstrate that H2S bioavailability and nuclear factor-erythroid 2-related factor 2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S-producing enzymes may contribute to the pathogenesis of CLI. PMID:25977470

  2. Platelet-Derived Growth Factor Receptor-Positive Pericytic Cells of White Adipose Tissue from Critical Limb Ischemia Patients Display Mesenchymal Stem Cell-Like Properties.

    PubMed

    Kim, Eo Jin; Seo, Sang Gyo; Shin, Hyuk Soo; Lee, Doo Jae; Kim, Ji Hye; Lee, Dong Yeon

    2017-06-01

    The pericytes in the blood vessel wall have recently been identified to be important in regulating vascular formation, stabilization, remodeling, and function. We isolated and identified pericyte-like platelet-derived growth factor receptor beta-positive (PDGFRβ+) cells from the stromal vascular fraction (SVF) of adipose tissue from critical limb ischemia (CLI) patients and investigated their potential as a reliable source of stem cells for cell-based therapy. De-identified subcutaneous fat tissues were harvested after amputation in CLI patients. Freshly isolated SVF cells and culture-expanded adipose-derived stem cells (ADSCs) were quantified using flow cytometry. A matrigel tube formation assay and multi-lineage differentiation were performed to assess pericytic and mesenchymal stem cell (MSC)-like characteristics of PDGFRβ+ ADSCs. PDGFRβ+ cells were located in the pericytic area of various sizes of blood vessels and coexpressed mesenchymal stem cell markers. PDGFRβ+ cells in freshly isolated SVF cells expressed a higher level of stem cell markers (CD34 and CXCR4) and mesenchymal markers (CD13, CD44, CD54, and CD90) than PDGFRβ- cells. In vitro expansion of PDGFRβ+ cells resulted in enrichment of the perivascular mesenchymal stem-like (PDGFRβ+/CD90+/CD45-/CD31-) cell fractions. The Matrigel tube formation assay revealed that PDGFRβ+ cells were located in the peritubular area. PDGFRβ+ ADSCs cells demonstrated a good multilineage differentiation potential. Pericyte-like PDGFRβ+ cells from the SVF of adipose tissue from CLI patients had MSC-like characteristics and could be amplified by in vitro culture with preservation of their cell characteristics. We believe PDGFRβ+ cells in the SVF of adipose tissue can be used as a reliable source of stem cells even in CLI patients.

  3. 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

    SciTech Connect

    Redlich, Ulf; Xiong, Yan Y.; Pech, Maciej; Tautenhahn, Joerg; Halloul, Zuhir; Lobmann, Ralf; Adolf, Daniela; Ricke, Jens; Dudeck, Oliver

    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 above 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.

  4. Three-year clinical outcome after infrapopliteal angioplasty for critical limb ischemia in hemodialysis patients with minor or major tissue loss.

    PubMed

    Nakano, Masatsugu; Hirano, Keisuke; Yamauchi, Yasutaka; Iida, Osamu; Soga, Yoshimitsu; Kawasaki, Daizo; Yamaoka, Terutosh; Suematsu, Nobuhiro; Suzuki, Kenji

    2015-08-01

    Among hemodialysis (HD)-dependent patients with critical limb ischemia (CLI), Endovascular therapy (EVT) of isolated infrapopliteal lesions improves limb salvage. Accordingly, we sought to determine the outcomes of this group of patients based on the extent of tissue loss at baseline. From 2004 to 2011, 449 consecutive HD patients with CLI had ischemic wounds and underwent EVT for isolated infrapopliteal lesions. The "minor tissue loss" (MI) group was confirmed by 340 HD patients with wounds located distal to the metatarsophalangeal joints, and the "major tissue loss" (MA) group included 109 HD patients with wounds that extended beyond this point. The two groups were compared for limb salvage and amputation free survival (AFS) rates by Kaplan-Meier analysis. There was no significant difference in the percentage of diabetic patients (MI: 76.5 vs. MA: 75.2%). The percentage with direct flow to the wound site was lower in the MA group than in the MI group (MI: 63.5 vs. MA: 45.9%, P < 0.01). After EVT the MI group had a significantly better limb salvage rate (MI: 83.7 vs. MA: 71.2% at 3 years, P < 0.01), and AFS rate (MI: 44.1 vs. MA: 29.1% at 3 years, P < 0.01) compared to the MA group. EVT is an efficient treatment for HD patients with minor tissue loss, achieving >80% limb salvage rates at 3 years. However, AFS rates in all HD patients with tissue loss are <50% at 3 years, making their prognosis poor. © 2015 Wiley Periodicals, Inc.

  5. Hydrogen Sulfide Levels and Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Activity Are Attenuated in the Setting of Critical Limb Ischemia (CLI).

    PubMed

    Islam, Kazi N; Polhemus, David J; Donnarumma, Erminia; Brewster, Luke P; Lefer, David J

    2015-05-14

    Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are endogenous enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythroid 2-related factor 2 is responsible for the expression of antioxidant response element-regulated genes and is known to be upregulated by H2S. We examined the levels of H2S, H2S-producing enzymes, and nuclear factor-erythroid 2-related factor 2 activation status in skeletal muscle obtained from critical limb ischemia (CLI) patients. Gastrocnemius tissues were attained postamputation from human CLI and healthy control patients. We found mRNA and protein levels of cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase were significantly decreased in skeletal muscle of CLI patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in nuclear factor-erythroid 2-related factor 2 activation as well as antioxidant proteins, such as Cu, Zn-superoxide dismutase, catalase, and glutathione peroxidase in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation, were significantly increased in skeletal muscle of CLI patients as compared to healthy controls. The data demonstrate that H2S bioavailability and nuclear factor-erythroid 2-related factor 2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S-producing enzymes may contribute to the pathogenesis of CLI. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  6. 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.

  7. 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.

  8. Muscle Derived Stem Cells Stimulate Muscle Myofiber Repair and Counteract Fat Infiltration in a Diabetic Mouse Model of Critical Limb Ischemia

    PubMed Central

    Tsao, J; Kovanecz, I; Awadalla, N; Gelfand, R; Sinha-Hikim, I; White, RA; Gonzalez-Cadavid, NF

    2017-01-01

    Background Critical Limb Ischemia (CLI) affects patients with Type 2 Diabetes (T2D) and obesity, with high risk of amputation and post-surgical mortality, and no effective medical treatment. Stem cell therapy, mainly with bone marrow mesenchymal, adipose derived, endothelial, hematopoietic, and umbilical cord stem cells, is promising in CLI mouse and rat models and is in clinical trials. Their general focus is on angiogenic repair, with no reports on the alleviation of necrosis, lipofibrosis, and myofiber regeneration in the ischemic muscle, or the use of Muscle Derived Stem Cells (MDSC) alone or in combination with pharmacological adjuvants, in the context of CLI in T2D. Methods Using a T2D mouse model of CLI induced by severe unilateral femoral artery ligation, we tested: a) the repair efficacy of MDSC implanted into the ischemic muscle and the effects of concurrent intraperitoneal administration of a nitric oxide generator, molsidomine; and b) whether MDSC may partially counteract their own repair effects by stimulating the expression of myostatin, the main lipofibrotic agent in the muscle and inhibitor of muscle mass. Results MDSC: a) reduced mortality, and b) in the ischemic muscle, increased stem cell number and myofiber central nuclei, reduced fat infiltration, myofibroblast number, and myofiber apoptosis, and increased smooth muscle and endothelial cells, as well as neurotrophic factors. The content of myosin heavy chain 2 (MHC-2) myofibers was not restored and collagen was increased, in association with myostatin overexpression. Supplementation of MDSC with molsidomine failed to stimulate the beneficial effects of MDSC, except for some reduction in myostatin overexpression. Molsidomine given alone was rather ineffective, except for inhibiting apoptosis and myostatin overexpression. Conclusions MDSC improved CLI muscle repair, but molsidomine did not stimulate this process. The combination of MDSC with anti-myostatin approaches should be explored to restore

  9. 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.

  10. Role of serum levels of angiogenic cytokines in assessment of angiogenesis after stem cell therapy of diabetic patients with critical limb ischemia.

    PubMed

    Dubsky, Michal; Jirkovska, Alexandra; Bem, Robert; Fejfarova, Vladimira; Varga, Martin; Kolesar, Libor; Pagacova, Libuse; Sykova, Eva; Jude, Edward B

    2014-01-01

    The release of proangiogenic cytokines into the circulation after stem cell (SC) therapy and compensatory increase of angiogenesis inhibitors may reflect local vasculogenesis but also can increase the risk of side effects. The aim of our study was to evaluate serum levels of angiogenic cytokines with regard to the assessment of local and systemic vasculogenesis in diabetic patients with no-option critical limb ischemia (NO-CLI). Twenty-five diabetic patients with NO-CLI treated with SCs isolated from bone marrow or stimulated peripheral blood were included in the study. Serum levels of proangiogenic cytokines (VEGF, bFGF, Ang-1, PDGF-AA, and PDGF-BB) and an antiangiogenic cytokine (endostatin) were assessed 6 months after cell treatment, compared to baseline values, and correlated with the number of injected CD34(+) cells. The clinical effect of SC therapy (assessed by changes in TcPO2) and potential systemic vasculogenesis (assessed by eye fundus examination) were evaluated after 6 months. Serum levels of angiogenic inhibitor endostatin increased significantly after 1 and 3 months (p = 0.0003), but no significant increase in serum levels of proangiogenic cytokines was observed. A significant correlation between number of injected CD34(+) cells and serum levels of endostatin was observed (r = 0.41, p < 0.05); however, proangiogenic cytokines did not correlate with CD34(+) cells. No correlation between increase in TcPO2 after treatment and serum levels of any of the angiogenic cytokines were seen, and no signs of systemic vasculogenesis in the retina were observed after 6 months. Despite the significant increase in the levels of the angiogenic inhibitor endostatin following SC treatment, there was no risk of systemic vasculogenesis after SC therapy as documented by serum levels of proangiogenic cytokines or changes in the retina.

  11. Antegrade vs Crossover Femoral Artery Access in the Endovascular Treatment of Isolated Below-the-Knee Lesions in Patients With Critical Limb Ischemia.

    PubMed

    Li, Yukun; Esmail, Ali; Donas, Konstantinos P; Pitoulias, Georgios; Torsello, Giovanni; Bisdas, Theodosios; Michelagnoli, Stefano; Troisi, Nicola

    2017-06-01

    To evaluate the safety and effectiveness of antegrade vs crossover femoral artery access in the endovascular treatment of isolated below-the-knee (BTK) lesions in patients with critical limb ischemia (CLI). Between January 2014 and December 2015, 224 high-risk patients (mean age 75.8±9.8 years; 151 men) with CLI underwent infragenicular interventions on 292 crural vessels in 3 European vascular centers. All patients had isolated TransAtlantic Inter-Society Consensus (TASC) C (n=26) or D (n=198) BTK lesions. Primary endpoints were freedom from access-related complications and technical success comparing the antegrade vs crossover access groups. Balloon angioplasty was the most used treatment modality (169 vessels, 75.4%). The technical success rate was 88.4% in the entire cohort and 88.0% in the antegrade group vs 90.4% in the crossover group (p>0.99). In all patients, the technical success rate was higher for stenotic lesions (100%) vs occlusions (85.5%, p=0.002) and in patients with TASC C BTK lesions (100%) vs TASC D (86.9%, p=0.033). The overall freedom from access-related complications was 97.8%: 99% in the antegrade group and 90.6% in the crossover group (p=0.022). Larger sheath size (5/6-F vs 4-F) was associated with a significantly higher risk for access-related complications (7.1% vs 1.1%, respectively; p=0.047). The present multicenter study showed high technical success and a low incidence of access-related complications in the treatment of isolated BTK lesions using either antegrade or crossover femoral access. The antegrade approach with the use of a 4-F system seems to have a significantly lower rate of access-related complications.

  12. Bilateral Administration of Autologous CD133+ Cells in Ambulatory Patients with Refractory Critical Limb Ischemia: Lessons Learned from a Pilot Randomized, Double blind, Placebo-controlled Trial

    PubMed Central

    Raval, Amish N.; Schmuck, Eric; Tefera, Girma; Leitzke, Cathlyn; Ark, Cassondra Vander; Hei, Derek; Centanni, John M.; de Silva, Ranil; Koch, Jill; Chappell, Richard; Hematti, Peiman

    2014-01-01

    Introduction CD133+ cells confer angiogenic potential and may be beneficial for the treatment of critical limb ischemia (CLI). However, patient selection, blinding methods and endpoints for clinical trials is challenging. We hypothesized that bilateral intramuscular administration of cytokine mobilized CD133+ cells in ambulatory patients with refractory CLI would be feasible and safe. Methods In this double-blind, randomized, sham-controlled trial, subjects received subcutaneous injections of granulocyte colony stimulating factor (10 mcg/kg/d) for 5 days, followed by leukapheresis, and intramuscular administration of 50-400 million sorted CD133+ cells delivered into both legs. Control subjects received normal saline injections, sham leukapheresis and intramuscular injection of placebo buffered solution. Subjects were followed for 1 year. An aliquot of CD133+ cells was collected from each subject to test for genes associated with cell senescence. Results 70 subjects were screened, of whom 10 were eligible. Subject enrollment was suspended due to a high rate of mobilization failure in subjects randomized to treatment. Of 10 subjects enrolled (7 randomized to treatment, 3 randomized to control), there were no differences in serious adverse events at 12 months and blinding was preserved. There were non-significant trends toward improved amputation free survival, 6 minute walk distance, walking impairment questionnaire and quality of life in subjects randomized to treatment. Successful CD133+ mobilizers expressed fewer senescence associated genes compared to poor mobilizers. Conclusion Bilateral administration of autologous CD133+ cell in ambulatory CLI subjects was safe and blinding was preserved. However, poor mobilization efficiency combined with high CD133+ senescence suggests futility in this approach. PMID:25239491

  13. Applicability of the Society for Vascular Surgery's Objective Performance Goals for Critical Limb Ischemia to Current Practice of Lower-Extremity Bypass.

    PubMed

    Saraidaridis, Julia T; Patel, Virendra I; Lancaster, Robert T; Cambria, Richard P; Conrad, Mark F

    2016-01-01

    In 2009, the Society for Vascular Surgery (SVS) established objective performance goals (OPGs) for critical limb ischemia (CLI) based on data from previous, randomized, controlled trials of lower-extremity bypass (LEB). These OPG sought to establish a benchmark of outcomes to which one could compare future endovascular therapy. However, the cohort used to develop the OPG excluded all patients who required prosthetic conduit and those with end-stage renal disease (ESRD), possibly limiting the generalizability of these results and the subsequent guidelines. The goal of this study was to determine if the SVS OPG are applicable to the current population of patients undergoing LEB. All patients who underwent infrainguinal LEB for CLI from January 2010 to December 2013 were identified in a prospectively maintained database. Patients were stratified into OPG eligible and ineligible (non-OPG) groups based on their demographic and operative characteristics. OPG eligible patients were further stratified into high risk and average risk. Outcomes included 30-day major adverse limb events (MALEs), 30-day major adverse cardiovascular events (MACE), 1-year survival, and 1-year freedom from amputation. A total of 89 individual patients were identified. Only 43 (48%) patients met OPG inclusion criteria and 46 (52%) were not OPG eligible (non-OPG). The 30-day MALE was 8.7% (13.0% non-OPG vs. 7.0% OPG, P = 0.34). The 30-day MACE was 11.2% (13.0% non-OPG vs. 9.3% OPG, P = 0.58). One-year survival was 80.3% ± 4.5% (71.2% non-OPG vs. 90.0% OPG, P = 0.21). One-year freedom from amputation was 71.7% ± 5.5% (58.8% non-OPG vs. 84.0% OPG, P = 0.03). The SVS OPG for LEB are likely not generalizable to current practice as 51% of patients would have been excluded from the SVS cohort because of ESRD and prosthetic conduit. Most SVS OPG (30-day MALE, 1-year survival, and 1-year limb salvage) were attainable in patients who met SVS OPG inclusion criteria; but for the patients who are not OPG

  14. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia

    PubMed Central

    2013-01-01

    Background Peripheral vascular disease of the lower extremities comprises a clinical spectrum that extends from no symptoms to presentation with critical limb ischemia (CLI). Bone marrow derived Mesenchymal Stem Cells (BM- MSCs) may ameliorate the consequences of CLI due to their combinatorial potential for inducing angiogenesis and immunomodulatory environment in situ. The primary objective was to determine the safety of BM- MSCs in patients with CLI. Methods Prospective, double blind randomized placebo controlled multi-center study was conducted in patients with established CLI as per Rutherford classification in category II-4, III-5, or III-6 with infra-inguinal arterial occlusive disease and were not suitable for or had failed revascularization treatment. The primary end point was incidence of treatment – related adverse events (AE). Exploratory efficacy end points were improvement in rest pain, increase in Ankle Brachial Pressure Index (ABPI), ankle pressure, healing of ulcers, and amputation rates. Twenty patients (BM-MSC: Placebo = 1:1) were administered with allogeneic BM-MSCs at a dose of 2 million cells/kg or placebo (PlasmaLyte A) at the gastrocnemius muscle of the ischemic limb. Results Improvement was observed in the rest pain scores in both the arms. Significant increase in ABPI and ankle pressure was seen in BM-MSC arm compared to the placebo group. Incidence of AEs in the BM-MSC arm was 13 vs. 45 in the placebo arm where as serious adverse events (SAE) were similar in both the arms (5 in BM-MSC and 4 in the placebo group). SAEs resulted in death, infected gangrene, amputations in these patients. It was observed that the SAEs were related to disease progression and not related to stem cells. Conclusion BM-MSCs are safe when injected IM at a dose of 2 million cells/kg body weight. Few efficacy parameters such as ABPI and ankle pressure showed positive trend warranting further studies. Trial registration NIH website (http

  15. RISK STRATIFICATION IN CRITICAL LIMB ISCHEMIA: DERIVATION AND VALIDATION OF A MODEL TO PREDICT AMPUTATION-FREE SURVIVAL USING MULTI-CENTER SURGICAL OUTCOMES DATA

    PubMed Central

    Schanzer, Andres; Mega, Jessica; Meadows, Judith; Samson, Russell H; Bandyk, Dennis F; Conte, Michael S

    2009-01-01

    Patients with critical limb ischemia (CLI) are a heterogeneous population with respect to risk for mortality and limb loss, complicating clinical decision-making. Endovascular options, as compared to bypass, offer a tradeoff between reduced procedural risk and inferior durability. Risk stratified data predictive of amputation-free survival (AFS) may improve clinical decision making and allow for better assessment of new technology in the CLI population. METHODS This was a retrospective analysis of prospectively collected data from patients who underwent infrainguinal vein bypass surgery for CLI. Two datasets were used: the PREVENT III randomized trial (n=1404) and a multicenter registry (n=716) from 3 distinct vascular centers (2 academic, 1 community-based). The PREVENT III cohort was randomly assigned to a derivation set (n=953) and to a validation set (n=451). The primary endpoint was AFS. Predictors of AFS identified on univariate screen (inclusion threshold, p<0.20) were included in a stepwise selection Cox model. The resulting 5 significant predictors were assigned an integer score to stratify patients into 3 risk groups. The prediction rule was internally validated in the PREVENT III validation set and externally validated in the multicenter cohort. RESULTS The estimated 1 year AFS in the derivation, internal validation, and external validation sets were 76.3%, 72.5%, and 77.0%, respectively. In the derivation set, dialysis (HR 2.81, p<.0001), tissue loss (HR 2.22, p=.0004), age ≥75 (HR 1.64, p=.001), hematocrit ≤30 (HR 1.61, p=.012), and advanced CAD (HR 1.41, p=.021) were significant predictors for AFS in the multivariable model. An integer score, derived from the β coefficients, was used to generate 3 risk categories (low ≤ 3 [44.4% of cohort], medium 4–7 [46.7% of cohort], high ≥8 [8.8% of cohort]). Stratification of the patients, in each dataset, according to risk category yielded 3 significantly different Kaplan-Meier estimates for one year

  16. IN.PACT Amphirion paclitaxel eluting balloon versus standard percutaneous transluminal angioplasty for infrapopliteal revascularization of critical limb ischemia: rationale and protocol for an ongoing randomized controlled trial

    PubMed Central

    2014-01-01

    Background The effectiveness and durability of endovascular revascularization therapies for chronic critical limb ischemia (CLI) are challenged by the extensive burden of infrapopliteal arterial disease and lesion-related characteristics (e.g., severe calcification, chronic total occlusions), which frequently result in poor clinical outcomes. While infrapopliteal vessel patency directly affects pain relief and wound healing, sustained patency and extravascular care both contribute to the ultimate “patient-centric” outcomes of functional limb preservation, mobility and quality of life (QoL). Methods/Design IN.PACT DEEP is a 2:1 randomized controlled trial designed to assess the efficacy and safety of infrapopliteal arterial revascularization between the IN.PACT Amphirion™ paclitaxel drug-eluting balloon (IA-DEB) and standard balloon angioplasty (PTA) in patients with Rutherford Class 4-5-6 CLI. Discussion This multicenter trial has enrolled 358 patients at 13 European centers with independent angiographic core lab adjudication of the primary efficacy endpoint of target lesion late luminal loss (LLL) and clinically driven target lesion revascularization (TLR) in major amputation-free surviving patients through 12-months. An independent wound core lab will evaluate all ischemic wounds to assess the extent of healing and time to healing at 1, 6, and 12 months. A QoL questionnaire including a pain scale will assess changes from baseline scores through 12 months. A Clinical Events Committee and Data Safety Monitoring Board will adjudicate the composite primary safety endpoints of all-cause death, major amputation, and clinically driven TLR at 6 months and other trial endpoints and supervise patient safety throughout the study. All patients will be followed for 5 years. A literature review is presented of the current status of endovascular treatment of CLI with drug-eluting balloon and standard PTA. The rationale and design of the IN.PACT DEEP Trial are

  17. Number of infrapopliteal arteries undergoing endovascular treatment is not associated with the limb salvage rate in patients with critical limb ischemia.

    PubMed

    de Athayde Soares, Rafael; Matielo, Marcelo Fernando; Brochado Neto, Francisco Cardoso; Martins Cury, Marcus Vinícius; Marques, Régis Campos; Sacilotto, Roberto

    2016-11-01

    The objective of this study was to determine whether the number of infrapopliteal arteries undergoing endovascular treatment is associated with the limb salvage rate in patients with critical limb ischemia (CLI). This was a retrospective, consecutive cohort study of CLI patients who underwent infrapopliteal angioplasty at the Vascular and Endovascular Surgery Service of the Hospital do Servidor Público Estadual, São Paulo, between January 2009 and January 2013. The primary outcome variable was the limb salvage rate. The secondary outcome variables were patency, survival, plantar arch quality, and operative mortality rate. Overall, 109 infrapopliteal angioplasties were performed in 92 patients, and the initial technical success rate was 95.6%. Based on the analyses of the arteriography of the endovascular procedures, the patients were classified into two groups according to whether they had undergone endovascular treatment of one artery (group 1) or two arteries (group 2). The mean outpatient follow-up time was 430 ± 377.5 days. The analyses were performed at 180 and 360 days. There were 72 angioplasties (66%) in group 1 and 37 (34%) in group 2. Hypertension was more frequent in group 1 (93.1%) than in group 2 (78.4%; P = .03). Other clinical characteristics were similar in both groups. Regarding postoperative complications, the incidence of acute kidney failure was lower in group 1 (0% vs 8.1%, respectively; P = .037). The limb salvage rate at 360 days was similar in groups 1 and 2 (89.4% vs 89.3%, respectively; P = .595). The secondary patency rate at 360 days was also similar in groups 1 and 2 (59.9% vs 60.9%, respectively; P = .571). The perioperative mortality rate was lower in group 1 (4.2% vs 16.2%, respectively; P = .039), but the survival rate at 360 days was similar in both groups (82.1% vs 75.1%, respectively; P = .931). The frequencies of complete, incomplete, and absent plantar arch were similar in both groups. The estimated limb

  18. Female gender and oral anticoagulants are associated with wound complications in lower extremity vein bypass: An analysis of 1404 operations for critical limb ischemia

    PubMed Central

    Nguyen, Louis L.; Brahmanandam, Soma; Bandyk, Dennis F.; Belkin, Michael; Clowes, Alexander W.; Moneta, Gregory L.; Conte, Michael S.

    2010-01-01

    Background Infrainguinal bypass (IB) surgery is an effective means of improving arterial circulation to the lower extremity for patients with critical limb ischemia (CLI). However, wound complications (WC) of the surgical incision following IB can impart significant morbidity. Methods A retrospective analysis of WC from the 1404 patients enrolled in a multicenter clinical trial of vein bypass grafting for CLI was performed. Univariate and multivariable regression models were used to determine WC predictors and associated outcomes, including graft patency, limb salvage, quality of life (QoL), resource utilization (RU), and mortality. Results A total of 543 (39%) patients developed a reported WC within 30 days of surgery, with infections (284, 52%) and hematoma/hemorrhage (121, 22%) being the most common type. Postoperative anticoagulation (odds ratio [OR], 1.554; 95% confidence interval [CI] 1.202 to 2.009; P = .0008) and female gender (OR, 1.376; 95% CI, 1.076 to 1.757; P = .0108) were independent factors associated with WC. Primary, primary-assisted, and secondary graft patency rates were not influenced by the presence of WC; though, patients with WC were at increased risk for limb loss (hazard ratio [HR], 1.511; 95% CI 1.096 to 2.079; P = .0116) and higher mortality (HR, 1.449; 95% CI 1.098 to 1.912; P = .0089). WC was not significantly associated with lower QoL at 3 months (4.67 vs 4.79, P = .1947) and 12 months (5.02 vs 5.13, P = .2806). However, the subset of patients with serious WC (SWC) demonstrated significantly lower QoL at 3 months compared with patients without WC, (4.43 vs 4.79, respectively, P = .0166), though this difference was not seen at 12 months (4.94 vs 5.13, P = .2411). Patients with WC had higher RU than patients who did not have WC. Mean index length of hospital stay (LOS) was 2.3 days longer, mean cumulative 1-year LOS was 8.1 days longer, and mean number of hospitalizations was 0.5 occurrences greater for patients with WC compared with

  19. Prospective multicenter study of quality of life before and after lower extremity vein bypass in 1404 patients with critical limb ischemia

    PubMed Central

    Nguyen, Louis L.; Moneta, Gregory L.; Conte, Michael S.; Bandyk, Dennis F.; Clowes, Alexander W.; Seely, B. Lynn

    2010-01-01

    Background Patients with critical limb ischemia (CLI) have multiple comorbidities and limited life spans. The ability of infrainguinal vein bypass to improve quality of life (QoL) in patients with CLI has therefore been questioned. Prospective preoperative and postoperative QoL data for patients undergoing lower extremity vein bypass for CLI are presented. Methods A validated, disease-specific QoL questionnaire (VascuQoL) with activity, symptom, pain, emotional, and social domains and responses scored 1 (lowest QoL) to 7 (best QoL) was administered before surgery and at 3 and 12 months after lower extremity vein bypass for CLI. Changes in QoL at 3 and 12 months after lower extremity vein bypass and multiple predetermined variables potentially influencing QoL after lower extremity vein bypass were analyzed to determine the effect of lower extremity vein bypass on QoL in CLI patients. Results A total of 1404 patients had lower extremity vein bypass for CLI at 83 centers in the United States and Canada as part of the PREVENT III clinical trial. Surveys were completed in 1296 patients at baseline, 862 patients at 3 months, and 732 patients at 12 months. The global QoL score (mean ± SD) was 2.8 ± 1.1 at baseline and was 4.7 ± 1.4 and 5.1 ± 1.4 at 3 and 12 months, respectively. Mean changes from baseline at 3 and 12 months were statistically significant (P < .0001). Improved QoL scores extended across all domains. Diabetes and the development of graft-related events were associated with decreased improvement in QoL scores, though the mean relative change from baseline remained positive. Conclusions Patients with CLI have a low QoL at baseline that is improved at 3 and 12 months after lower extremity vein bypass. QoL improvements are lower in diabetic patients and those who develop graft-related events. Successful revascularization can be expected to improve QoL in patients with CLI, with benefits that are sustained to at least 1 year. PMID:17098529

  20. 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

  1. Bare nitinol stent enabled recanalization of long-segment, chronic total occlusion of superficial femoral and adjacent proximal popliteal artery in diabetic patients presenting with critical limb ischemia.

    PubMed

    Taneja, Manish; Tay, Kiang Hiong; Dewan, Atul; Sebastian, Mathew G; Pasupathy, Shanker; Lin, Sheuh En; Teo, Terence; Lo, Richard; Tan, Seck Guan; Irani, Farah G; Tan, Bien Soo

    2010-01-01

    To evaluate our experience of limb salvage with bare nitinol stent enabled recanalization of long length occlusions of superficial femoral artery (SFA) and adjacent proximal popliteal artery (PPA) in diabetic patients. A total of 573 patients underwent 842 lower limb interventions from August 2006 to September 2008 at our institute. A retrospective review was done of diabetic patients undergoing recanalization of long length SFA/adjacent PPA (>10 cm) occlusions with self expanding bare nitinol stents evaluating their impact on limb salvage. Forty-four patients (mean age 65.2 years, M:F 25:19) underwent 49 long-length (>10 cm) SFA/PPA stenting procedures over a period of 26 months. Diabetics comprised 66% of patients (n=29, mean age: 63.7 years, M: F 19:10). The infrapopliteal distal run-off in this diabetic subgroup comprised one vessel (n=14/29, 48%), two vessels (n=12/29, 41%), and three vessels (n=3/29, 10%). The spectrum of critical limb ischemia included rest pain (n=8), ulcer (n=7) and gangrene (n=14). The lengths of occlusions recanalized were 10-39 cm. A total of 58 stents (individual length 10-17 cm, average diameter 6 mm, mean 2 stents per patient) were placed with average length of stented segment being 23.8 cm. Four patients had stents placed through ipsilateral popliteal artery approach with rest placed through femoral artery approach. Significant complications of the procedure included distal embolization (n=3) successfully managed with thrombolysis and popliteal arteriovenous fistula in one patient undergoing recanalization through popliteal approach, managed with covered stent placement. No procedure related mortality occurred during thirty-day follow-up period. All were followed up over an average duration of twelve months post-procedure. Three patients died due to associated medical conditions during this period. The following amputations were done on follow-up (three toe amputations, five forefoot amputations, three below-knee amputations, two

  2. Rodent models of cerebral ischemia

    SciTech Connect

    Ginsberg, M.D.; Busto, R. )

    1989-12-01

    The use of physiologically regulated, reproducible animal models is crucial to the study of ischemic brain injury--both the mechanisms governing its occurrence and potential therapeutic strategies. Several laboratory rodent species (notably rats and gerbils), which are readily available at relatively low cost, are highly suitable for the investigation of cerebral ischemia and have been widely employed for this purpose. We critically examine and summarize several rodent models of transient global ischemia, resulting in selective neuronal injury within vulnerable brain regions, and focal ischemia, typically giving rise to localized brain infarction. We explore the utility of individual models and emphasize the necessity for meticulous experimental control of those variables that modulate the severity of ischemic brain injury.169 references.

  3. Strategy of Revascularization for Critical Limb Ischemia Due to Infragenicular Lesions—Which Should Be Selected Firstly, Bypass Surgery or Endovascular Therapy?

    PubMed Central

    Iwasa, Kazuomi; Yamaoka, Terutoshi

    2015-01-01

    Background and Objectives: In patients with peripheral arterial diseases (PADs) due to infra-popliteal (below the knee; BTK) lesions, we often encounter situations requiring the immediate selection of either of two revascularization methods, namely bypass surgery or endovascular therapy (EVT). However, the question of whether endovascular or surgical revascularization should be performed initially for critical limb ischemia (CLI) patients with BTK lesions has not been clarified. To assess the efficacy and durability of EVT or bypass as a first approach, we evaluated the short- and mid-term outcomes of the first revascularizations achieved using EVT (EVT First Group; EVT-first) compared with bypass (Bypass First Group; Bypass-first). To verify the validity of each initial revascularization, we explored factors influencing overall survival (OS) rates using multivariate analyses. Methods: A total of 169 consecutive BTK revascularization procedures (150 patients) for CLI conducted at our facility between November 2006 and July 2012 were analyzed. Patients undergoing revascularization were divided into two groups (EVT-first or Bypass-first), with 102 patients undergoing endovascular therapy first (EVT-first) and 51 undergoing bypass surgery first (Bypass-first). No statistically significant differences were noted between the two groups with respect to preoperative background including age, gender, and cardiovascular risk factors (hypertension, diabetes, hyperlipidemia, coronary arterial disease (CAD), chronic heart failure (CHF), cerebrovascular disease, and hemodialysis). Technical success was defined as a single straight-line flow to the ankle after completion angiography of the first revascularization method. Hemodynamic success was defined as a postoperative skin perfusion pressure of the foot exceeding 40 mmHg. Results: The average age of patients was 76.0 years (range, 46–98 years; 65 men and 37 women) and 72.3 years (range, 43–93 years; 35 men and 13 women

  4. A multicenter comparison between autologous saphenous vein and heparin-bonded expanded polytetrafluoroethylene (ePTFE) graft in the treatment of critical limb ischemia in diabetics.

    PubMed

    Dorigo, Walter; Pulli, Raffaele; Castelli, Patrizio; Dorrucci, Vittorio; Ferilli, Fiore; De Blasis, Giovanni; Monaca, Vincenzo; Vecchiati, Enrico; Pratesi, Carlo

    2011-11-01

    The aim of this study was to evaluate early and follow-up results of below-knee bypasses performed using a bioactive heparin-treated expanded polytetrafluoroethylene (ePTFE) graft in diabetic patients with critical limb ischemia (CLI) in a multicenter retrospective registry involving seven Italian vascular centers and to compare them with those obtained in patients operated on with autologous saphenous vein (ASV) in the same centers in the same period of time. Over an 8-year period, ending in 2009, a heparin-bonded prosthetic graft (Propaten Gore-Tex; W. L. Gore & Associates Inc, Flagstaff, Ariz) was implanted in 180 diabetic patients undergoing below-knee revascularization for CLI in seven Italian hospitals (group 1). In the same period in these seven centers, 133 below-knee bypasses with ipsilateral ASV in diabetics with CLI were performed (group 2). Data concerning these interventions were retrospectively collected in a multicenter registry with a dedicated database. Early (<30 days) results were analyzed in terms of graft patency, major amputation rates, and mortality. Follow-up results were analyzed in terms of primary and secondary graft patency, limb salvage, and survival. The interventions consisted of below-knee bypasses in 132 cases in group 1 (73%) and in 45 cases in group 2 (33%; P < .001); 48 patients in group 1 (27%) and 88 patients in group 2 (67%; P < .001) had distal tibial anastomosis. Patients in group 1 had more frequently adjunctive procedures performed at distal anastomotic sites to improve run-off status. Postoperative and long-term medical treatment consisted of single antiplatelet therapy in 93 cases (52%) in group 1 and in 64 cases (48%, P = ns) in group 2, of double antiplatelet therapy in 18 cases (10%) in group 1 and in four cases (3%; P = .05) in group 2 and of oral anticoagulants in 69 patients in group 1 (38%) and in 65 (49%; P = .02) in group 2. Mean duration of follow-up was 28.3 ± 21.4 months; 308 patients (98%) had at least one

  5. Outcome of infrainguinal single-segment great saphenous vein bypass for critical limb ischemia is superior to alternative autologous vein bypass, especially in patients with high operative risk.

    PubMed

    Arvela, Eva; Venermo, Maarit; Söderström, Maria; Albäck, Anders; Lepäntalo, Mauri

    2012-04-01

    Single-segment great saphenous vein (ssGSV) is the conduit of choice in infrainguinal bypass for critical limb ischemia (CLI). The aim of this study was to assess results of other autologous vein grafts and risk factors for graft stenosis development and graft failure. The purpose was also to evaluate outcome of patients with high operative risk undergoing infrainguinal alternative autologous vein bypass for CLI. We retrospectively reviewed 1,109 consecutive infrainguinal bypasses performed between 2000 and 2007 for CLI. Rate and type of operations needed to maintain graft patency were evaluated. Outcome of different types of vein grafts in terms of primary patency, assisted primary patency, secondary patency, and limb salvage was assessed using Kaplan-Meier method. Predictors of poor outcome as well as patient- and graft-related risk factors for graft revision and graft failure were analyzed using multivariate analysis. Median follow-up period was 37 (0-121) months. Primary patency, assisted primary patency, secondary patency, and limb salvage at 1 and 3 years were significantly better in ssGSV graft group than in alternative autologous vein graft (AAVG) group-74.4% and 67.1% versus 53.7% and 42.0% (P < 0.0001), 82.8% and 78.2% versus 67.2% and 57.8% (P < 0.0001), 84.8% and 80.8% versus 69.9% and 61.4% (P < 0.0001), and 88.9% and 86.9% versus 83.0% and 77.2% (P < 0.0001), respectively. In multivariate analysis, non-ssGSV graft was the only independent risk factor for the graft stenosis development (relative risk [RR]: 2.62, 95% confidence interval [CI]: 1.56-4.38, P < 0.0001), for graft occlusion (RR: 2.27, 95% CI: 1.52-3.40, P < 0.0001), and for graft failure (stenosis or occlusion) (RR: 2.00, 95% CI: 1.39-2.88, P < 0.0001). Revision rate of non-ssGSV conduits was higher than that of ssGSV grafts (18% vs. 12%, P = 0.007). High-risk patients (age of >80 years, coronary artery disease, estimated glomerular filtration rate of <30 mL/min/1.73 m(2)) who underwent

  6. An analysis of IN.PACT DEEP randomized trial on the limitations of the societal guidelines-recommended hemodynamic parameters to diagnose critical limb ischemia.

    PubMed

    Shishehbor, Mehdi H; Hammad, Tarek A; Zeller, Thomas; Baumgartner, Iris; Scheinert, Dierk; Rocha-Singh, Krishna J

    2016-05-01

    Recent small single-center data indicate that the current hemodynamic parameters used to diagnose critical limb ischemia are insensitive. We investigated the validity of the societal guidelines-recommended hemodynamic parameters against core laboratory-adjudicated angiographic data from the multicenter IN.PACT DEEP (RandomIzed AmPhirion DEEP DEB vs StAndard PTA for the treatment of below the knee Critical limb ischemia) Trial. Of the 358 patients in the IN.PACT DEEP Trial to assess drug-eluting balloon vs standard balloon angioplasty for infrapopliteal disease, 237 had isolated infrapopliteal disease with an available ankle-brachial index (ABI), and only 40 of the latter had available toe pressure measurements. The associations between ABI, ankle pressure, and toe pressure with tibial runoff, Rutherford category, and plantar arch were examined according to the cutoff points recommended by the societal guidelines. Abnormal tibial runoff was defined as severely stenotic (≥70%) or occluded and scored as one-, two-, or three-vessel disease. A stenotic or occluded plantar arch was considered abnormal. Only 14 of 237 patients (6%) had an ABI <0.4. Abnormal ankle pressure, defined as <50 mm Hg if Rutherford category 4 and <70 mm Hg if Rutherford category 5 or 6, was found only in 37 patients (16%). Abnormal toe pressure, defined as <30 mm Hg if Rutherford category 4 and <50 mm Hg if Rutherford category 5 or 6, was found in 24 of 40 patients (60%) with available measurements. Importantly, 29% of these 24 patients had an ABI within normal reference ranges. A univariate multinomial logistic regression found no association between the above hemodynamic parameters and the number of diseased infrapopliteal vessels. However, there was a significant paradoxic association where patients with Rutherford category 6 had higher ABI and ankle pressure than those with Rutherford category 5. Similarly, there was no association between ABI and pedal arch patency. The current

  7. Mannose-Binding Lectin: Biologic Characteristics and Role in the Susceptibility to Infections and Ischemia-Reperfusion Related Injury in Critically Ill Neonates

    PubMed Central

    Moriondo, Maria; Bertaina, Chiara; Mondì, Vito; Inglese, Rita

    2017-01-01

    The mannose-binding lectin (MBL) is a member of the collectin family, belonging to the innate immunity system. Genetic, biologic, and clinical properties of MBL have been widely investigated throughout the last decades, although some interesting aspects of its potential clinical relevance are still poorly understood. Low circulating concentrations of MBL have been associated with increased risk of infection and poor neurologic outcome in neonates. On the other hand, an excessive and uncontrolled inflammatory response by the neonatal intestine after the exposure to luminal bacteria, leading to an increased production of MBL, may be involved in the onset of necrotizing enterocolitis. The purpose of the present review is to summarize the current knowledge about genetic and biologic characteristics of MBL and its role in the susceptibility to infections and to ischemia-reperfusion related tissue injuries to better explore its clinical relevance during the perinatal period and the possible future therapeutic applications. PMID:28246614

  8. Monitored extended secondary arterial ischemia in a free muscle transfer.

    PubMed

    Sværdborg, Mille; Birke-Sørensen, Hanne

    2012-02-01

    In reconstructive microsurgery, flap failure can be catastrophic to the patient. Different monitoring methods have been implemented in an attempt to recognize secondary ischemia during its early stages. However, the exact onset of secondary ischemia can be difficult to determine because there are no well-documented and reliable monitoring techniques that offer true continuous monitoring in a clinical setting. Because of the uncertain time in terms of the onset of secondary ischemia, the exact length of ischemia before revascularization, the secondary ischemia time, cannot be obtained. This is probably part of the reason why not much has been published regarding the effect of secondary ischemia time in reference to flap survival. We present a case of a free gracilis muscle flap that was salvaged despite more than 11 hours of arterial ischemia. The flap was monitored using microdialysis and at no time was the ischemia clearly demonstrated by clinical inspection. We conclude that clinical monitoring in some cases can be an unreliable method for monitoring free muscle transfers suffering from arterial ischemia and that further studies are needed for more specific guidelines regarding the critical secondary ischemia time in muscle flaps.

  9. Thrombangiitis obliterans (Buerger's disease): still a limb threatening disease.

    PubMed

    Van Damme, H; De Leval, L; Creemers, E; Limet, R

    1997-10-01

    A series of 29 well-documented and properly analysed patients with thrombangiitis obliterans (Buerger's disease) is presented. The diagnosis of Buerger's disease was based on following criteria: smoking history, onset before the age of 50 years, infrapopliteal arterial occlusive disease, either upper limb involvement or phlebitis migrans, absence of atherosclerotic risk factors other than smoking. In the last 10 years (1986-1996), we identified 29 patients who met these rigid criteria. There were 24 men and 5 women, aged 32.4 years at the moment of the disease first clinical symptom. The cumulative tobacco use averaged 16 pack-years for each patient. The initial symptom was limited gangrene of a toe (n = 9) or a finger (n = 2), foot claudication (n = 6), calf claudication (n = 3), rest pain (n = 3), migratory superficial phlebitis (n = 4), and Raynaud phenomenon (n = 2). Angiography and/or Doppler ultrasound revealed digital, pedal and calf artery involvement in all patients, with proximal extension in ten patients (femoropopliteal in ten, including three cases with external iliac artery involvement). Seven patients had also evidence of upper limb involvement. Histologic proof was available in only seven patients. Only nine patients completely stopped smoking. Treatment was exclusively medical in five cases. Twenty-four underwent sympathectomy (20 at lumbar, and four at thoracic level), with good immediate result in 16. In 11 patients a vascular reconstruction was done (eight femorocrural and three iliofemoral bypasses), with a patency rate of only 36% at two years. Amputation was required in 16 patients (a mean of 2.7 amputations per patient) at one or more levels: toe (n = 19), forefoot (n = 5), below knee (n = 8), above knee (n = 2), finger (n = 3). Two patients ended up with bilateral leg amputation. Overall, 23% (7/30) of the patients required major leg amputation during the course of the disease. Disease progression was moderately related to continued tobacco use. Buerger's disease still entails considerable risk of major amputation. Complete abstinence from tobacco use is crucial to expect stabilization of the process. However, in advanced stages of the disease and despite cessation of smoking recurrent episodes of ischaemia or tissue loss are not excluded.

  10. Complications following limb-threatening lower extremity trauma.

    PubMed

    Harris, Anthony M; Althausen, Peter L; Kellam, James; Bosse, Michael J; Castillo, Renan

    2009-01-01

    Our objective is to report the nature and incidence of major complications after severe lower extremity trauma. Multicenter, prospective, observational study. Eight level-1 trauma centers. Five hundred forty-five patients were followed for 2 years. Amputation or reconstruction. The type and number of complications associated with these injuries were recorded at baseline, 3-, 6-, 12-, and 24-month intervals. One hundred forty-nine underwent amputation during the initial hospitalization. The revision amputation rate was 5.4%. Among the amputation group, a complication was noted most frequently at 3 months (24.8%), and the most commonly seen complication was wound infection (34.2%). Wound complications including dehiscence (13.4%) were seen more commonly in the amputation group. Three hundred seventy-one limb reconstructions were performed with 25 patients (3.9%) requiring late amputation. The most frequently reported complication was at 6 months for the salvage group (37.7%), and the most commonly seen complication was wound infection (23.2%). Not surprisingly, osteomyelitis (8.6%) and nonunions (31%) were seen more commonly in the salvage group. Complications of wound infection, osteomyelitis, nonunion, malunion, and prominent hardware resulted in rehospitalization in at least one-third of patients. However, patients who underwent reconstruction were more likely to be hospitalized for these complications. Patients with severe lower extremity injuries can expect a significant number of complications, most notably wound infection, nonunion, wound necrosis, and osteomyelitis. A large portion of these will require additional inpatient or operative treatment. Patients electing for reconstruction can expect a higher risk of complications.

  11. The Mid-Term Clinical Follow-Up Using Drug-Eluting Balloons on Tibial Artery "De Novo" Lesions in Patients With Critical Limb Ischemia: A Cohort Study.

    PubMed

    Tolva, Valerio; Casana, Renato; Huibers, Anne; Parati, Gianfranco; Bianchi, Paolo; Cireni, Lea; Ferrero, Emanuele; Halliday, Allison

    2016-07-01

    Restenosis due to intimal hyperplasia (IH) is a major clinical issue that affects the success of lower limb endovascular surgery. After 1 year, restenosis occurs in 40% to 60% of the treated vessels. The possibility to reduce IH using local antiproliferative drugs, such as taxols, has been the rationale for the clinical applications of drug-eluting stents and drug-eluting balloons (DEBs). The purpose of this study was to evaluate the clinical and instrumental efficacy of DEBs versus simple percutaneous transluminal angioplasty (PTA) in patients affected by chronic limb ischemia (CLI) with tibial artery "de novo" lesions. A retrospective analysis was performed and included all consecutive patients who underwent endovascular treatment for CLI in our centers between January 2011 and March 2013. Inclusion criteria were (1) "de novo" tibial artery stenosis and (2) Rutherford class >4. Lesions were further divided by TransAtlantic Inter-Societal Consensus (TASC) classification into groups A, B, C, and D. Between January 2010 and March 2013, a total of 138 patients underwent simple PTA or DEB for CLI, and the groups were clinically and demographically homogenous. We decided to use DEBs in 70 cases. An improvement in the Rutherford Scale in cumulative and single TASC lesions classification was better in the DEB group (74% vs 51%; P = .024) at 24 months than in the PTA group. In the DEB group, the increase in ankle-brachial index was significantly higher than in the PTA group (P = .039). Our experience in addition to the existing literature supports the use of DEB in patients with CLI Rutherford class >3. © The Author(s) 2016.

  12. Activation of the Pro-Oxidant PKCβII-p66Shc Signaling Pathway Contributes to Pericyte Dysfunction in Skeletal Muscles of Patients With Diabetes With Critical Limb Ischemia.

    PubMed

    Vono, Rosa; Fuoco, Claudia; Testa, Stefano; Pirrò, Stefano; Maselli, Davide; Ferland McCollough, David; Sangalli, Elena; Pintus, Gianfranco; Giordo, Roberta; Finzi, Giovanna; Sessa, Fausto; Cardani, Rosanna; Gotti, Ambra; Losa, Sergio; Cesareni, Gianni; Rizzi, Roberto; Bearzi, Claudia; Cannata, Stefano; Spinetti, Gaia; Gargioli, Cesare; Madeddu, Paolo

    2016-12-01

    Critical limb ischemia (CLI), foot ulcers, former amputation, and impaired regeneration are independent risk factors for limb amputation in subjects with diabetes. The present work investigates whether and by which mechanism diabetes negatively impacts on functional properties of muscular pericytes (MPs), which are resident stem cells committed to reparative angiomyogenesis. We obtained muscle biopsy samples from patients with diabetes who were undergoing major limb amputation and control subjects. Diabetic muscles collected at the rim of normal tissue surrounding the plane of dissection showed myofiber degeneration, fat deposition, and reduction of MP vascular coverage. Diabetic MPs (D-MPs) display ultrastructural alterations, a differentiation bias toward adipogenesis at the detriment of myogenesis and an inhibitory activity on angiogenesis. Furthermore, they have an imbalanced redox state, with downregulation of the antioxidant enzymes superoxide dismutase 1 and catalase, and activation of the pro-oxidant protein kinase C isoform β-II (PKCβII)-dependent p66(Shc) signaling pathway. A reactive oxygen species scavenger or, even more effectively, clinically approved PKCβII inhibitors restore D-MP angiomyogenic activity. Inhibition of the PKCβII-dependent p66(Shc) signaling pathway could represent a novel therapeutic approach for the promotion of muscle repair in individuals with diabetes. © 2016 by the American Diabetes Association.

  13. [Chronic mesenteric ischemia revisited].

    PubMed

    do Carmo, Germano; Rosa, António; Ministro, Augusto; Pestana, Cristina

    2013-01-01

    The authors report two clinical cases of rare and complex situations - an aortic dissection and an aortitis -, which had as a common denominator a chronic mesenteric ischemia. They discuss the indications and surgical strategies adopted.

  14. [Spinal cord ischemia].

    PubMed

    Masson, C; Leys, D; Meder, J F; Dousset, V; Pruvo, J P

    2004-01-01

    Traditional data and recent advances in the field of spinal cord ischemia are reviewed, with special attention to clinical and radiological features, as well as underlying etiology, outcome, and pathophysiology. Acute spinal cord ischemia includes arterial and venous infarction and global ischemia resulting from cardiac arrest or severe hypotension. MRI has become the technique of choice for the imaging diagnosis of spinal cord infarction. Correlation of clinical and MRI data has allowed diagnosis of clinical syndromes due to small infarcts in the central or peripheral arterial territory of the spinal cord. Diffusion-weighted MR imaging may increase the sensitivity and specificity for diagnosis of acute spinal cord infarction. Diagnosis of venous spinal cord infarction remains difficult. As for global ischemia, neuropathological studies demonstrated a great sensitivity of spinal cord to ischemia, with selective vulnerability of lumbosacral neurons. Chronic spinal cord ischemia results in a syndrome of progressive myelopathy. The cause is usually an arteriovenous malformation. Most often, diagnosis may be suspected on MRI, leading to diagnostic, and eventually therapeutic, spinal angiography.

  15. Administration of Adult Human Bone Marrow-Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells in Critical Limb Ischemia Due to Buerger's Disease: Phase II Study Report Suggests Clinical Efficacy.

    PubMed

    Gupta, Pawan K; Krishna, Murali; Chullikana, Anoop; Desai, Sanjay; Murugesan, Rajkumar; Dutta, Santanu; Sarkar, Uday; Raju, Radhakrishnan; Dhar, Anita; Parakh, Rajiv; Jeyaseelan, Lakshmanan; Viswanathan, Pachaiyappan; Vellotare, Prasanth Kulapurathu; Seetharam, Raviraja N; Thej, Charan; Rengasamy, Mathiyazhagan; Balasubramanian, Sudha; Majumdar, Anish S

    2017-03-01

    Critical limb ischemia (CLI) due to Buerger's disease is a major unmet medical need with a high incidence of morbidity. This phase II, prospective, nonrandomized, open-label, multicentric, dose-ranging study was conducted to assess the efficacy and safety of i.m. injection of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (BMMSC) in CLI due to Buerger's disease. Patients were allocated to three groups: 1 and 2 million cells/kg body weight (36 patients each) and standard of care (SOC) (18 patients). BMMSCs were administered as 40-60 injections in the calf muscle and locally, around the ulcer. Most patients were young (age range, 38-42 years) and ex-smokers, and all patients had at least one ulcer. Both the primary endpoints-reduction in rest pain (0.3 units per month [SE, 0.13]) and healing of ulcers (11% decrease in size per month [SE, 0.05])-were significantly better in the group receiving 2 million cells/kg body weight than in the SOC arm. Improvement in secondary endpoints, such as ankle brachial pressure index (0.03 [SE, 0.01] unit increase per month) and total walking distance (1.03 [SE, 0.02] times higher per month), were also significant in the group receiving 2 million cells/kg as compared with the SOC arm. Adverse events reported were remotely related or unrelated to BMMSCs. In conclusion, i.m. administration of BMMSC at a dose of 2 million cells/kg showed clinical benefit and may be the best regimen in patients with CLI due to Buerger's disease. However, further randomized controlled trials are required to confirm the most appropriate dose. Stem Cells Translational Medicine 2017;6:689-699.

  16. 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.

  17. [Cerebral ischemia and histamine].

    PubMed

    Adachi, Naoto

    2002-10-01

    Cerebral ischemia induces excess release of glutamate and an increase in the intracellular Ca2+ concentration, which provoke catastrophic enzymatic processes leading to irreversible neuronal injury. Histamine plays the role of neurotransmitter in the central nervous system, and histaminergic fibers are widely distributed in the brain. In cerebral ischemia, release of histamine from nerve endings has been shown to be enhanced by facilitation of its activity. An inhibition of the histaminergic activity in ischemia aggravates the histologic outcome. In contrast, intracerebroventricular administration of histamine improves the aggravation, whereas blockade of histamine H2 receptors aggravates ischemic injury. Furthermore, H2 blockade enhances ischemic release of glutamate and dopamine. These findings suggest that central histamine provides beneficial effects against ischemic neuronal damage by suppressing release of excitatory neurotransmitters. However, histaminergic H2 action facilitates the permeability of the blood-brain barrier and shows deleterious effects on cerebral edema.

  18. Critical Limb Ischemia: Reporting Outcomes and Quality

    PubMed Central

    2012-01-01

    The impetus to pursue quality in limb salvage is high in the current economic environment. This has been spurred on by the diffusion of multiple technologies, the lack of well-defined cost-effectiveness benchmarks, and the paucity of process and structure benchmarks. Furthermore, no national database exists to capture current activity and trends, and lead structure and process changes that could analyze outcomes and improve standards in peripheral interventions for limb salvage. This manuscript examines the challenges in measuring outcomes and quality in limb salvage and explores the components necessary for ensuring quality in limb salvage interventions. PMID:23342183

  19. 20-HETE contributes to ischemia-induced angiogenesis.

    PubMed

    Chen, Li; Joseph, Gregory; Zhang, Frank F; Nguyen, Huyen; Jiang, Houli; Gotlinger, Katherine H; Falck, John R; Yang, Jing; Schwartzman, Michal L; Guo, Austin M

    2016-08-01

    Angiogenesis is an important adaptation for recovery from peripheral ischemia. Here, we determined whether 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia-induced angiogenesis and assessed its underlying molecular and cellular mechanisms using a mouse hindlimb-ischemia angiogenesis model. Hindlimb blood flow was measured by Laser Doppler Perfusion Imaging and microvessel density was determined by CD31 and tomato lectin staining. We found that systemic and local administration of a 20-HETE synthesis inhibitor, DDMS, or a 20-HETE antagonist, 6,15-20-HEDGE significantly reduced blood flow recovery and microvessel formation in response to ischemia. 20-HETE production, measured by LC/MS/MS, was markedly increased in ischemic muscles (91±11 vs. 8±2pg/mg in controls), which was associated with prominent upregulation of the 20-HETE synthase, CYP4A12. Immunofluorescence co-localized increased CYP4A12 expression in response to ischemia to CD31-positive EC in the ischemic hindlimb microvessels. We further showed that ischemia increased HIF-1α, VEGF, and VEGFR2 expression in gracilis muscles and that these increases were negated by DDMS and 6,15-20-HEDGE. Lastly, we showed that ERK1/2 of MAPK is a component of 20-HETE regulated ischemic angiogenesis. Taken together, these data indicate that 20-HETE is a critical contributor of ischemia-induced angiogenesis in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. The evolving concept of physiological ischemia training vs. ischemia preconditioning.

    PubMed

    Ni, Jun; Lu, Hongjian; Lu, Xiao; Jiang, Minghui; Peng, Qingyun; Ren, Caili; Xiang, Jie; Mei, Chengyao; Li, Jianan

    2015-11-01

    Ischemic heart diseases are the leading cause of death with increasing numbers of patients worldwide. Despite advances in revascularization techniques, angiogenic therapies remain highly attractive. Physiological ischemia training, which is first proposed in our laboratory, refers to reversible ischemia training of normal skeletal muscles by using a tourniquet or isometric contraction to cause physiologic ischemia for about 4 weeks for the sake of triggering molecular and cellular mechanisms to promote angiogenesis and formation of collateral vessels and protect remote ischemia areas. Physiological ischemia training therapy augments angiogenesis in the ischemic myocardium by inducing differential expression of proteins involved in energy metabolism, cell migration, protein folding, and generation. It upregulates the expressions of vascular endothelial growth factor, and induces angiogenesis, protects the myocardium when infarction occurs by increasing circulating endothelial progenitor cells and enhancing their migration, which is in accordance with physical training in heart disease rehabilitation. These findings may lead to a new approach of therapeutic angiogenesis for patients with ischemic heart diseases. On the basis of the promising results in animal studies, studies were also conducted in patients with coronary artery disease without any adverse effect in vivo, indicating that physiological ischemia training therapy is a safe, effective and non-invasive angiogenic approach for cardiovascular rehabilitation. Preconditioning is considered to be the most protective intervention against myocardial ischemia-reperfusion injury to date. Physiological ischemia training is different from preconditioning. This review summarizes the preclinical and clinical data of physiological ischemia training and its difference from preconditioning.

  1. Radiological Evaluation of Bowel Ischemia

    PubMed Central

    Dhatt, Harpreet S.; Behr, Spencer C; Miracle, Aaron; Wang, Zhen Jane; Yeh, Benjamin M.

    2015-01-01

    Intestinal ischemia, which refers to insufficient blood flow to the bowel, is a potentially catastrophic entity that may require emergent intervention or surgery in the acute setting. Although the clinical signs and symptoms of intestinal ischemia are nonspecific, CT findings can be highly suggestive in the correct clinical setting. In this chapter we review the CT diagnosis of arterial, venous, and non-occlusive intestinal ischemia. We discuss the vascular anatomy, pathophysiology of intestinal ischemia, CT techniques for optimal imaging, key and ancillary radiological findings, and differential diagnosis. In the setting of an acute abdomen, rapid evaluation is necessary to identify intraabdominal processes that require emergent surgical intervention (1). While a wide-range of intraabdominal diseases may be present from trauma to inflammation, one of the most feared disorders is mesenteric ischemia, also known as intestinal ischemia, which refers to insufficient blood flow to the bowel (2). Initial imaging evaluation for intestinal ischemia is typically obtained with CT. Close attention to technique and search for key radiologic features with relation to the CT technique is required. Accurate diagnosis depends on understanding the vascular anatomy, epidemiology, and pathophysiology of various forms of mesenteric ischemia and their corresponding radiological findings on MDCT. At imaging, not only is inspection of the bowel itself important, but evaluation of the mesenteric fat, vasculature, and surrounding peritoneal cavity also helps improves accuracy in the diagnosis of bowel ischemia. PMID:26526436

  2. The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia Reperfusion Injury

    PubMed Central

    Zhou, Haoming; Zhu, Jianjun; Yue, Shi; Lu, Ling; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.; Wang, Xuehao; Zhai, Yuan

    2015-01-01

    Endoplasmic reticulum (ER) stress plays critical roles in the pathogenesis of liver ischemia and reperfusion injury (IRI). As ER stress triggers an adaptive cellular response, the question of what determines its functional outcome in liver IRI remains to be defined. In a murine liver partial warm ischemia model, we studied how transient (30m) or prolonged (90m) liver ischemia regulated local ER stress response and autophagy activities and their relationship with liver IRI. Effects of chemical chaperon 4-phenylbutyrate (4-PBA) or autophagy inhibitor 3-methyladenine (3-MA) was evaluated. Our results showed that while the ATF6 branch of ER stress response was induced in livers by both types of ischemia, liver autophagy was activated by transient, but inhibited by prolonged, ischemia. Although 3-MA had no effects on liver IRI after prolonged ischemia, it significantly increased liver IRI after transient ischemia. The 4-PBA treatment protected livers from IRI after prolonged ischemia by restoring autophagy flux, and the adjunctive 3-MA treatment abrogated its liver protective effect. The same 4-PBA treatment, however, increased liver IRI and disrupted autophagy flux after transient ischemia. Although both types of ischemia activated 5′ adenosine monophosphate-activated protein kinase (AMPK) and inactivated protein kinase B (Akt), prolonged ischemia also resulted in downregulations of autophagy-related gene (Atg) 3 and Atg5 in ischemic livers. These results indicate a functional dichotomy of ER stress response in liver IRI via its regulation of autophagy. Transient ischemia activates autophagy to protect livers from IRI, while prolonged ischemia inhibits autophagy to promote the development of liver IRI. PMID:26683513

  3. The Dichotomy of Endoplasmic Reticulum Stress Response in Liver Ischemia-Reperfusion Injury.

    PubMed

    Zhou, Haomming; Zhu, Jianjun; Yue, Shi; Lu, Ling; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Wang, Xuehao; Zhai, Yuan

    2016-02-01

    Endoplasmic reticulum (ER) stress plays critical roles in the pathogenesis of liver ischemia-reperfusion injury (IRI). As ER stress triggers an adaptive cellular response, the question of what determines its functional outcome in liver IRI remains to be defined. In a murine liver partial warm ischemia model, we studied how transient (30 minutes) or prolonged (90 minutes) liver ischemia regulated local ER stress response and autophagy activities and their relationship with liver IRI. Effects of chemical chaperon 4-phenylbutyrate (4-PBA) or autophagy inhibitor 3-methyladenine (3-MA) were evaluated. Our results showed that although the activating transcription factor 6 branch of ER stress response was induced in livers by both types of ischemia, liver autophagy was activated by transient, but inhibited by prolonged, ischemia. Although 3-MA had no effects on liver IRI after prolonged ischemia, it significantly increased liver IRI after transient ischemia. The 4-PBA treatment protected livers from IRI after prolonged ischemia by restoring autophagy flux, and the adjunctive 3-MA treatment abrogated its liver protective effect. The same 4-PBA treatment, however, increased liver IRI and disrupted autophagy flux after transient ischemia. Although both types of ischemia activated 5' adenosine monophosphate-activated protein kinase and inactivated protein kinase B (Akt), prolonged ischemia also resulted in downregulations of autophagy-related gene 3 and autophagy-related gene 5 in ischemic livers. These results indicate a functional dichotomy of ER stress response in liver IRI via its regulation of autophagy. Transient ischemia activates autophagy to protect livers from IRI, whereas prolonged ischemia inhibits autophagy to promote the development of liver IRI.

  4. Vasospastic Limb Ischemia Presenting Acute and Chronic Limb Ischemia

    PubMed Central

    2014-01-01

    Vasospastic limb ischemia might have been underappreciated compared to vasospasm in other territories such as heart and brain. However, an increasing awareness of this vascular disorder can be translated to an improved patients’ care. Herein, we report a case of vasospasm presenting acute and chronic limb ischemia in four extremities. PMID:24995065

  5. Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia

    PubMed Central

    Ryan, Terence E.; Schmidt, Cameron A.; Alleman, Rick J.; Tsang, Alvin M.; Green, Thomas D.; Neufer, P. Darrell; Brown, David A.; McClung, Joseph M.

    2016-01-01

    Critical limb ischemia is a devastating manifestation of peripheral arterial disease with no effective strategies for improving morbidity and mortality outcomes. We tested the hypothesis that cellular mitochondrial function is a key component of limb pathology and that improving mitochondrial function represents a novel paradigm for therapy. BALB/c mice were treated with a therapeutic mitochondrial-targeting peptide (MTP-131) and subjected to limb ischemia (HLI). Compared to vehicle control, MTP-131 rescued limb muscle capillary density and blood flow (64.7±11% of contralateral vs. 39.9±4%), and improved muscle regeneration. MTP-131 also increased electron transport system flux across all conditions at HLI day-7. In vitro, primary muscle cells exposed to experimental ischemia demonstrated markedly reduced (~75%) cellular respiration, which was rescued by MTP-131 during a recovery period. Compared to muscle cells, endothelial cell (HUVEC) respiration was inherently protected from ischemia (~30% reduction), but was also enhanced by MTP-131. These findings demonstrate an important link between ischemic tissue bioenergetics and limb blood flow and indicate that the mitochondria may be a pharmaceutical target for therapeutic intervention during critical limb ischemia. PMID:27262673

  6. Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia.

    PubMed

    Ryan, Terence E; Schmidt, Cameron A; Alleman, Rick J; Tsang, Alvin M; Green, Thomas D; Neufer, P Darrell; Brown, David A; McClung, Joseph M

    2016-08-01

    Critical limb ischemia is a devastating manifestation of peripheral arterial disease with no effective strategies for improving morbidity and mortality outcomes. We tested the hypothesis that cellular mitochondrial function is a key component of limb pathology and that improving mitochondrial function represents a novel paradigm for therapy. BALB/c mice were treated with a therapeutic mitochondrial-targeting peptide (MTP-131) and subjected to limb ischemia (HLI). Compared to vehicle control, MTP-131 rescued limb muscle capillary density and blood flow (64.7±11% of contralateral vs. 39.9±4%), and improved muscle regeneration. MTP-131 also increased electron transport system flux across all conditions at HLI day-7. In vitro, primary muscle cells exposed to experimental ischemia demonstrated markedly reduced (~75%) cellular respiration, which was rescued by MTP-131 during a recovery period. Compared to muscle cells, endothelial cell (HUVEC) respiration was inherently protected from ischemia (~30% reduction), but was also enhanced by MTP-131. These findings demonstrate an important link between ischemic tissue bioenergetics and limb blood flow and indicate that the mitochondria may be a pharmaceutical target for therapeutic intervention during critical limb ischemia. Copyright © 2016. Published by Elsevier Ltd.

  7. Ischemia causes muscle fatigue

    NASA Technical Reports Server (NTRS)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D. M.

    2001-01-01

    The purpose of this investigation was to determine whether ischemia, which reduces oxygenation in the extensor carpi radialis (ECR) muscle, causes a reduction in muscle force production. In eight subjects, muscle oxygenation (TO2) of the right ECR was measured noninvasively and continuously using near infrared spectroscopy (NIRS) while muscle twitch force was elicited by transcutaneous electrical stimulation (1 Hz, 0.1 ms). Baseline measurements of blood volume, muscle oxygenation and twitch force were recorded continuously, then a tourniquet on the upper arm was inflated to one of five different pressure levels: 20, 40, 60 mm Hg (randomized order) and diastolic (69 +/- 9.8 mm Hg) and systolic (106 +/- 12.8 mm Hg) blood pressures. Each pressure level was maintained for 3-5 min, and was followed by a recovery period sufficient to allow measurements to return to baseline. For each respective tourniquet pressure level, mean TO2 decreased from resting baseline (100% TO2) to 99 +/- 1.2% (SEM), 96 +/- 1.9%, 93 +/- 2.8%, 90 +/- 2.5%, and 86 +/- 2.7%, and mean twitch force decreased from resting baseline (100% force) to 99 +/- 0.7% (SEM), 96 +/- 2.7%, 93 +/- 3.1%, 88 +/- 3.2%, and 86 +/- 2.6%. Muscle oxygenation and twitch force at 60 mm Hg tourniquet compression and above were significantly lower (P < 0.05) than baseline value. Reduced twitch force was correlated in a dose-dependent manner with reduced muscle oxygenation (r = 0.78, P < 0.001). Although the correlation does not prove causation, the results indicate that ischemia leading to a 7% or greater reduction in muscle oxygenation causes decreased muscle force production in the forearm extensor muscle. Thus, ischemia associated with a modest decline in TO2 causes muscle fatigue.

  8. Ischemia causes muscle fatigue

    NASA Technical Reports Server (NTRS)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D. M.

    2001-01-01

    The purpose of this investigation was to determine whether ischemia, which reduces oxygenation in the extensor carpi radialis (ECR) muscle, causes a reduction in muscle force production. In eight subjects, muscle oxygenation (TO2) of the right ECR was measured noninvasively and continuously using near infrared spectroscopy (NIRS) while muscle twitch force was elicited by transcutaneous electrical stimulation (1 Hz, 0.1 ms). Baseline measurements of blood volume, muscle oxygenation and twitch force were recorded continuously, then a tourniquet on the upper arm was inflated to one of five different pressure levels: 20, 40, 60 mm Hg (randomized order) and diastolic (69 +/- 9.8 mm Hg) and systolic (106 +/- 12.8 mm Hg) blood pressures. Each pressure level was maintained for 3-5 min, and was followed by a recovery period sufficient to allow measurements to return to baseline. For each respective tourniquet pressure level, mean TO2 decreased from resting baseline (100% TO2) to 99 +/- 1.2% (SEM), 96 +/- 1.9%, 93 +/- 2.8%, 90 +/- 2.5%, and 86 +/- 2.7%, and mean twitch force decreased from resting baseline (100% force) to 99 +/- 0.7% (SEM), 96 +/- 2.7%, 93 +/- 3.1%, 88 +/- 3.2%, and 86 +/- 2.6%. Muscle oxygenation and twitch force at 60 mm Hg tourniquet compression and above were significantly lower (P < 0.05) than baseline value. Reduced twitch force was correlated in a dose-dependent manner with reduced muscle oxygenation (r = 0.78, P < 0.001). Although the correlation does not prove causation, the results indicate that ischemia leading to a 7% or greater reduction in muscle oxygenation causes decreased muscle force production in the forearm extensor muscle. Thus, ischemia associated with a modest decline in TO2 causes muscle fatigue.

  9. Oligodendrogenesis after cerebral ischemia

    PubMed Central

    Zhang, Ruilan; Chopp, Michael; Zhang, Zheng Gang

    2013-01-01

    Neural stem cells in the subventricular zone (SVZ) of the lateral ventricle of adult rodent brain generate oligodendrocyte progenitor cells (OPCs) that disperse throughout the corpus callosum and striatum where some of OPCs differentiate into mature oligodendrocytes. Studies in animal models of stroke demonstrate that cerebral ischemia induces oligodendrogenesis during brain repair processes. This article will review evidence of stroke-induced proliferation and differentiation of OPCs that are either resident in white matter or are derived from SVZ neural progenitor cells and of therapies that amplify endogenous oligodendrogenesis in ischemic brain. PMID:24194700

  10. 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

  11. Astroglial acid-base dynamics in hyperglycemic and normoglycemic global ischemia.

    PubMed

    Lascola, C; Kraig, R P

    1997-03-01

    Biochemical, histological, and physiological evidence suggest strongly that astrocytes may either defend or damage brain tissue, depending on the brain carbohydrate content preceding global ischemia (28,43). This paper will first review the concept of acidosis in ischemia and the possible role of severe, compartmentalized astrocytic acidosis in pan necrosis. Results are then presented demonstrating that astrocytes are also capable of maintaining an alkaline intracellular pH (pHi) during normoglycemic global ischemia. Mechanisms underlying depolarization-dependent astroglial alkalosis are then reviewed. Recent experiments indicate that bicarbonate (HCO3-) transport is a major mechanism by which astroglia not only alkalinize their interior but also acidify the interstitium. Maintenance of alkalosis during normoglycemic ischemia supports the hypothesis that astroglial HCO3- transport might ultimately protect neurons from excitotoxicity in ischemia without infarction (17). Inhibition of astroglial HCO3- transport may be a critical and requisite event, ultimately leading to compartmentalized astroglial acidosis and irreversible injury to all cell types.

  12. Intestinal ischemia in neonates and children.

    PubMed

    Jeican, Ionuţ Isaia; Ichim, Gabriela; Gheban, Dan

    2016-01-01

    The article reviews the intestinal ischemia theme on newborn and children. The intestinal ischemia may be either acute - intestinal infarction (by vascular obstruction or by reduced mesenteric blood flow besides the occlusive mechanism), either chronic. In neonates, acute intestinal ischemia may be caused by aortic thrombosis, volvulus or hypoplastic left heart syndrome. In children, acute intestinal ischemia may be caused by fibromuscular dysplasia, volvulus, abdominal compartment syndrome, Burkitt lymphoma, dermatomyositis (by vascular obstruction) or familial dysautonomia, Addison's disease, situs inversus abdominus (intraoperative), burns, chemotherapy administration (by nonocclusive mesenteric ischemia). Chronic intestinal ischemia is a rare condition in pediatrics and can be seen in abdominal aortic coarctation or hypoplasia, idiopathic infantile arterial calcinosis.

  13. Local and Remote Postconditioning Decrease Intestinal Injury in a Rabbit Ischemia/Reperfusion Model

    PubMed Central

    Yang, Mu; Dong, Jian-Xin; Li, Lu-Bin; Che, Hai-Jie; Yong, Jun; Song, Fu-Bo; Wang, Tao; Zhang, Jv-Wen

    2016-01-01

    Intestinal ischemia/reperfusion (I/R) injury is a significant problem that is associated with high morbidity and mortality in critical settings. This injury may be ameliorated using postconditioning protocol. In our study, we created a rabbit intestinal I/R injury model to analyze the effects of local ischemia postconditioning (LIPo) and remote ischemia postconditioning (RIPo) on intestinal I/R injury. We concluded that LIPo affords protection in intestinal I/R injury in a comparable fashion with RIPo by decreasing oxidative stress, neutrophil activation, and apoptosis. PMID:26819600

  14. [Retinal ischemia and nitric oxide].

    PubMed

    Neroev, V V; Arkhipova, M M

    2003-01-01

    Retinal ischemia is the main chain in the pathogenesis of vascular diseases of the eye. It was established that nitric oxide (NO) plays the key role in the development of ischemia. Recent understanding of the NO role, as a universal regulator of the cellular and tissue metabolism, is presented. The authors' and published data were used to design a scheme of pathogenesis of retinal ischemia with regard for the NO role. NO can produce both positive and negative effects depending on a stage of the process, NO concentration and on a number of other factors if they are present. Initial stages of hypoxia/ischemia are accompanied by an activation of all forms of NO-synthases (NOS) caused by the influence of biologically active substances (cytokines, prostaglandins, serotonin, bradykinin, glycolisis suboxide products etc.). The activation of inducible NOS, which synthesize a bigger quantity of NO possessing a direct cytotoxic action and contributing to the production of highly toxic radical of peroxinitrit, is in the focus of attention. The damage of cellular structures due to free-radical processes leads to the development of endothelial, macrophage and thrombocyte malfunctions, which manifest itself through a reduced activity of endothelial NOS and through disruption of NO-dependent processes (vasospasm, an increased aggregation of platelets and a reduced fibrinolytic activity). A sharp reduction of NO synthesis substrate (L-arginine) is observed in patients with retinal ischemia. The aggravation of ischemia causes a decrease of NO synthesis due to an exhaustion of L-arginine and its intensified consumption in the course of free-radical processes. The use of NO-inhibitors and of NO-donors at different stages of retinal ischemia prevents the development of neovascularization and proliferation.

  15. Protective effects of sevoflurane in hepatic ischemia-reperfusion injury.

    PubMed

    Li, Ji; Yuan, Tong; Zhao, Xin; Lv, Guo-Yue; Liu, Huan-Qiu

    2016-06-01

    The endothelial glycocalyx plays a critical role in the regulation of vascular structure and functions. Previous studies have demonstrated that sevoflurane, a volatile anesthetic, can preserve the endothelial glycocalyx in heart tissues against ischemia-reperfusion injury. However, little is known about the effects of sevoflurane pretreatment on the vascular structure and functions of liver tissues following ischemia-reperfusion injury. To this end, female Sprague-Dawley rats (n = 28) were anesthetized either with ketamine (80-120 mg/kg, i.p.) or with one minimum alveolar concentration (MAC) sevoflurane (2% v/v). Following in vivo hepatic ischemia procedure, the liver was isolated and reperfusion was produced. During the period of reperfusion, liver reperfusion samples were collected, and the concentrations of heparan sulfate and syndecan-1 (Syn-1), and the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes, were measured. The morphology of hepatocytes and endothelial glycocalyx were then assessed by using the light and electron microscopies, respectively. Ischemia-reperfusion increased the release of HS and Syn-1, and elevated the levels of ALT and AST in a time-dependent manner. However, sevoflurane pretreatment reduced the release of HS and Syn-1and attenuated the levels of ALT and AST, in a time-dependent manner, as compared with ketamine pretreatment. Furthermore, sevoflurane pretreatment decreased the shedding of endothelial glycocalyx and hepatocytes necrosis. Sevoflurane pretreatment preserved the endothelial glycocalyx in the liver tissue against ischemia-reperfusion injury. The effect appears to help protect hepatocytes against ischemia-reperfusion-induced necrosis. © The Author(s) 2016.

  16. Monitoring Tissue Ischemia After Potentially Life Threatening Post-Traumatic Injuries

    DTIC Science & Technology

    2011-12-01

    Monitoring Tissue Ischemia After Potentially Life Threatening Post-Traumatic Injuries Dr. Wanchun Tang Institute of Critical Care Medicine Rancho Mirage, CA...the study was to develop a PSLCO2 sensor based on the existing Sensation platform. The Sensation carbon nanotube sensor technology provided a...severity of tissue ischemia and there better guide for optimizing fluid resuscitation. It is especially significant for the military application since

  17. Nonhuman primate models of focal cerebral ischemia

    PubMed Central

    Fan, Jingjing; Li, Yi; Fu, Xinyu; Li, Lijuan; Hao, Xiaoting; Li, Shasha

    2017-01-01

    Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model. PMID:28400817

  18. [Recurrent intestinal ischemia due to factor VIII].

    PubMed

    Castellanos Monedero, Jesús Javier; Legaz Huidobro, María Luisa; Galindo Andugar, María Angeles; Rodríguez Pérez, Alvaro; Mantrana del Valle, José María

    2008-01-01

    Intestinal ischemia is difficult to diagnose and can be caused by several etiologic processes. We report the case of a female patient with recurrent bowel ischemia due to small vessel thrombosis, which is caused by factor VIII, a procoagulant factor.

  19. Long-term follow-up of patients with silent ischemia during exercise radionuclide angiography

    SciTech Connect

    Breitenbuecher, A.P.; Pfisterer, M.; Hoffmann, A.; Burckhardt, D. )

    1990-04-01

    A retrospective 5 year follow-up study was performed in 140 patients with unequivocal ischemia during exercise radionuclide angiography (greater than or equal to 10% decrease in left ventricular ejection fraction or greater than or equal to 5% decrease in ejection fraction together with a distinct regional wall motion abnormality). In 84 patients (60%), ischemia during radionuclide angiography was silent (silent ischemia group), whereas 56 patients experienced angina during the test (symptomatic group). Work load and antianginal medication were similar in both groups. Critical cardiac events (unstable angina, myocardial infarction, cardiac death) occurred in 27% of patients in the silent ischemia group and 16% of those in the symptomatic group (p = NS); however, myocardial infarction or death was more frequent in patients with silent ischemia (22% versus 9%; p less than 0.05). If there was additional exercise-induced ST segment depression, the rate of critical events was further increased (p less than 0.05). The difference in critical cardiac events seemed to be influenced by the higher incidence of revascularization procedures in symptomatic patients, whereas medical therapy had no similar effect. Thus, these findings suggest that patients with documented severe ischemia should undergo left heart catheterization and revascularization irrespective of symptoms to improve their prognosis.

  20. Trimodal rescue of hind limb ischemia with growth factors, cells, and nanocarriers: fundamentals to clinical trials.

    PubMed

    Lakshmanan, Rajesh; Ukani, Gopi; Rishi, Muhammad Tipu; Maulik, Nilanjana

    2017-10-01

    Peripheral artery disease is a severe medical condition commonly characterized by critical or acute limb ischemia. Gradual accumulation of thrombotic plaques in peripheral arteries of the lower limb may lead to intermittent claudication or ischemia in muscle tissue. Ischemic muscle tissue with lesions may become infected, resulting in a non-healing wound. Stable progression of the non-healing wound associated with severe ischemia might lead to functional deterioration of the limb, which, depending on the severity, can result in amputation. Immediate rescue of ischemic muscles through revascularization strategies is considered the gold standard to treat critical limb ischemia. Growth factors offer multiple levels of protection in revascularization of ischemic tissue. In this review, the basic mechanism through which growth factors exert their beneficial properties to rescue the ischemic limb is extensively discussed. Moreover, clinical trials based on growth factor and stem cell therapy to treat critical limb ischemia are considered. The clinical utility of stem cell therapy for the treatment of limb ischemia is explained and recent advances in nanocarrier technology for selective growth factor and stem cell supplementation are summarized.

  1. Endothelin Receptors, Mitochondria and Neurogenesis in Cerebral Ischemia

    PubMed Central

    Gulati, Anil

    2016-01-01

    Background: Neurogenesis is most active during pre-natal development, however, it persists throughout the human lifespan. The putative role of mitochondria in neurogenesis and angiogenesis is gaining importance. Since, ETB receptor mediated neurogenesis and angiogenesis has been identified, the role of these receptors with relevance to mitochondrial functions is of interest. Methods: In addition to work from our laboratory, we undertook an extensive search of bibliographic databases for peer-reviewed research literature. Specific technical terms such as endothelin, mitochondria and neurogenesis were used to seek out and critically evaluate literature that was relevant. Results: The ET family consists of three isopeptides (ET-1, ET-2 and ET-3) that produce biological actions by acting on two types of receptors (ETA and ETB). In the central nervous system (CNS) ETA receptors are potent constrictors of the cerebral vasculature and appear to contribute in the causation of cerebral ischemia. ETA receptor antagonists have been found to be effective in animal model of cerebral ischemia; however, clinical studies have shown no efficacy. Mitochondrial functions are critically important for several neural development processes such as neurogenesis, axonal and dendritic growth, and synaptic formation. ET appears to impair mitochondrial functions through activation of ETA receptors. On the other hand, blocking ETB receptors has been shown to trigger apoptotic processes by activating intrinsic mitochondrial pathway. Mitochondria are important for their role in molecular regulation of neurogenesis and angiogenesis. Stimulation of ETB receptors in the adult ischemic brain has been found to promote angiogenesis and neurogenesis mediated through vascular endothelial growth factor and nerve growth factor. It will be interesting to investigate the effect of ETB receptor stimulation on mitochondrial functions in the CNS following cerebral ischemia. Conclusion: The findings of this

  2. Animal models of cerebral ischemia

    NASA Astrophysics Data System (ADS)

    Khodanovich, M. Yu.; Kisel, A. A.

    2015-11-01

    Cerebral ischemia remains one of the most frequent causes of death and disability worldwide. Animal models are necessary to understand complex molecular mechanisms of brain damage as well as for the development of new therapies for stroke. This review considers a certain range of animal models of cerebral ischemia, including several types of focal and global ischemia. Since animal models vary in specificity for the human disease which they reproduce, the complexity of surgery, infarct size, reliability of reproduction for statistical analysis, and adequate models need to be chosen according to the aim of a study. The reproduction of a particular animal model needs to be evaluated using appropriate tools, including the behavioral assessment of injury and non-invasive and post-mortem control of brain damage. These problems also have been summarized in the review.

  3. Feasibility of quantitative diffuse reflectance spectroscopy for targeted measurement of renal ischemia during laparoscopic partial nephrectomy.

    PubMed

    Goel, Utsav O; Maddox, Michael M; Elfer, Katherine N; Dorsey, Philip J; Wang, Mei; McCaslin, Ian Ross; Brown, J Quincy; Lee, Benjamin R

    2014-01-01

    Reduction of warm ischemia time during partial nephrectomy (PN) is critical to minimizing ischemic damage and improving postoperative kidney function, while maintaining tumor resection efficacy. Recently, methods for localizing the effects of warm ischemia to the region of the tumor via selective clamping of higher-order segmental artery branches have been shown to have superior outcomes compared with clamping the main renal artery. However, artery identification can prolong operative time and increase the blood loss and reduce the positive effects of selective ischemia. Quantitative diffuse reflectance spectroscopy (DRS) can provide a convenient, real-time means to aid in artery identification during laparoscopic PN. The feasibility of quantitative DRS for real-time longitudinal measurement of tissue perfusion and vascular oxygenation in laparoscopic nephrectomy was investigated in vivo in six Yorkshire swine kidneys (n=three animals ). DRS allowed for rapid identification of ischemic areas after selective vessel occlusion. In addition, the rates of ischemia induction and recovery were compared for main renal artery versus tertiary segmental artery occlusion, and it was found that the tertiary segmental artery occlusion trends toward faster recovery after ischemia, which suggests a potential benefit of selective ischemia. Quantitative DRS could provide a convenient and fast tool for artery identification and evaluation of the depth, spatial extent, and duration of selective tissue ischemia in laparoscopic PN.

  4. Transient ischemia/hypoxia enhances gentamicin ototoxicity via caspase-dependent cell death pathway.

    PubMed

    Lin, Chia-Der; Kao, Ming-Ching; Tsai, Ming-Hsui; Lai, Chih-Ho; Wei, I-Hua; Tsai, Mang-Hung; Tang, Chih-Hsin; Lin, Cheng-Wen; Hsu, Chuan-Jen; Lin, Ching-Yuang

    2011-07-01

    Aminoglycoside ototoxicity is a common cause of drug-induced hearing loss. Toxicity is dose related, but some patients may still develop hearing loss even under safe dosage. Apart for genetic idiosyncrasy, indirect evidences imply that ischemia may increase the aminoglycoside ototoxic sensitivity because common clinical situations associated with cochlear ischemia such as noise, sepsis, and shock are known to augment the development of aminoglycoside ototoxicity. At present, a direct interaction of cochlear ischemia and aminoglycoside ototoxicity is still lacking. This study demonstrated a direct evidence of increased gentamicin (GM) ototoxic sensitivity in chronic guinea pig models of transient cochlear ischemia. No permanent auditory changes were observed after a single dose of GM (125 mg/kg) or after transient cochlear ischemia for 30 min. Persistent and significant auditory threshold shift was detected when GM was given after transient cochlear ischemia. Cochlear hair cells and spiral ganglion neurons are the major regions affected. Apoptosis contributes to hair cell death during acute interaction of ischemia and GM ototoxicity. Increased apoptotic cell death was also depicted when GM crossreacted with hypoxia in vitro, using cochlear cell lines. Generation of reactive oxygen species, loss of mitochondrial membrane potential, calcium release, and caspase-dependent apoptotic cell death were shown during the interaction of hypoxia and GM ototoxicity in vitro. This synergistic ototoxicity may be critical to aminoglycoside-induced hearing loss in clinical scenarios. The results should improve our understanding of the interacting mechanism and potential preventive strategy to aminoglycoside ototoxicity.

  5. Feasibility of quantitative diffuse reflectance spectroscopy for targeted measurement of renal ischemia during laparoscopic partial nephrectomy

    NASA Astrophysics Data System (ADS)

    Goel, Utsav O.; Maddox, Michael M.; Elfer, Katherine N.; Dorsey, Philip J.; Wang, Mei; McCaslin, Ian Ross; Brown, J. Quincy; Lee, Benjamin R.

    2014-10-01

    Reduction of warm ischemia time during partial nephrectomy (PN) is critical to minimizing ischemic damage and improving postoperative kidney function, while maintaining tumor resection efficacy. Recently, methods for localizing the effects of warm ischemia to the region of the tumor via selective clamping of higher-order segmental artery branches have been shown to have superior outcomes compared with clamping the main renal artery. However, artery identification can prolong operative time and increase the blood loss and reduce the positive effects of selective ischemia. Quantitative diffuse reflectance spectroscopy (DRS) can provide a convenient, real-time means to aid in artery identification during laparoscopic PN. The feasibility of quantitative DRS for real-time longitudinal measurement of tissue perfusion and vascular oxygenation in laparoscopic nephrectomy was investigated in vivo in six Yorkshire swine kidneys (n=three animals). DRS allowed for rapid identification of ischemic areas after selective vessel occlusion. In addition, the rates of ischemia induction and recovery were compared for main renal artery versus tertiary segmental artery occlusion, and it was found that the tertiary segmental artery occlusion trends toward faster recovery after ischemia, which suggests a potential benefit of selective ischemia. Quantitative DRS could provide a convenient and fast tool for artery identification and evaluation of the depth, spatial extent, and duration of selective tissue ischemia in laparoscopic PN.

  6. Controversies in cardiovascular care: silent myocardial ischemia

    NASA Technical Reports Server (NTRS)

    Hollenberg, N. K.

    1987-01-01

    The objective evidence of silent myocardial ischemia--ischemia in the absence of classical chest pain--includes ST-segment shifts (usually depression), momentary left ventricular failure, and perfusion defects on scintigraphic studies. Assessment of angina patients with 24-hour ambulatory monitoring may uncover episodes of silent ischemia, the existence of which may give important information regarding prognosis and may help structure a more effective therapeutic regimen. The emerging recognition of silent ischemia as a significant clinical entity may eventually result in an expansion of current therapy--not only to ameliorate chest pain, but to minimize or eliminate ischemia in the absence of chest pain.

  7. Controversies in cardiovascular care: silent myocardial ischemia

    NASA Technical Reports Server (NTRS)

    Hollenberg, N. K.

    1987-01-01

    The objective evidence of silent myocardial ischemia--ischemia in the absence of classical chest pain--includes ST-segment shifts (usually depression), momentary left ventricular failure, and perfusion defects on scintigraphic studies. Assessment of angina patients with 24-hour ambulatory monitoring may uncover episodes of silent ischemia, the existence of which may give important information regarding prognosis and may help structure a more effective therapeutic regimen. The emerging recognition of silent ischemia as a significant clinical entity may eventually result in an expansion of current therapy--not only to ameliorate chest pain, but to minimize or eliminate ischemia in the absence of chest pain.

  8. Sirt1 in cerebral ischemia

    PubMed Central

    Koronowski, Kevin B.; Perez-Pinzon, Miguel A.

    2015-01-01

    Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacylases has been shown to govern several processes within the central nervous system as well as to possess neuroprotective properties in a variety of pathological conditions such as Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease, among others. Recently, Sirt1 in particular has been identified as a mediator of cerebral ischemia, with potential as a possible therapeutic target. To gather studies relevant to this topic, we used PubMed and previous reviews to locate, select, and resynthesize the lines of evidence presented here. In this review, we will first describe some functions of Sirt1 in the brain, mainly neurodevelopment, learning and memory, and metabolic regulation. Second, we will discuss the experimental evidence that has implicated Sirt1 as a key protein in the regulation of cerebral ischemia as well as a potential target for the induction of ischemic tolerance. PMID:26819971

  9. Oxidative stress in brain ischemia.

    PubMed

    Love, S

    1999-01-01

    Brain ischemia initiates a complex cascade of metabolic events, several of which involve the generation of nitrogen and oxygen free radicals. These free radicals and related reactive chemical species mediate much of damage that occurs after transient brain ischemia, and in the penumbral region of infarcts caused by permanent ischemia. Nitric oxide, a water- and lipid-soluble free radical, is generated by the action of nitric oxide synthases. Ischemia causes a surge in nitric oxide synthase 1 (NOS 1) activity in neurons and, possibly, glia, increased NOS 3 activity in vascular endothelium, and later an increase in NOS 2 activity in a range of cells including infiltrating neutrophils and macrophages, activated microglia and astrocytes. The effects of ischemia on the activity of NOS 1, a Ca2+-dependent enzyme, are thought to be secondary to reversal of glutamate reuptake at synapses, activation of NMDA receptors, and resulting elevation of intracellular Ca2+. The up-regulation of NOS 2 activity is mediated by transcriptional inducers. In the context of brain ischemia, the activity of NOS 1 and NOS 2 is broadly deleterious, and their inhibition or inactivation is neuroprotective. However, the production of nitric oxide in blood vessels by NOS 3, which, like NOS 1, is Ca2+-dependent, causes vasodilatation and improves blood flow in the penumbral region of brain infarcts. In addition to causing the synthesis of nitric oxide, brain ischemia leads to the generation of superoxide, through the action of nitric oxide synthases, xanthine oxidase, leakage from the mitochondrial electron transport chain, and other mechanisms. Nitric oxide and superoxide are themselves highly reactive but can also combine to form a highly toxic anion, peroxynitrite. The toxicity of the free radicals and peroxynitrite results from their modification of macromolecules, especially DNA, and from the resulting induction of apoptotic and necrotic pathways. The mode of cell death that prevails probably

  10. Noninvasive Multimodal Imaging to Predict Recovery of Locomotion after Extended Limb Ischemia.

    PubMed

    Radowsky, Jason S; Caruso, Joseph D; Luthra, Rajiv; Bradley, Matthew J; Elster, Eric A; Forsberg, Jonathan A; Crane, Nicole J

    2015-01-01

    Acute limb ischemia is a common cause of morbidity and mortality following trauma both in civilian centers and in combat related injuries. Rapid determination of tissue viability and surgical restoration of blood flow are desirable, but not always possible. We sought to characterize the response to increasing periods of hind limb ischemia in a porcine model such that we could define a period of critical ischemia (the point after which irreversible neuromuscular injury occurs), evaluate non-invasive methods for characterizing that ischemia, and establish a model by which we could predict whether or not the animal's locomotion would return to baselines levels post-operatively. Ischemia was induced by either application of a pneumatic tourniquet or vessel occlusion (performed by clamping the proximal iliac artery and vein at the level of the inguinal ligament). The limb was monitored for the duration of the procedure with both 3-charge coupled device (3CCD) and infrared (IR) imaging for tissue oxygenation and perfusion, respectively. The experimental arms of this model are effective at inducing histologically evident muscle injury with some evidence of expected secondary organ damage, particularly in animals with longer ischemia times. Noninvasive imaging data shows excellent correlation with post-operative functional outcomes, validating its use as a non-invasive means of viability assessment, and directly monitors post-occlusive reactive hyperemia. A classification model, based on partial-least squares discriminant analysis (PLSDA) of imaging variables only, successfully classified animals as "returned to normal locomotion" or "did not return to normal locomotion" with 87.5% sensitivity and 66.7% specificity after cross-validation. PLSDA models generated from non-imaging data were not as accurate (AUC of 0.53) compared the PLSDA model generated from only imaging data (AUC of 0.76). With some modification, this limb ischemia model could also serve as a means on which

  11. [The role of BDNF in brain ischemia pulmonary edema].

    PubMed

    Zhang, Yun-Hui; Wang, Ting-Hua

    2012-11-01

    Brain ischemia pulmonary edema(BIPE)is a critical type of the neurogenic pulmonary edema (NPE), with acute development and progression and high mortality. The study on mechanism of BIPE has important scientific significance and substantial practice values. NPE, as a complicated physiopathology condition, is not resulted from single factor but systemic events including the changes in nervous system, body fluid regulation and endocrine involved in central nervous system after the injury. The studies on this topic in this current issue suggested that brain-derived neurotrophic factor (BDNF) could involve in the pathogenesis procedure of NPE following brain ischemia, which indicated that the crucial role of BDNF in the NPE after BIPE. The findings of these studies pave a way for the treatment of BIPE by using BDNF administration in future clinic trail.

  12. Protection of bile ducts in liver transplantation: looking beyond ischemia.

    PubMed

    Op den Dries, Sanna; Sutton, Michael E; Lisman, Ton; Porte, Robert J

    2011-08-27

    Biliary complications, especially nonanastomotic biliary strictures (NAS), are a major cause of morbidity after orthotopic liver transplantation. Of all donor and recipient characteristics known to increase the risk of developing NAS, the role of prolonged ischemia times is most extensively described in the literature. However, there is increasing evidence that several other, non-ischemia-related factors play a critical role in the pathogenesis of NAS as well. The clinical presentation of NAS may vary considerably among liver transplant recipients, including large variations in time of occurrence, and in location and severity of the strictures. Additional underlying causes such as bile salt toxicity and immune-mediated injury are believed to explain the wide spectrum of biliary strictures after orthotopic liver transplantation. Current and emerging insight in the pathogenesis of NAS and potential targets to reduce biliary injury and preserve bile ducts are discussed in this overview.

  13. Oxidative Stress and Lung Ischemia-Reperfusion Injury

    PubMed Central

    Ferrari, Renata Salatti; Andrade, Cristiano Feijó

    2015-01-01

    Ischemia-reperfusion (IR) injury is directly related to the formation of reactive oxygen species (ROS), endothelial cell injury, increased vascular permeability, and the activation of neutrophils and platelets, cytokines, and the complement system. Several studies have confirmed the destructiveness of the toxic oxygen metabolites produced and their role in the pathophysiology of different processes, such as oxygen poisoning, inflammation, and ischemic injury. Due to the different degrees of tissue damage resulting from the process of ischemia and subsequent reperfusion, several studies in animal models have focused on the prevention of IR injury and methods of lung protection. Lung IR injury has clinical relevance in the setting of lung transplantation and cardiopulmonary bypass, for which the consequences of IR injury may be devastating in critically ill patients. PMID:26161240

  14. [Prothrombotic states and cerebral ischemia].

    PubMed

    Barinagarrementeria, F; González-Duarte, A; Cantú-Brito, C

    1998-01-01

    Hematological disorders per se represent unusual causes of cerebral ischemia, explaining in young people 4% of strokes. Hematological disorders that induce a thrombotic tendency contribute to overall ischemic stroke risk and may directly cause cerebral ischemia in patients without other risk factors. The frequency of cerebral infarctions caused by prothrombotic states is not known. This review will focus on disorders such as prothrombotic coagulopaties, including resistance to activated protein C and antiphospholipid syndrome as cause of cerebral infarction. Cerebral venous thrombosis and cerebral infarction from arterial origin are the most common form of neurological involvement. Pathophysiological mechanism of stroke in these patients are multiple and can include as in antiphospholipid syndrome embolism from valves abnormalities related to hematological disturbance, as well as thrombosis of extracranial or intracranial vessels. Is clear, however, that prothrombotic states could explains a high percentage of cases of those so called cryptogenic cerebral infarction in young people.

  15. Experimental myocardial ischemia. Pt. 2

    SciTech Connect

    Serur, J.R.; Als, A.V.; Paulin, S.

    1982-01-01

    The comparative effects of meglumine sodium diatrizoate (MSD), sodium meglumine calcium metrizoate (SMCM), and metrizamide (M) were studied in an isolated canine heart preparation. The parameters observed were coronary blood flow (CBF), myocardial contractile force (MCF), positive and negative dF/dt, and perfusion pressure during normal and ischemic perfusion conditions. MSD had an initial negative inotropic effect but baseline MCF returned in 1 min during normal perfusion and 2 min under ischemic conditions. SMCM and M had only a positive inotropic effect under normal perfusion. However, during ischemia, the positive effect of SMCM was followed by a decrease in contractile force. M showed only a positive effect on force during ischemia. Our results indicate that calcium additive may increase the risk of coronary arteriography in patients with severe coronary artery disease.

  16. Intracellular Signalling in Retinal Ischemia

    DTIC Science & Technology

    1990-07-01

    36) However, vascularization of the RPE is not known to occur in human diseases of photoreceptor degeneration, such as retinitis pigmentosa ...A.C. (1986) Retinitis pigmentosa and retinal neovascularization. Ophthalmology 91, 1599- 1603. Figure la: Control rat retina, 8 weeks of age, central...TITLE (Include Security Classification) Intracellular Signalling in Retinal Ischemia 12. PERSONAL AUTHOR(S) Burns, Margaret Sue; Bellhorn, Roy William

  17. Functional tests for myocardial ischemia

    SciTech Connect

    Levinson, J.R.; Guiney, T.E.; Boucher, C.A. )

    1991-01-01

    Functional tests for myocardial ischemia are numerous. Most depend upon a combination of either exercise or pharmacologic intervention with analysis of the electrocardiogram, of regional perfusion with radionuclide imaging, or of regional wall motion with radionuclide imaging or echocardiography. While each test has unique features, especially at the research level, they are generally quite similar in clinical practice, so the clinician is advised to concentrate on one or two in which local expertise is high.22 references.

  18. Predictive Modeling of Cardiac Ischemia

    NASA Technical Reports Server (NTRS)

    Anderson, Gary T.

    1996-01-01

    The goal of the Contextual Alarms Management System (CALMS) project is to develop sophisticated models to predict the onset of clinical cardiac ischemia before it occurs. The system will continuously monitor cardiac patients and set off an alarm when they appear about to suffer an ischemic episode. The models take as inputs information from patient history and combine it with continuously updated information extracted from blood pressure, oxygen saturation and ECG lines. Expert system, statistical, neural network and rough set methodologies are then used to forecast the onset of clinical ischemia before it transpires, thus allowing early intervention aimed at preventing morbid complications from occurring. The models will differ from previous attempts by including combinations of continuous and discrete inputs. A commercial medical instrumentation and software company has invested funds in the project with a goal of commercialization of the technology. The end product will be a system that analyzes physiologic parameters and produces an alarm when myocardial ischemia is present. If proven feasible, a CALMS-based system will be added to existing heart monitoring hardware.

  19. Severe Hypokalemia Masquerading Myocardial Ischemia

    PubMed Central

    Petrov, Daniel Bogdanov; Sardovski, Svetlozar Ivanov; Milanova, Maria Hristova

    2012-01-01

    An advanced degree of body potassium deficit may produce striking changes in the electrocardiogram (ECG). These changes can result in incidental findings on the 12-lead ECG or precipitate potentially life-threatening dysrhythmias. Although usually readily recognized, at times these abnormalities may be confused with myocardial ischemia. The object was to report a case of severe hypokalemia mimicking myocardial ischemia. A 33-year-old, previously healthy man, presented to the Emergency Department (ED) with a progressive weakness and chest discomfort. The electrocardiogram showed a marked ST-segment depression in leads II, III, aVF, V1-V6. The initial diagnosis was non ST-elevation myocardial infarction. Echocardiography was normal and troponin levels were within normal limits. A more detailed history revealed that the patient had an episode of acute gastroenteritis with diarrhea and vomiting. Serum chemistries were notable for a potassium concentration of 1,8 mmol per liter. With aggressive electrolyte correction, the ECG abnormalities reverted as potassium levels normalized. Hypokalemia induced ST-segment depression may simulate myocardial ischemia. The differential diagnosis might be difficult, especially in the cases when ST changes are accompanied with chest discomfort.

  20. Chronic Gastric Ischemia Leading to Gastric Perforation

    PubMed Central

    Lundsmith, Emma; Zheng, Matthew; McCue, Peter

    2016-01-01

    A 69-year-old man with diabetes, peripheral vascular disease, and hypertension presented with 3 months of diffuse abdominal pain that worsened with meals, weight loss, and dysphagia. Esophagogastroduodenoscopy and computed tomography revealed findings consistent with chronic gastric ischemia secondary to atherosclerosis. Gastric ischemia eventually led to perforation. We discuss causes, symptoms, diagnosis, and management of gastric ischemia, an underdiagnosed and potentially fatal condition that requires urgent diagnosis and treatment. PMID:28119945

  1. Purkinje fibers after myocardial ischemia-reperfusion.

    PubMed

    García Gómez-Heras, Soledad; Álvarez-Ayuso, Lourdes; Torralba Arranz, Amalia; Fernández-García, Héctor

    2015-07-01

    The purpose of this study was to evaluate the effects of ischemia-reperfusion on Purkinje fibers, comparing them with the adjacent cardiomyocytes. In a model of heterotopic heart transplantation in pigs, the donor heart was subjected to 2 hours of ischemia (n=9), preserved in cold saline, and subjected to 24 hours of ischemia with preservation in Wisconsin solution, alone (n=6), or with an additive consisting of calcium (n=4), Nicorandil (n=6) or Trolox (n=7). After 2 hours of reperfusion, we evaluated the recovery of cardiac electrical activity and took samples of ventricular myocardium for morphological study. The prolonged ischemia significantly affected atrial automaticity and A-V conduction in all the groups subjected to 24 hours of ischemia, as compared to 2 hours. There were no significant differences among the groups that underwent prolonged ischemia. Changes in the electrical activity did not correlate with the morphological changes. In the Purkinje fibers, ischemia-reperfusion produced a marked decrease in the glycogen content in all the groups. In the gap junctions the immunolabeling of connexin-43 decreased significantly, adopting a dispersed distribution, and staining the sarcolemma adjacent to the connective tissue. These changes were less marked in the group preserved exclusively with Wisconsin solution, despite the prolonged ischemia. The addition of other substances did not improve the altered morphology. In all the groups, the injury appeared to be more prominent in the Purkinje fibers than in the neighboring cardiomyocytes, indicating the greater susceptibility of the former to ischemia-reperfusion injury.

  2. Nimesulide as a promising neuroprotectant in brain ischemia: new experimental evidences.

    PubMed

    Candelario-Jalil, Eduardo

    2008-04-01

    Nimesulide is a preferential inhibitor of cyclooxygenase-2 (COX-2) and it is one of the most prescribed non-steroidal anti-inflammatory drugs (NSAID) worldwide. Nimesulide was recently shown to have neuroprotective properties in animal models of acute neurologic injury. In particular, nimesulide is highly effective in reducing ischemic brain injury. This neuroprotective efficacy has been demonstrated in animal models of transient and permanent focal cerebral ischemia, global brain ischemia, embolic stroke, and chronic cerebral hypoperfusion. Nimesulide has been shown to reduce infarction, improve neurological function, attenuate blood-brain barrier disruption and edema, and reduce leukocyte infiltration into the ischemic brain. These beneficial effects have been observed even when the first treatment is given several hours after the onset of ischemia, demonstrating the wide therapeutic time window for nimesulide's neuroprotection. This is of great relevance since most stroke patients reach the emergency room several hours after the onset of symptoms, a time at which most medical interventions are not effective. In addition, nimesulide produces a long-lasting neuroprotection. This is of importance since some 'neuroprotective' compounds only produce a delay in cell death, and not a permanent protection. Its several mechanisms of action in neuroprotection make nimesulide a desirable and promising candidate as therapy for acute brain ischemia. This article reviews recent knowledge on the effects of nimesulide against brain injury, with particular emphasis in cerebral ischemia, and makes a critical appraisal of its therapeutic potential in the management of patients with brain ischemia.

  3. Gastric Tissue Damage Analysis Generated by Ischemia: Bioimpedance, Confocal Endomicroscopy, and Light Microscopy

    PubMed Central

    Beltran, Nohra E.; Garcia, Laura E.; Garcia-Lorenzana, Mario

    2013-01-01

    The gastric mucosa ischemic tissular damage plays an important role in critical care patients' outcome, because it is the first damaged tissue by compensatory mechanism during shock. The aim of the study is to relate bioimpedance changes with tissular damage level generated by ischemia by means of confocal endomicroscopy and light microscopy. Bioimpedance of the gastric mucosa and confocal images were obtained from Wistar male rats during basal and ischemia conditions. They were anesthetized, and stain was applied (fluorescein and/or acriflavine). The impedance spectroscopy catheter was inserted and then confocal endomicroscopy probe. After basal measurements and biopsy, hepatic and gastric arteries clamping induced ischemia. Finally, pyloric antrum tissue was preserved in buffered formaldehyde (10%) for histology processing using light microscopy. Confocal images were equalized, binarized, and boundary defined, and infiltrations were quantified. Impedance and infiltrations increased with ischemia showing significant changes between basal and ischemia conditions (P < 0.01). Light microscopy analysis allows detection of general alterations in cellular and tissular integrity, confirming gastric reactance and confocal images quantification increments obtained during ischemia. PMID:23841094

  4. Real time measurement of myocardial oxygen dynamics during cardiac ischemia-reperfusion of rats.

    PubMed

    Lee, Gi-Ja; Kim, Seung Ki; Kang, Sung Wook; Kim, Ok-Kyun; Chae, Su-Jin; Choi, Samjin; Shin, Jae Ho; Park, Hun-Kuk; Chung, Joo-Ho

    2012-11-21

    Because oxygen plays a critical role in the pathophysiology of myocardial injury during subsequent reperfusion, as well as ischemia, the accurate measurement of myocardial oxygen tension is crucial for the assessment of myocardial viability by ischemia-reperfusion (IR) injury. Therefore, we utilized a sol-gel derived electrochemical oxygen microsensor to monitor changes in oxygen tension during myocardial ischemia-reperfusion. We also analyzed differences in oxygen tension recovery in post-ischemic myocardium depending on ischemic time to investigate the correlation between recovery parameters for oxygen tension and the severity of IR injury. An oxygen sensor was built using a xerogel-modified platinum microsensor and a coiled Ag/AgCl reference electrode. Rat hearts were randomly divided into 5 groups: control (0 min ischemia), I-10 (10 min ischemia), I-20 (20 min ischemia), I-30 (30 min ischemia), and I-40 (40 min ischemia) groups (n = 3 per group, respectively). After the induction of ischemia, reperfusion was performed for 60 min. As soon as the ischemia was initiated, oxygen tension rapidly declined to near zero levels. When reperfusion was initiated, the changes in oxygen tension depended on ischemic time. The normalized peak level of oxygen tension during the reperfusion episode was 188 ± 27 in group I-10, 120 ± 24 in group I-20, 12.5 ± 10.6 in group I-30, and 1.24 ± 1.09 in group I-40 (p < 0.001, n = 3, respectively). After 60 min of reperfusion, the normalized restoration level was 129 ± 30 in group I-10, 88 ± 4 in group I-20, 3.40 ± 4.82 in group I-30, and 0.99 ± 0.94 in group I-40 (p < 0.001, n = 3, respectively). The maximum and restoration values of oxygen tension in groups I-30 and I-40 after reperfusion were lower than pre-ischemic values. In particular, oxygen tension in the I-40 group was not recovered at all. These results were also demonstrated by TTC staining. We suggest that these recovery parameters could be utilized as an index of

  5. Recipient twin limb ischemia with postnatal onset.

    PubMed

    Broadbent, Roland Spencer

    2007-02-01

    After the occurrence of 3 local cases of limb ischemia in newborn twins, we reviewed the literature to investigate this combination systematically. This review reveals a distinct condition: postnatal onset limb ischemia affecting recipient twins in twin-twin transfusion syndrome.

  6. Chick Embryo Partial Ischemia Model: A New Approach to Study Ischemia Ex Vivo

    PubMed Central

    Majumder, Syamantak; Ilayaraja, M.; Seerapu, Himabindu Reddy; Sinha, Swaraj; Siamwala, Jamila H.; Chatterjee, Suvro

    2010-01-01

    Background Ischemia is a pathophysiological condition due to blockade in blood supply to a specific tissue thus damaging the physiological activity of the tissue. Different in vivo models are presently available to study ischemia in heart and other tissues. However, no ex vivo ischemia model has been available to date for routine ischemia research and for faster screening of anti-ischemia drugs. In the present study, we took the opportunity to develop an ex vivo model of partial ischemia using the vascular bed of 4th day incubated chick embryo. Methodology/Principal Findings Ischemia was created in chick embryo by ligating the right vitelline artery using sterile surgical suture. Hypoxia inducible factor- 1 alpha (HIF-1α), creatine phospho kinase-MB and reactive oxygen species in animal tissues and cells were measured to confirm ischemia in chick embryo. Additionally, ranolazine, N-acetyl cysteine and trimetazidine were administered as an anti-ischemic drug to validate the present model. Results from the present study depicted that blocking blood flow elevates HIF-1α, lipid peroxidation, peroxynitrite level in ischemic vessels while ranolazine administration partially attenuates ischemia driven HIF-1α expression. Endothelial cell incubated on ischemic blood vessels elucidated a higher level of HIF-1α expression with time while ranolazine treatment reduced HIF-1α in ischemic cells. Incubation of caprine heart strip on chick embryo ischemia model depicted an elevated creatine phospho kinase-MB activity under ischemic condition while histology of the treated heart sections evoked edema and disruption of myofibril structures. Conclusions/Significance The present study concluded that chick embryo partial ischemia model can be used as a novel ex vivo model of ischemia. Therefore, the present model can be used parallel with the known in vivo ischemia models in understanding the mechanistic insight of ischemia development and in evaluating the activity of anti

  7. [Ischemia-reperfusion injury after lung transplantation].

    PubMed

    Gennai, Stéphane; Pison, Christophe; Briot, Raphaël

    2014-09-01

    Lung ischemia-reperfusion is characterized by diffuse alveolar damage arising from the first hours after transplantation. The first etiology of the primary graft dysfunction in lung is ischemia-reperfusion. It is burdened by an important morbi-mortality. Lung ischemia-reperfusion increases the oxidative stress, inactivates the sodium pump, increases the intracellular calcium, leads to cellular death and the liberation of pro-inflammatory mediators. Researches relative to the reduction of the lung ischemia-reperfusion injuries are numerous but few of them found a place in common clinical practice, because of an insufficient level of proofs. Ex vivolung evaluation is a suitable technique in order to evaluate therapeutics supposed to limit lung ischemia-reperfusion injuries.

  8. Intestinal Ischemia: US-CT findings correlations

    PubMed Central

    2013-01-01

    Background Intestinal ischemia is an abdominal emergency that accounts for approximately 2% of gastrointestinal illnesses. It represents a complex of diseases caused by impaired blood perfusion to the small and/or large bowel including acute arterial mesenteric ischemia (AAMI), acute venous mesenteric ischemia (AVMI), non occlusive mesenteric ischemia (NOMI), ischemia/reperfusion injury (I/R), ischemic colitis (IC). In this study different study methods (US, CT) will be correlated in the detection of mesenteric ischemia imaging findings due to various etiologies. Methods Basing on experience of our institutions, over 200 cases of mesenteric ischemia/infarction investigated with both US and CT were evaluated considering, in particular, the following findings: presence/absence of arterial/venous obstruction, bowel wall thickness and enhancement, presence/absence of spastic reflex ileus, hypotonic reflex ileus or paralitic ileus, mural and/or portal/mesenteric pneumatosis, abdominal free fluid, parenchymal ischemia/infarction (liver, kidney, spleen). Results To make an early diagnosis useful to ensure a correct therapeutic approach, it is very important to differentiate between occlusive (arterial,venous) and nonocclusive causes (NOMI). The typical findings of each forms of mesenteric ischemia are explained in the text. Conclusion At present, the reference diagnostic modality for intestinal ischaemia is contrast-enhanced CT. However, there are some disadvantages associated with these techniques, such as radiation exposure, potential nephrotoxicity and the risk of an allergic reaction to the contrast agents. Thus, not all patients with suspected bowel ischaemia can be subjected to these examinations. Despite its limitations, US could constitutes a good imaging method as first examination in acute settings of suspected mesenteric ischemia. PMID:23902826

  9. Silent myocardial ischemia: Current perspectives and future directions

    PubMed Central

    Ahmed, Amany H; Shankar, KJ; Eftekhari, Hossein; Munir, MS; Robertson, Jillian; Brewer, Alan; Stupin, Igor V; Casscells, S Ward

    2007-01-01

    Silent myocardial ischemia (SMI) is increasingly being recognized as part of the spectrum of ischemic heart disease. The spectrum of SMI ranges from asymptomatic coronary artery disease to critical illness necessitating intensive care. Although many diagnostic tools have been used to identify low- and high-risk subgroups, their use is limited by modest sensitivities and specificities. The present review identifies current concepts in the management of SMI in various clinical settings, as well as emerging technologies that may simplify the diagnosis and treatment of this condition. PMID:18651003

  10. Metabolic Adaptation to Muscle Ischemia

    NASA Technical Reports Server (NTRS)

    Cabrera, Marco E.; Coon, Jennifer E.; Kalhan, Satish C.; Radhakrishnan, Krishnan; Saidel, Gerald M.; Stanley, William C.

    2000-01-01

    Although all tissues in the body can adapt to varying physiological/pathological conditions, muscle is the most adaptable. To understand the significance of cellular events and their role in controlling metabolic adaptations in complex physiological systems, it is necessary to link cellular and system levels by means of mechanistic computational models. The main objective of this work is to improve understanding of the regulation of energy metabolism during skeletal/cardiac muscle ischemia by combining in vivo experiments and quantitative models of metabolism. Our main focus is to investigate factors affecting lactate metabolism (e.g., NADH/NAD) and the inter-regulation between carbohydrate and fatty acid metabolism during a reduction in regional blood flow. A mechanistic mathematical model of energy metabolism has been developed to link cellular metabolic processes and their control mechanisms to tissue (skeletal muscle) and organ (heart) physiological responses. We applied this model to simulate the relationship between tissue oxygenation, redox state, and lactate metabolism in skeletal muscle. The model was validated using human data from published occlusion studies. Currently, we are investigating the difference in the responses to sudden vs. gradual onset ischemia in swine by combining in vivo experimental studies with computational models of myocardial energy metabolism during normal and ischemic conditions.

  11. [Tonic pupil caused by ischemia].

    PubMed

    Wilhelm, H

    1989-01-01

    Tonic pupil is usually an idiopathic condition. In some cases, the cause of the ciliary ganglion lesion leading to tonic pupils is obvious. Rarely ischemia causes a lesion of the ciliary ganglion or the short ciliary nerves due to the good blood supply of the ciliary ganglion. Only two cases of tonic pupils in the course of giant cell arteritis are mentioned in the literature, but tonic pupils are probably much more common with this disease. Five cases are demonstrated here. All had associated ischemic optic neuropathy, and stagnation of the blood flow in the supratrochlear artery could be demonstrated in two cases by Doppler sonography. Tonic pupils may also occur when an oclusion of the internal carotid artery resolves, probably because of transient stasis of the orbital blood flow. In another case, tonic pupils were associated with choroidal ischemia (proved by video fluorescent angiography) of unknown origin. The diagnosis of tonic pupils was made by pharmacological testing for cholinergic hypersensitivity with 0.1% pilocarpine.

  12. Inflammatory Responses in Brain Ischemia

    PubMed Central

    Kawabori, Masahito; Yenari, Midori A.

    2017-01-01

    Brain infarction causes tissue death by ischemia due to occlusion of the cerebral vessels and recent work has shown that post stroke inflammation contributes significantly to the development of ischemic pathology. Because secondary damage by brain inflammation may have a longer therapeutic time window compared to the rescue of primary damage following arterial occlusion, controlling inflammation would be an obvious therapeutic target. A substantial amount of experimentall progress in this area has been made in recent years. However, it is difficult to elucidate the precise mechanisms of the inflammatory responses following ischemic stroke because inflammation is a complex series of interactions between inflammatory cells and molecules, all of which could be either detrimental or beneficial. We review recent advances in neuroinflammation and the modulation of inflammatory signaling pathways in brain ischemia. Potential targets for treatment of ischemic stroke will also be covered. The roles of the immune system and brain damage versus repair will help to clarify how immune modulation may treat stroke. PMID:25666795

  13. Metabolic Adaptation to Muscle Ischemia

    NASA Technical Reports Server (NTRS)

    Cabrera, Marco E.; Coon, Jennifer E.; Kalhan, Satish C.; Radhakrishnan, Krishnan; Saidel, Gerald M.; Stanley, William C.

    2000-01-01

    Although all tissues in the body can adapt to varying physiological/pathological conditions, muscle is the most adaptable. To understand the significance of cellular events and their role in controlling metabolic adaptations in complex physiological systems, it is necessary to link cellular and system levels by means of mechanistic computational models. The main objective of this work is to improve understanding of the regulation of energy metabolism during skeletal/cardiac muscle ischemia by combining in vivo experiments and quantitative models of metabolism. Our main focus is to investigate factors affecting lactate metabolism (e.g., NADH/NAD) and the inter-regulation between carbohydrate and fatty acid metabolism during a reduction in regional blood flow. A mechanistic mathematical model of energy metabolism has been developed to link cellular metabolic processes and their control mechanisms to tissue (skeletal muscle) and organ (heart) physiological responses. We applied this model to simulate the relationship between tissue oxygenation, redox state, and lactate metabolism in skeletal muscle. The model was validated using human data from published occlusion studies. Currently, we are investigating the difference in the responses to sudden vs. gradual onset ischemia in swine by combining in vivo experimental studies with computational models of myocardial energy metabolism during normal and ischemic conditions.

  14. Protective approaches against myocardial ischemia reperfusion injury

    PubMed Central

    Li, Xianchi; Liu, Min; Sun, Rongrong; Zeng, Yi; Chen, Shuang; Zhang, Peiying

    2016-01-01

    Myocardial ischemia-reperfusion is the leading cause for the events of cardiovascular disease, and is considered as a major contributor to the morbidity and mortality associated with coronary occlusion. The myocardial damage caused by ischemia-reperfusion injury constitutes the primary pathological manifestation of coronary artery disease. It results from the interaction between the substances that accumulate during ischemia and those that are delivered on reperfusion. The level of this damage can range from a small insult resulting in limited myocardial damage to a large injury culminating in myocyte death. Importantly, major ischemia-reperfusion injury to the heart can result in permanent disability or death. Given the worldwide prevalence of coronary artery disease, developing a strategy to provide cardioprotection against ischemia-reperfusion-induced damage is of great importance. Currently, the treatment of reperfusion injury following ischemia is primarily supportive, since no specific target-oriented therapy has been validated thus far. Nevertheless, therapeutic approaches to protect against myocardial ischemia-reperfusion injury remain an active area of investigation given the detrimental effects of this phenomenon. PMID:28101167

  15. Acute mesenteric ischemia in young adults.

    PubMed

    Ozturk, Gurkan; Aydinli, Bulent; Atamanalp, S Selcuk; Yildirgan, M Ilhan; Ozoğul, Bünyami; Kısaoğlu, Abdullah

    2012-08-01

    Acute mesenteric ischemia is commonly seen in old patients. This study was undertaken to show that mesenteric ischemia might be seen in individuals under 40 years of age and that its diagnosis is challenging. Twenty-six patients with acute mesenteric ischemia under the age of 40 were studied. The main symptom on admission was abdominal pain. Symptom duration varied between 12 h and 5 days. The medical history of the patients revealed that 9 had no previous diseases. Other 17 had predisposing factors in the first evaluation. None of the patients had any history of narcotic or drug abuse. Ten patients presented with signs and symptoms of sepsis and septic shock. Preoperative diagnosis was acute intestinal ischemia only in 6 patients. Preoperatively, all the patients had intestinal or colonic ischemia and necrosis; one had additional ischemia of the liver, stomach, duodenum, and pancreas. Six patients had massive intestinal necrosis. The overall postoperative complication and overall mortality rates were 61.5 and 26.9 %, respectively. Complications and mortality were determined to be associated with previous pulmonary disease, acidosis, presence of septic shock, acute renal failure, extent of the ischemia and extent of resection, second look operations, previous cardiac events, and the kind of affected bowel (colon involvement).

  16. The value of core lab stress echocardiography interpretations: observations from the ISCHEMIA Trial.

    PubMed

    Kataoka, Akihisa; Scherrer-Crosbie, Marielle; Senior, Roxy; Gosselin, Gilbert; Phaneuf, Denis; Guzman, Gabriela; Perna, Gian; Lara, Alfonso; Kedev, Sasko; Mortara, Andrea; El-Hajjar, Mohammad; Shaw, Leslee J; Reynolds, Harmony R; Picard, Michael H

    2015-12-18

    Stress echocardiography (SE) is dependent on subjective interpretations. As a prelude to the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) Trial, potential sites were required to submit two SE, one with moderate or severe left ventricular (LV) myocardial ischemia and one with mild ischemia. We evaluated the concordance of site and core lab interpretations. Eighty-one SE were submitted from 41 international sites. Ischemia was classified by the number of new or worsening segmental LV wall motion abnormalities (WMA): none, mild (1 or 2) or moderate or severe (3 or more) by the sites and the core lab. Core lab classified 6 SE as no ischemia, 35 mild and 40 moderate or greater. There was agreement between the site and core in 66 of 81 total cases (81%, weighted kappa coefficient [K] =0.635). Agreement was similar for SE type - 24 of 30 exercise (80%, K = 0.571) vs. 41 of 49 pharmacologic (84%, K = 0.685). The agreement between poor or fair image quality (27 of 36 cases, 75%, K = 0.492) was not as good as for the good or excellent image quality cases (39 of 45 cases, 87%, K = 0.755). Differences in concordance were noted for degree of ischemia with the majority of discordant interpretations (87%) occurring in patients with no or mild LV myocardial ischemia. While site SE interpretations are largely concordant with core lab interpretations, this appears dependent on image quality and the extent of WMA. Thus core lab interpretations remain important in clinical trials where consistency of interpretation across a range of cases is critical. ClinicalTrials.gov NCT01471522.

  17. [Myocardial ischemia and ventricular arrhythmia].

    PubMed

    Vester, E G

    1998-01-01

    A relation between myocardial ischemia and induction of ventricular arrhythmias can be demonstrated in patients with coronary heart disease--in contrast to patients with primary non ischemic cardiac diseases--using a combined metabolic-electrophysiological investigation protocol consisting of programmed atrial and ventricular stimulation with simultaneous measurement of the arterio/coronary venous difference for lactate, pyruvate, free fatty acids and amino acids. There are significant metabolic distinctions between both ischemic and non ischemic heart disease under pacing stress conditions as well as at rest. Areas of "hibernating myocardium" resp. "mismatch" zones in the myocardium showing reduced or abolished perfusion and preserved metabolism during scintographic SPECT/PET studies, may be found more often in patients with ventricular tachycardias (VT) or ventricular fibrillation (VF) in the chronic post myocardial infarction state than in patients without VT/VF. The proof of such zones may be considered a possible risk factor for arrhythmic events and sudden cardiac death after myocardial infarction. Hereby the concept of an interaction between acute and chronic ischemia triggering the onset of polymorphic VT or VF gaines increasing acceptance. In contrast, monomorphic reentrant VT are usually generated in the border zone of scarred areas where islands of vital fibers are surrounded by fibrotic tissue. These arrhythmogenic origin regions are characterized by a "match" pattern presenting a comparably severe reduction of perfusion and metabolism. Under those circumstances a control resp. suppression of the VT focus can only be provided by interventional techniques like catheter ablation, antitachycardiac surgery or implantation of a cardioverter/defibrillator beyond antiarrhythmic drug therapy. An antiischemic causal treatment (bypass surgery or angioplasty) represents for maximal 40% of patients with ischemically induced ventricular arrhythmias an adequate and

  18. Transient Hemi-Lower Limb Ischemia in the Newborn: Arterial Thrombosis or Persistent Sciatic Artery?

    PubMed Central

    Kirino, Makiko; Ochiai, Masayuki; Ichiyama, Masako; Inoue, Hirosuke; Kusuda, Takeshi; Kinjo, Tadamune; Ishimura, Masataka; Ohga, Shouichi

    2017-01-01

    Neonatal thromboembolism occurs with various predispositions and triggers. Early diagnosis of the thrombosis is challenging and essential for the therapeutic interventions. We herein report two newborns who presented with transient hemi-lower limb ischemia due to (1) arterial thrombosis or (2) a persistent sciatic artery (PSA). The patient with arterial thrombosis showed elevations of fibrin degradation product and D-dimer and received antithrombin and heparin intravenously. The patient with PSA was immediately assessed by a contrast-enhanced computed tomography because of a transient ischemic episode with no evidence of hypercoagulability. Newborns suspected of having arterial thrombosis may need urgent surgical intervention along with thrombolytic and anticoagulant therapy to prevent organ ischemia and amputation of extremities. Conversely, some PSA cases have reportedly been treated conservatively. This vascular anomaly was previously reported as a cause of lower limb ischemia only in a newborn. PSA is a critical differential diagnosis of neonatal arterial thrombosis that needs urgent therapeutic intervention. PMID:28228977

  19. 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.

  20. Kupffer cell activation after no-flow ischemia versus hemorrhagic shock.

    PubMed

    Jaeschke, Hartmut; Farhood, Anwar

    2002-07-15

    Kupffer cell-derived oxidant stress is critical for reperfusion injury after no-flow ischemia. However, the importance of Kupffer cells as source of reactive oxygen formation is unclear in a hemorrhagic shock model. Therefore, we evaluated Kupffer cell activation after 60 or 120 min of hemorrhage and 90 min of resuscitation (HS/RS) in pentobarbital-anesthetized male Fischer rats. Plasma glutathione disulfide (GSSG) as indicator for a vascular oxidant stress showed no significant changes after HS/RS. Plasma ALT activities were only moderately increased (100-200 U/L). Kupffer cells isolated from postischemic livers did not generate more superoxide than cells from sham controls. In contrast, the 10-fold increase of plasma GSSG and the 9-fold higher spontaneous superoxide formation of Kupffer cells after 60 min of hepatic no-flow ischemia followed by 90 min of reperfusion demonstrated the activation of Kupffer cells in this experimental model. Plasma ALT activities (1930 +/- 240 U/L) indicated severe liver injury. These results demonstrate a fundamental difference in the degree of Kupffer cell activation between the two models of warm hepatic ischemia. Our findings suggest that different therapeutic strategies are necessary to ameliorate the initial injury after low flow ischemia (hemorrhage) compared to cold (transplantation) or warm (Pringle maneuver) no-flow ischemia.

  1. Astroglial Acid–Base Dynamics in Hyperglycemic and Normoglycemic Global Ischemia

    PubMed Central

    Lascola, Christopher; Kraig, Richard P.

    2009-01-01

    Biochemical, histological, and physiological evidence suggest strongly that astrocytes may either defend or damage brain tissue, depending on the brain carbohydrate content preceding global ischemia (28,43). This paper will first review the concept of acidosis in ischemia and the possible role of severe, compartmentalized astrocytic acidosis in pan necrosis. Results are then presented demonstrating that astrocytes are also capable of maintaining an alkaline intracellular pH (pHi) during normoglycemic global ischemia. Mechanisms underlying depolarization-dependent astroglial alkalosis are then reviewed. Recent experiments indicate that bicarbonate (HCO3−) transport is a major mechanism by which astroglia not only alkalinize their interior but also acidify the interstitium. Maintenance of alkalosis during normoglycemic ischemia supports the hypothesis that astroglial HCO3− transport might ultimately protect neurons from excitotoxicity in ischemia without infarction (17). Inhibition of astroglial HCO3− transport may be a critical and requisite event, ultimately leading to compartmentalized astroglial acidosis and irreversible injury to all cell types. PMID:9062937

  2. Role of Toll-like receptor-4 in renal graft ischemia-reperfusion injury.

    PubMed

    Zhao, Hailin; Perez, Jessica Santiváñez; Lu, Kaizhi; George, Andrew J T; Ma, Daqing

    2014-04-15

    Toll-like receptor-4 (TLR-4) has been increasingly recognized as playing a critical role in the pathogenesis of ischemia-reperfusion injury (IRI) of renal grafts. This review provides a detailed overview of the new understanding of the involvement of TLR-4 in ischemia-reperfusion injury of renal grafts and its clinical significance in renal transplantation. TLR-4 not only responds to exogenous microbial motifs but can also recognize molecules which are released by stressed and necrotic cells, as well as degraded products of endogenous macromolecules. Upregulation of TLR-4 is found in tubular epithelial cells, vascular endothelial cells, and infiltrating leukocytes during renal ischemia-reperfusion injury, which is induced by massive release of endogenous damage-associated molecular pattern molecules such as high-mobility group box chromosomal protein 1. Activation of TLR-4 promotes the release of proinflammatory mediators, facilitates leukocyte migration and infiltration, activates the innate and adaptive immune system, and potentiates renal fibrosis. TLR-4 inhibition serves as the target of pharmacological agents, which could attenuate ischemia-reperfusion injury and associated delayed graft function and allograft rejection. There is evidence in the literature showing that targeting TLR-4 could improve long-term transplantation outcomes. Given the pivotal role of TLR-4 in ischemia-reperfusion injury and associated delayed graft function and allograft rejection, inhibition of TLR-4 using pharmacological agents could be beneficial for long-term graft survival.

  3. Ethanol-induced myocardial ischemia: close relation between blood acetaldehyde level and myocardial ischemia.

    PubMed

    Ando, H; Abe, H; Hisanou, R

    1993-05-01

    A patient with vasospastic angina who developed myocardial ischemia following ethanol ingestion but not after exercise was described. Myocardial ischemia was evidenced by electrocardiograms (ECGs) and thallium-201 scintigrams. The blood acetaldehyde level after ethanol ingestion was abnormally high. The time course and severity of myocardial ischemia coincided with those of the blood ethanol and acetaldehyde level. Coronary arteriography showed ergonovine maleate-induced coronary vasospasm at the left anterior descending coronary artery. ECG changes similar to those induced by ethanol ingestion were observed at the same time. These findings suggest that the high blood acetaldehyde level might be responsible for the development of coronary vasospasm and myocardial ischemia in this patient.

  4. Molecular mechanisms of skeletal muscle atrophy in a mouse model of cerebral ischemia.

    PubMed

    Desgeorges, Marine Maud; Devillard, Xavier; Toutain, Jérome; Divoux, Didier; Castells, Josiane; Bernaudin, Myriam; Touzani, Omar; Freyssenet, Damien Gilles

    2015-06-01

    Loss of muscle mass and function is a severe complication in patients with stroke that contributes to promoting physical inactivity and disability. The deleterious consequences of skeletal muscle mass loss underline the necessity to identity the molecular mechanisms involved in skeletal muscle atrophy after cerebral ischemia. Transient focal cerebral ischemia (60 minutes) was induced by occlusion of the right middle cerebral artery in C57BL/6J male mice. Skeletal muscles were removed 3 days later and analyzed for the regulation of critical determinants of muscle mass homeostasis (Akt/mammalian target of rapamycin pathway, myostatin-Smad2/3 and bone morphogenetic protein-Smad1/5/8 signaling pathways, ubiquitin-proteasome and autophagy-lysosome proteolytic pathways). Cerebral ischemia induced severe sensorimotor deficits associated with muscle mass loss of the paretic limbs. Mechanistically, cerebral ischemia repressed Akt/mammalian target of rapamycin pathway and increased expression of key players of ubiquitin-proteasome pathway (MuRF1 [muscle RING finger-1], MAFbx [muscle atrophy F-box], Musa1 [muscle ubiquitin ligase of SCF complex in atrophy-1]), together with a marked increase in myostatin expression, in both paretic and nonparetic skeletal muscles. The Smad1/5/8 pathway was also activated. Our data fit with a model in which a repression of Akt/mammalian target of rapamycin pathway and an increase in the expression of key players of ubiquitin-proteasome pathway are critically involved in skeletal muscle atrophy after cerebral ischemia. Cerebral ischemia also caused an activation of bone morphogenetic protein-Smad1/5/8 signaling pathway, suggesting that compensatory mechanisms are also concomitantly activated to limit the extent of skeletal muscle atrophy. © 2015 American Heart Association, Inc.

  5. Acute limb ischemia due to ergotism.

    PubMed

    Naz, Iram; Sophie, Ziad

    2006-08-01

    Acute ischemia of an extremity potentially threatens limb loss and occasionally the life of the patient. We are reporting two cases of extremity ischemia secondary to ergot poisoning. The first patient was a 60 years old woman, who presented with a 15 days history of ischemia of the left arm with gangrene of the fingers and pain in the resting right hand for one day. Right brachial artery catheterization showed severe spasm of the artery which was resolved by passage of the inflated balloon catheter. She underwent amputation for gangrene of the left hand. The second patient presented with bilateral symmetrical ischemia of the lower extremities which improved upon withdrawal of the ergot containing medicine. She responded to nifedipine.

  6. Mitochondrial Targeted Antioxidant in Cerebral Ischemia.

    PubMed

    Ahmed, Ejaz; Donovan, Tucker; Yujiao, Lu; Zhang, Quanguang

    There has been much evidence suggesting that reactive oxygen species (ROS) generated in mitochondria during cerebral ischemia play a major role in programming the senescence of organism. Antioxidants dealing with mitochondria slow down the appearance and progression of symptoms in cerebral ischemia and increase the life span of organisms. The mechanisms of mitochondrial targeted antioxidants, such as SKQ1, Coenzyme Q10, MitoQ, and Methylene blue, include increasing adenosine triphosphate (ATP) production, decreasing production of ROS and increasing antioxidant defenses, providing benefits in neuroprotection following cerebral ischemia. A number of studies have shown the neuroprotective role of these mitochondrial targeted antioxidants in cerebral ischemia. Here in this short review we have compiled the literature supporting consequences of mitochondrial dysfunction, and the protective role of mitochondrial targeted antioxidants.

  7. Cumulative Effect of Repeated Brief Cerebral Ischemia

    DTIC Science & Technology

    1993-05-31

    KL, Pohost GM and Conger KA, Correlating EEG and Lactate Kinetics During Repeated Brief Cerebral Ischemia, Proceedings of the American Heart Association 1993...Cornelating EEG and Lactate Kinetics During Repeated Brief Cerebral Ischemia, Proceedings of the American Heart Association 1993. 4) HP Hetherington...thes Bernhard Foundation. ass- 134 󈧑&.1 n5. 9# American Heart Association 026085 66th Scientific Sessions Abstract Form Medical Research Nursing

  8. The ubiquitin proteasome system and myocardial ischemia

    PubMed Central

    Calise, Justine

    2013-01-01

    The ubiquitin proteasome system (UPS) has been the subject of intensive research over the past 20 years to define its role in normal physiology and in pathophysiology. Many of these studies have focused in on the cardiovascular system and have determined that the UPS becomes dysfunctional in several pathologies such as familial and idiopathic cardiomyopathies, atherosclerosis, and myocardial ischemia. This review presents a synopsis of the literature as it relates to the role of the UPS in myocardial ischemia. Studies have shown that the UPS is dysfunctional during myocardial ischemia, and recent studies have shed some light on possible mechanisms. Other studies have defined a role for the UPS in ischemic preconditioning which is best associated with myocardial ischemia and is thus presented here. Very recent studies have started to define roles for specific proteasome subunits and components of the ubiquitination machinery in various aspects of myocardial ischemia. Lastly, despite the evidence linking myocardial ischemia and proteasome dysfunction, there are continuing suggestions that proteasome inhibitors may be useful to mitigate ischemic injury. This review presents the rationale behind this and discusses both supportive and nonsupportive studies and presents possible future directions that may help in clarifying this controversy. PMID:23220331

  9. Acute small bowel ischemia: CT imaging findings.

    PubMed

    Segatto, Enrica; Mortelé, Koenraad J; Ji, Hoon; Wiesner, Walter; Ros, Pablo R

    2003-10-01

    Small bowel ischemia is a disorder related to a variety of conditions resulting in interruption or reduction of the blood supply of the small intestine. It may present with various clinical and radiologic manifestations, and ranges pathologically from localized transient ischemia to catastrophic necrosis of the intestinal tract. The primary causes of insufficient blood flow to the small intestine are various and include thromboembolism (50% of cases), nonocclusive causes, bowel obstruction, neoplasms, vasculitis, abdominal inflammatory conditions, trauma, chemotherapy, radiation, and corrosive injury. Computed tomography (CT) can demonstrate changes because of ischemic bowel accurately, may be helpful in determining the primary cause of ischemia, and can demonstrate important coexistent findings or complications. However, common CT findings in acute small bowel ischemia are not specific and, therefore, it is often a combination of clinical, laboratory and radiologic signs that may lead to a correct diagnosis. Understanding the pathogenesis of various conditions leading to mesenteric ischemia and being familiar with the spectrum of diagnostic CT signs may help the radiologist recognize ischemic small bowel disease and avoid delayed diagnosis. The aim of this article is to provide a review of the pathogenesis and various causes of acute small bowel ischemia and to demonstrate the contribution of CT in the diagnosis of this complex disease.

  10. Digital Ischemia Associated With Cancer

    PubMed Central

    Le Besnerais, Maëlle; Miranda, Sébastien; Cailleux, Nicole; Girszyn, Nicolas; Marie, Isabelle; Lévesque, Hervé; Benhamou, Ygal

    2014-01-01

    Abstract Digital ischemia associated with cancer (DIAC) is increasing in frequency and recent reports have suggested the concept of paraneoplastic manifestation. The aims of this study were to characterize the clinical presentation of DIAC and identify clinical features that could lead physicians to diagnose underlying cancer. From January 2004 to December 2011, 100 patients were hospitalized in the Department of Internal Medicine at Rouen University Hospital, France for a first episode of DI. Fifteen (15%) exhibited symptomatic or asymptomatic cancer during the year preceding or following vascular episode and constituted the DIAC group. Other patients without cancer made up the digital ischemia (DI) group. Median time between diagnosis of cancer and episode of digital necrosis was 2 months [0.25–9]. Diagnosis of DI and concomitant cancer was made in 7 of the 15 patients, while DI preceded the malignant disorder in 2 cases and followed it in 6 cases. Histological types were adenocarcinoma for 7 (46.7%), squamous cell carcinoma for 4 (26.7%), and lymphoid neoplasia for 3 patients (20%). Six patients (40%) had extensive cancer. Three patients were lost to follow-up and 5 patients died <1 year after diagnosis of cancer. Cancer treatment improved vascular symptoms in 6 patients (40%). Patients with DIAC, compared to patients with DI, were significantly older (56 years [33–79] vs 46 [17–83] P =0.005), and had significantly lower hemoglobin and hematocrit levels (12.7 g/dl vs 13.9 g/dl; P =0.003 and 38% vs 42%; P =0.003, respectively). Patients with DIAC had a higher platelet rate (420 vs 300 G/L P =0.01), and 6 patients with DIAC (40%) had thrombocytosis. There was no difference between groups either in C-reactive protein level (12 mg/L vs 5 mg/L; P =0.08) or regarding cardiovascular risk factors, presence of autoimmunity, or monoclonal protein. This retrospective study suggests that DIAC may be more prevalent than previously reported. Outcomes

  11. Plasma exosomes protect the myocardium from ischemia-reperfusion injury.

    PubMed

    Vicencio, Jose M; Yellon, Derek M; Sivaraman, Vivek; Das, Debashish; Boi-Doku, Claire; Arjun, Sapna; Zheng, Ying; Riquelme, Jaime A; Kearney, Jessica; Sharma, Vikram; Multhoff, Gabriele; Hall, Andrew R; Davidson, Sean M

    2015-04-21

    Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit signals throughout the body. Shown to act on the heart, exosomes' composition and the signaling pathways they activate have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and provide protection against ischemia and reperfusion injury. This study sought to isolate and characterize exosomes from rats and healthy volunteers, evaluate their cardioprotective actions, and identify the molecular mechanisms involved. The exosome-rich fraction was isolated from the blood of adult rats and human volunteers and was analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. This was then used in ex vivo, in vivo, and in vitro settings of ischemia-reperfusion, with the protective signaling pathways activated on cardiomyocytes identified using Western blot analyses and chemical inhibitors. Exosomes exhibited the expected size and expressed marker proteins CD63, CD81, and heat shock protein (HSP) 70. The exosome-rich fraction was powerfully cardioprotective in all tested models of cardiac ischemia-reperfusion injury. We identified a pro-survival signaling pathway activated in cardiomyocytes involving toll-like receptor (TLR) 4 and various kinases, leading to activation of the cardioprotective HSP27. Cardioprotection was prevented by a neutralizing antibody against a conserved HSP70 epitope expressed on the exosome surface and by blocking TLR4 in cardiomyocytes, identifying the HSP70/TLR4 communication axis as a critical component in exosome-mediated cardioprotection. Exosomes deliver endogenous protective signals to the myocardium by a pathway involving TLR4 and classic cardioprotective HSPs. Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  12. Production of anterior segment ischemia.

    PubMed Central

    Hiatt, R L

    1977-01-01

    Anterior segment ischemic changes can occur without detachment of any muscles. The most common cause of such ischemic changes of the anterior segment is the removal of too many rectus muscles in one operation. Twenty dog eyes and eight monkey eyes were subjected to the disinsertion and detachment of various combinations of extraocular muscles. The dogs were sacrificed at intervals from 30 to 90 days. During the observation period, they were observed for gross and slit-lamp changes. The enucleated eyes were studied microscopically for signs of ischemic and necrotic changes. Two patients who were studied, observed, and treated for anterior segment ischemia following muscle surgery are described. The changes which occur after extraocular muscle surgery are extensive and include corneal edema, cataract, chemosis, corneal changes, decreases in intraocular pressure, decreases in outflow or glaucoma, and frank necrosis. The variables which lead to this reaction are described in detail. Also, some unanswered queries, such as the duration of the reaction and the time interval of the reaction after multiple muscle operations are discussed. Images FIGURE 1 A FIGURE 1 B FIGURE 1 C FIGURE 2 A FIGURE 2 B FIGURE 2 C FIGURE 2 D FIGURE 3 FIGURE 4 PMID:418549

  13. Epigenetic mechanisms in cerebral ischemia

    PubMed Central

    Schweizer, Sophie; Meisel, Andreas; Märschenz, Stefanie

    2013-01-01

    Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration. PMID:23756691

  14. Non-occlusive mesenteric ischemia.

    PubMed

    Lock, G; Schölmerich, J

    1995-07-01

    Non-occlusive disease of the mesentery is still a rather underdiagnosed and underestimated condition. It is associated with circumstances that may compromise circulation or the intake of drugs that may lower mesenteric blood flow. Pathophysiologically, a "low flow syndrome" of mesenteric circulation is followed by vasoconstriction; a reperfusion injury may contribute to the ischemic injury. Histopathological changes vary between superficial localized lesions and transmural gangrene. Diagnosis within the initial 24 hours of the development of symptoms is crucial for prognosis but remains a difficult task. Clinical presentation, laboratory tests and ultrasound lack specificity; the role of duplex ultrasound, tonometry and reflectance spectophotometry is still under evaluation. Mesenteric angiography remains the only reliable diagnostic tool and should be applied early in all patients in whom acute mesenteric ischemia is a real possibility. Therapy is aimed at the rapid correction of predisposing and precipitating factors and an effective treatment of mesenteric vasoconstriction. Treatment of choice is a papaverine infusion into the superior mesenteric artery via an angiography catheter. Patients with peritoneal signs have to be treated surgically.

  15. Echocardiographic assessment of myocardial ischemia

    PubMed Central

    Dworrak, Birgit; Sanchis-Gomar, Fabian; Lucia, Alejandro; Buck, Thomas; Erbel, Raimund

    2016-01-01

    Over the last 60 years, echocardiography has emerged as a dominant and indispensable technique for the detection and assessment of coronary heart disease (CHD). In this review, we will describe and discuss this powerful tool of cardiology, especially in the hands of an experienced user, with a focus on myocardial ischemia. Technical development is still on-going, and various new ultrasound techniques have been established in the field of echocardiography in the last several years, including tissue Doppler imaging (TDI), contrast echocardiography, three-dimensional echocardiography (3DE), and speckle tracking echocardiography (i.e., strain/strain rate-echocardiography). High-end equipment with harmonic imaging, high frame rates and the opportunity to adjust mechanical indices has improved imaging quality. Like all new techniques, these techniques must first be subjected to comprehensive scientific assessment, and appropriate training that accounts for physical and physiological limits should be provided. These limits will constantly be redefined as echocardiographic techniques continue to change, which will present new challenges for the further development of ultrasound technology. PMID:27500160

  16. Assessment of Renal Ischemia By Optical Spectroscopy

    SciTech Connect

    Fitzgerald, J T; Demos, S; Michalopoulou, A; Pierce, J L; Troppmann, C

    2004-01-07

    Introduction: No reliable method currently exists for quantifying the degree of warm ischemia in kidney grafts prior to transplantation. We describe a method for evaluating pretransplant warm ischemia time using optical spectroscopic methods. Methods: Lewis rat kidney vascular pedicles were clamped unilaterally in vivo for 0, 5, 10, 20, 30, 60, 90 or 120 minutes; 8 animals were studied at each time point. Injured and contra-lateral control kidneys were then flushed with Euro-Collins solution, resected and placed on ice. 335 nm excitation autofluorescence as well as cross polarized light scattering images were taken of each injured and control kidney using filters of various wavelengths. The intensity ratio of the injured to normal kidneys was compared to ischemia time. Results: Autofluorescence intensity ratios through a 450 nm filter and light scattering intensity ratios through an 800 nm filter both decreased significantly with increasing ischemia time (p < 0.0001 for each method, one-way ANOVA). All adjacent and non-adjacent time points between 0 and 90 minutes were distinguishable using one of these two modalities by Fisher's PLSD. Conclusions: Optical spectroscopic methods can accurately quantify warm ischemia time in kidneys that have been subsequently hypothermically preserved. Further studies are needed to correlate results with physiological damage and posttransplant performance.

  17. Assessment of renal ischemia by optical spectroscopy.

    PubMed

    Fitzgerald, Jason T; Demos, Stavros; Michalopoulou, Andromachi; Pierce, Jonathan L; Troppmann, Christoph

    2004-11-01

    No reliable method currently exists for quantifying the degree of warm ischemia in kidney grafts before transplantation. We describe a method for evaluating pretransplant warm ischemia time using optical spectroscopic methods. Lewis rat kidney vascular pedicles were clamped unilaterally in vivo for 0, 5, 10, 20, 30, 60, 90, or 120 min; eight animals were studied at each time point. Injured and contralateral control kidneys were then flushed with Euro-Collins solution, resected, and placed on ice. 335 nm excitation autofluorescence as well as cross-polarized light scattering images were then taken of each injured and control kidney using filters of various wavelengths. The intensity ratio of the injured to normal kidneys was compared to ischemia time. Autofluorescence intensity ratios through a 450-nm filter and light scattering intensity ratios through an 800-nm filter both decreased significantly with increasing ischemia time (P < 0.0001 for each method, one-way analysis of variance). All adjacent and nonadjacent time points between 0 and 90 min were distinguishable using one of these two modalities by Fisher's protected least significant difference. Optical spectroscopic methods correlate with warm ischemia time in kidneys that have been subsequently hypothermically preserved. Further studies are needed to correlate results with physiological damage and posttransplant performance.

  18. Ischemia-induced endothelial cell dysfunction.

    PubMed

    Keep, R F; Andjelkovic, A V; Stamatovic, S M; Shakui, P; Ennis, S R

    2005-01-01

    Hemorrhagic transformation upon reperfusion therapy has focused attention on ischemia-induced endothelial dysfunction. This study examined whether hyperglycemia may induce hemorrhagic transformation by enhancing endothelial mitochondrial damage during ischemia and whether preconditioning (PC) stimuli may limit ischemia-induced endothelial damage. In vivo, rats received 2.8 M D-glucose or arabinose (1 ml/100 g; i.p.) prior to undergoing two hours of middle cerebral artery occlusion and transcardiac fixation for electron microscopy. In vitro, brain endothelial cells were exposed to a PC impulse (short-term oxygen glucose deprivation; OGD) prior to an injurious event (5 hours OGD). Endothelial injury was assessed by measuring lactate dehydrogenase release. Hyperglycemia during cerebral ischemia resulted in marked changes in endothelial morphology and mitochondrial swelling. Thus, in the ischemic hemisphere, there was no evidence of endothelial mitochondrial swelling in normoglycemic rats (mean profile width 0.22 +/- 0.04 vs. 0.17 +/- 0.01 microm in contralateral hemisphere) but there was marked swelling in hyperglycemic rats (0.44 +/- 0.02 microm). In vitro, cells preconditioned with one hour of OGD one day prior to 5 hours of OGD, showed reduced lactate dehydrogenase release (p < 0.05). In conclusion, hyperglycemia may have specific adverse effects on endothelial cell mitochondria during ischemia. Preventing those effects may help to ameliorate blood-brain barrier disruption on reperfusion. Insights into how to prevent endothelial injury may come from determining the mechanisms involved in endothelial preconditioning.

  19. 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 WIf

  20. 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

  1. The role of mitochondrial permeability transition in reperfusion-induced cardiomyocyte death depends on the duration of ischemia.

    PubMed

    Ruiz-Meana, Marisol; Inserte, Javier; Fernandez-Sanz, Celia; Hernando, Victor; Miro-Casas, Elisabet; Barba, Ignasi; Garcia-Dorado, David

    2011-11-01

    Mitochondrial permeability transition (MPT) is critical in cardiomyocyte death during reperfusion but it is not the only mechanism responsible for cell injury. The objectives of the study is to investigate the role of the duration of myocardial ischemia on mitochondrial integrity and cardiomyocyte death. Mitochondrial membrane potential (ΔΨm, JC-1) and MPT (calcein) were studied in cardiomyocytes from wild-type and cyclophilin D (CyD) KO mice refractory to MPT, submitted to simulated ischemia and 10 min reperfusion. Reperfusion after 15 min simulated ischemia induced a rapid recovery of ΔΨm, extreme cell shortening (contracture) and mitochondrial calcein release, and CyD ablation did not affect these changes or cell death. However, when reperfusion was performed after 25 min simulated ischemia, CyD ablation improved ΔΨm recovery and reduced calcein release and cell death (57.8 ± 4.9% vs. 77.3 ± 4.8%, P < 0.01). In a Langendorff system, CyD ablation increased infarct size after 30 min of ischemia (61.3 ± 6.4% vs. 45.3 ± 4.0%, P = 0.02) but reduced it when ischemia was prolonged to 60 min (52.8 ± 8.1% vs. 87.6 ± 3.7%, P < 0.01). NMR spectroscopy in rat hearts showed a rapid recovery of phosphocreatine after 30 min ischemia followed by a marked decay associated with contracture and LDH release, that were preventable with contractile blockade but not with cyclosporine A. In contrast, after 50 min ischemia, phosphocreatine recovery was impaired even with contractile blockade (65.2 ± 4% at 2 min), and cyclosporine A reduced contracture, LDH release and infarct size (52.1 ± 4.2% vs. 82.8 ± 3.6%, P < 0.01). In conclusion, the duration of ischemia critically determines the importance of MPT on reperfusion injury. Mechanisms other than MPT may play an important role in cell death after less severe ischemia.

  2. Intermittent ischemia enhances the uptake of indocyanine green to livers subject to ischemia and reperfusion.

    PubMed

    Steenks, Mathilde; Peters, Jeroen; Rademacher, Willem; Nieuwenhuijs, Vincent B; Padbury, Robert T A; Barritt, Greg J

    2017-03-01

    Intermittent ischemia is known to promote post perfusion bile flow, and hence recovery of liver function following ischemia reperfusion of the liver. However, the mechanisms involved are not well understood. The aim of this study was to identify the step(s) in the bile acid transport pathway altered by intermittent ischemia. Arat model of segmental hepatic ischemia in which the bilateral median and left lateral lobes were made ischemic by clamping the blood vessels was used. Indocyanine green (ICG), infrared spectroscopy, and compartmental kinetic analysis, were used to indirectly monitor the movement of bile acids across hepatocytes in situ. Rates of bile flow were measured gravimetrically. In control livers (not subjected to ischemia), the movement of ICG from the blood to bile fluid could be described by a three compartment model comprising the blood, a rapidly-exchangeable compartment, and the hepatocyte cytoplasmic space. In livers subjected to continuous clamping, the rates of ICG uptake to the liver, and outflow from the liver, were greatly reduced compared with those in control livers. Intermittent clamping (three episodes of 15 min clamping) compared with continuous clamping substantially increased the rate of ICG uptake from the blood but had less effect on the rate of ICG outflow from hepatocytes. It is concluded that intermittent ischemia promotes post reperfusion bile flow in the early phase of ischemia reperfusion injury principally by enhancing the movement of bile acids from the blood to hepatocytes. © 2012 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  3. Functional Recovery From Extended Warm Ischemia Associated With Partial Nephrectomy.

    PubMed

    Zhang, Zhiling; Zhao, Juping; Velet, Lily; Ercole, Cesar E; Remer, Erick M; Mir, Carme M; Li, Jianbo; Takagi, Toshio; Demirjian, Sevag; Campbell, Steven C

    2016-01-01

    To evaluate the impact of extended warm ischemia on incidence of acute kidney injury (AKI) and ultimate functional recovery after partial nephrectomy (PN), incorporating rigorous control for loss of parenchymal mass, and embedded within comparison to cohorts of patients managed with hypothermia or limited warm ischemia. From 2007 to 2014, 277 patients managed with PN had appropriate studies to evaluate changes in function/mass specifically within the operated kidney. Recovery from ischemia was defined as %function saved/%parenchymal mass saved. AKI was based on global renal function and defined as a ≥1.5-fold increase in serum creatinine above the preoperative level. Hypothermia was utilized in 112 patients (median = 27 minutes) and warm ischemia in 165 (median = 21 minutes). AKI strongly correlated with solitary kidney (P < .001) and duration (P < .001) but not type (P = .49) of ischemia. Median recovery from ischemia in the operated kidney was 100% (interquartile range [IQR] = 88%-109%) for cold ischemia, with 6 (5%) noted to have <80% recovery from ischemia. For the warm ischemia group, median recovery from ischemia was 91% (IQR = 82%-101%, P < .001 compared with hypothermia), and 34 (21%) had recovery from ischemia <80% (P < .001). For warm ischemia subgrouped by duration <25 minutes (n = 114), 25-35 minutes (n = 35), and >35 minutes (n = 16), median recovery from ischemia was 92% (IQR = 86%-100%), 90% (IQR = 78%-104%), and 91% (IQR = 80%-96%), respectively (P = .77). Our results suggest that AKI after PN correlates with duration but not with type of ischemia. However, subsequent recovery, which ultimately defines the new baseline glomerular filtration rate, is most reliable with hypothermia. However, most patients undergoing PN with warm ischemia still recover relatively strongly from ischemia, even if extended to 35-45 minutes. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. [Chronic cerebral ischemia associated with Raynaud's syndrome].

    PubMed

    Putilina, M V

    2015-01-01

    Over the last years, a number of patients with chronic cerebral ischemia has been increased significantly. Compensatory possibilities of the brain and cerebral circulatory system are so great that even serious disturbances of blood circulation could not cause clinical signs of brain dysfunction for a long time. At the same time, long-term ischemia can lead to peripheral local disturbances of microcirculation that is appears to be a first signal of the problems with homeostasis. Therefore, Raynaud's syndrome may be one of the predictors of standard symptoms of chronic cerebral ischemia (CCI). This phenomenon is explicitly considered as a sign of blood circulation impairment while the pathogenetic mechanism of vascular arterial bed instability is completely ignored. Detailed study of clinical correlations of Raynaud's syndrome in CCI would help to develop a common pharmacotherapeutic approach to its treatment.

  5. Control of cerebral ischemia with magnetic nanoparticles.

    PubMed

    Jia, Jie-Min; Chowdary, Praveen D; Gao, Xiaofei; Ci, Bo; Li, Wenjun; Mulgaonkar, Aditi; Plautz, Erik J; Hassan, Gedaa; Kumar, Amit; Stowe, Ann M; Yang, Shao-Hua; Zhou, Wei; Sun, Xiankai; Cui, Bianxiao; Ge, Woo-Ping

    2017-02-01

    The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.

  6. Infrared laser hemotherapy in cerebral ischemia modeling

    NASA Astrophysics Data System (ADS)

    Musienko, Julia I.; Nechipurenko, Natalia I.

    2003-10-01

    Use of intravenous laser irradiation of blood (ILIB) is considered to be the most effective method of laser therapy and its application is expedient pathogenetically in the ischemic disturbances. The aim of this study is to investigate ILIB influence with infrared laser (IL) with 860 nm wavelength on hemostasis, acid-base status (ABS) of blood in normal rabbits and after modeling of local ischemia of brain (LIB). Experimental cerebral ischemia is characterized by development of hypercoagulation syndrom and metabolic acidosis. ILIB with infrared radiation of 2.0 mW power provokes hypocoagulation in intact animals. Application of ILIB in rabbits after LIB contributes for hemostasis and acid-base status normalizing compared to operated animals. IL radiation with 8,5 mW power results in marked hemostatic activation in all animals. Therefore, beneficial effect of low power laser radiation (LPLR) manifests in narrow power diapason in experimental brain ischemia.

  7. Myocardial Ischemia Caused by Subepicardial Hematoma

    PubMed Central

    Grieshaber, Philippe; Nef, Holger; Böning, Andreas; Niemann, Bernd

    2017-01-01

    Background Bleeding from bypass anastomosis leakage occurs early after coronary artery bypass grafting. Later, once the anastomosis is covered by intima, spontaneous bleeding is unlikely. Case Description A 63-year-old male patient developed a pseudoaneurysm-like, subepicardial late-term bleeding resulting in a hematoma that compromised coronary artery flow by increasing extracoronary pressure. This resulted in severe angina pectoris (Canadian Cardiovascular Society IV) and myocardial ischemia within the affected area. After surgical removal of the hematoma and repair of the anastomosis, the patient's symptoms disappeared and no signs of myocardial ischemia were present. Conclusion Surgical removal is an efficient therapy for subepicardial hematoma inducing myocardial ischemia. PMID:28352501

  8. Mitochondrial Dynamics Following Global Cerebral Ischemia

    PubMed Central

    Kumar, Rita; Bukowski, Melissa J.; Wider, Joseph M.; Reynolds, Christian A.; Calo, Lesley; Lepore, Bradley; Tousignant, Renee; Jones, Michelle; Przyklenk, Karin; Sanderson, Thomas H.

    2016-01-01

    Global brain ischemia/reperfusion induces neuronal damage in vulnerable brain regions, leading to mitochondrial dysfunction and subsequent neuronal death. Induction of neuronal death is mediated by release of cytochrome c (cyt c) from the mitochondria though a well-characterized increase in outer mitochondrial membrane permeability. However, for cyt c to be released it is first necessary for cyt c to be liberated from the cristae junctions which are gated by Opa1 oligomers. Opa1 has two known functions: maintenance of the cristae junction and mitochondrial fusion. These roles suggest that Opa1 could play a central role in both controlling cyt c release and mitochondrial fusion/fission processes during ischemia/reperfusion. To investigate this concept, we first utilized in vitro real-time imaging to visualize dynamic changes in mitochondria. Oxygen-glucose deprivation (OGD) of neurons grown in culture induced a dual-phase mitochondrial fragmentation profile: (i) fragmentation during OGD with no apoptosis activation, followed by fusion of mitochondrial networks after reoxygenation and a (ii) subsequent extensive fragmentation and apoptosis activation that preceded cell death. We next evaluated changes in mitochondrial dynamic state during reperfusion in a rat model of global brain ischemia. Evaluation of mitochondrial morphology with confocal and electron microscopy revealed a similar induction of fragmentation following global brain ischemia. Mitochondrial fragmentation aligned temporally with specific apoptotic events, including cyt c release, caspase 3/7 activation, and interestingly, release of the fusion protein Opa1. Moreover, we uncovered evidence of loss of Opa1 complexes during the progression of reperfusion, and electron microscopy micrographs revealed a loss of cristae architecture following global brain ischemia. These data provide novel evidence implicating a temporal connection between Opa1 alterations and dysfunctional mitochondrial dynamics following

  9. Using operations research to plan improvement of the transport of critically ill patients.

    PubMed

    Chen, Jing; Awasthi, Anjali; Shechter, Steven; Atkins, Derek; Lemke, Linda; Fisher, Les; Dodek, Peter

    2013-01-01

    Operations research is the application of mathematical modeling, statistical analysis, and mathematical optimization to understand and improve processes in organizations. The objective of this study was to illustrate how the methods of operations research can be used to identify opportunities to reduce the absolute value and variability of interfacility transport intervals for critically ill patients. After linking data from two patient transport organizations in British Columbia, Canada, for all critical care transports during the calendar year 2006, the steps for transfer of critically ill patients were tabulated into a series of time intervals. Statistical modeling, root-cause analysis, Monte Carlo simulation, and sensitivity analysis were used to test the effect of changes in component intervals on overall duration and variation of transport times. Based on quality improvement principles, we focused on reducing the 75th percentile and standard deviation of these intervals. We analyzed a total of 3808 ground and air transports. Constraining time spent by transport personnel at sending and receiving hospitals was projected to reduce the total time taken by 33 minutes with as much as a 20% reduction in standard deviation of these transport intervals in 75% of ground transfers. Enforcing a policy of requiring acceptance of patients who have life- or limb-threatening conditions or organ failure was projected to reduce the standard deviation of air transport time by 63 minutes and the standard deviation of ground transport time by 68 minutes. Based on findings from our analyses, we developed recommendations for technology renovation, personnel training, system improvement, and policy enforcement. Use of the tools of operations research identifies opportunities for improvement in a complex system of critical care transport.

  10. Myocardial Ischemia Caused by a Coronary Anomaly

    PubMed Central

    Aydin, Mustafa; Ozeren, Ali; Peksoy, Irfan; Cabuk, Mehmet; Bilge, Mehmet; Dursun, Aydin; Elbey, Mehmet Ali

    2004-01-01

    We present the case of a patient in whom a previously undetected anomalous origin of the circumflex coronary artery caused myocardial ischemia and led to positive myocardial scintigraphic results. Subsequent coronary angiography showed that the left circumflex coronary artery arose from the right coronary ostium—an anomaly that has been associated with chest discomfort—without atherosclerotic lesions. The peripheral distribution of the left circumflex artery was normal. We describe the clinical and angiographic findings in our patient and discuss the relationship between coronary artery anomalies and ischemia. PMID:15562848

  11. Development of an albumin copper binding (ACuB) assay to detect ischemia modified albumin.

    PubMed

    Eom, Ji-Eun; Lee, Eunyoung; Jeon, Kyung-Hwa; Sim, Jeongeun; Suh, Minah; Jhon, Gil-Ja; Kwon, Youngjoo

    2014-01-01

    Myocardial ischemia (MI) induces many changes in the body, including pH decrease and electrolyte imbalance. No obvious symptoms of MI appear until irreversible cellular injuries occur. Since early treatment is critical for recovery from ischemia, the development of reliable diagnostic tool is demanded to detect the early ischemic status. Ischemia modified albumin (IMA), formed by cleavage of the last two amino acids of the human serum albumin (HSA) N-terminus, has been considered so far as the most trustworthy and accurate marker for the investigation of ischemia. IMA levels are elevated in plasma within a few minutes of ischemic onset, and may last for up to 6 h. In the present study, we developed a novel assay for the examination of IMA levels to ameliorate the known albumin cobalt binding (ACB) test established previously. We observed a stronger copper ion bound to the HSA N-terminal peptide than cobalt ion by HPLC and ESI-TOF mass spectrometric analyses. The copper ion was employed with lucifer yellow (LY), a copper-specific reagent to develop a new albumin copper binding (ACuB) assay. The parameters capable of affecting the assay results were optimized, and the finally-optimized ACuB assay was validated. The result of the IMA level measurement in normal versus stroke rat serum suggests that the ACuB assay is likely to be a reliable and sensitive method for the detection of ischemic states.

  12. Pulsed electromagnetic field improves postnatal neovascularization in response to hindlimb ischemia

    PubMed Central

    Li, Rui-Lin; Huang, Jing-Juan; Shi, Yi-Qin; Hu, An; Lu, Zhao-Yang; Weng, Liang; Wang, Shen-Qi; Han, Yi-Peng; Zhang, Lan; Hao, Chang-Ning; Duan, Jun-Li

    2015-01-01

    Pulsed electromagnetic fields (PEMF) have been shown to promote proliferation and regeneration in the damaged tissue. Here, we examined whether PEMF therapy improved postnatal neovascularization using murine model of hindlimb ischemia, and the underlying cellular/molecular mechanisms were further investigated. Hindlimb ischemia was induced by unilateral femoral artery resection using 6-8 week-old male C57BL6 mice. Then, mice were exposed to extracorporeal PEMF therapy (4 cycles, 8min/cycle, 30 ± 3 Hz, 5 mT) every day until day 14. Our data demonstrated that PEMF therapy significantly accelerated wound healing, decreased prevalence of gangrene and increased postnatal neovascularization. Moreover, the levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in ischemic muscles were markedly enhanced following PEMF therapy. In vitro, PEMF inhibited the process of hypoxia-induced apoptosis and augmented tube formation, migration and proliferative capacities of human umbilical vein endothelial cells (HUVECs). Additionally, PEMF exposure increased VEGF secretion, as well as the eNOS and Akt phosphorylation, and these benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. In conclusion, our data indicated that PEMF therapy enhanced ischemia-mediated angiogenesis, through up-regulating VEGF expression and activating the PI3K-Akt-eNOS pathway. Therefore, PEMF should be a valuable treatment for the patients with critical limb ischemia. PMID:26045885

  13. Pulsed electromagnetic field improves postnatal neovascularization in response to hindlimb ischemia.

    PubMed

    Li, Rui-Lin; Huang, Jing-Juan; Shi, Yi-Qin; Hu, An; Lu, Zhao-Yang; Weng, Liang; Wang, Shen-Qi; Han, Yi-Peng; Zhang, Lan; Hao, Chang-Ning; Duan, Jun-Li

    2015-01-01

    Pulsed electromagnetic fields (PEMF) have been shown to promote proliferation and regeneration in the damaged tissue. Here, we examined whether PEMF therapy improved postnatal neovascularization using murine model of hindlimb ischemia, and the underlying cellular/molecular mechanisms were further investigated. Hindlimb ischemia was induced by unilateral femoral artery resection using 6-8 week-old male C57BL6 mice. Then, mice were exposed to extracorporeal PEMF therapy (4 cycles, 8min/cycle, 30 ± 3 Hz, 5 mT) every day until day 14. Our data demonstrated that PEMF therapy significantly accelerated wound healing, decreased prevalence of gangrene and increased postnatal neovascularization. Moreover, the levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in ischemic muscles were markedly enhanced following PEMF therapy. In vitro, PEMF inhibited the process of hypoxia-induced apoptosis and augmented tube formation, migration and proliferative capacities of human umbilical vein endothelial cells (HUVECs). Additionally, PEMF exposure increased VEGF secretion, as well as the eNOS and Akt phosphorylation, and these benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. In conclusion, our data indicated that PEMF therapy enhanced ischemia-mediated angiogenesis, through up-regulating VEGF expression and activating the PI3K-Akt-eNOS pathway. Therefore, PEMF should be a valuable treatment for the patients with critical limb ischemia.

  14. 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.

  15. Zinc: new clues to diverse roles in brain ischemia

    PubMed Central

    Shuttleworth, C. William; Weiss, John H.

    2011-01-01

    Cerebral ischemia is a leading cause of morbidity and mortality, reflecting the extraordinary sensitivity of the brain to a brief loss of blood flow. A significant goal has been to identify neuronal injury pathways that are selectively activated following stroke and may be amenable to drug therapy. An important advance was made close to a quarter century ago, when Ca2+ overload was implicated as a critical link between glutamate excitotoxicity and ischemic neurodegeneration. However, early hope for effective therapies faded to frustration, as glutamate-targetted trials repeatedly failed to demonstrate efficacy in humans. In a review in 2000 in this journal, we described new evidence linking a related cation, zinc (Zn2+), to neuronal injury, emphasizing sources and mechanisms of Zn2+ toxicity. The current review highlights progress over the last decade, emphasizing mechanisms through which Zn2+ ions, from multiple sources, participate together with Ca2+ in different stages of ischemic injury cascades. PMID:21621864

  16. [Evaluation of brain ischemia by mitochondrial respiration: experimental model].

    PubMed

    Carlotti, C G; Colli, B O; Kazuo, J Y

    2001-06-01

    Brain ischemia occurs in several diseases. One of the critical factors for recovery of patients is the duration of the ischemic process. Brain activity depends on the energetic supply, it suggests that the study of mitochondrial function can be useful for evaluation of neuronal damage. The purpose of the present research was to study the mitochondrial respiration by occlusion of the left middle cerebral artery by intraluminal suture technique. Adults Wistar rats were subdivided in 4 groups: control, 15, 30 and 60 minutes of occlusion. Results showed that there was no significant difference between the group of 15 minutes and the control group. The group of 30 minutes had significant decrease of state III of mitochondrial respiration compared with control group. The group of 60 minutes had significant decrease in state III and IV of mitochondrial respiration compared with control group. Mitochondrial respiration allowed an early and effective evaluation of focal ischemic process of the rat brain.

  17. The Effects of Antecedent Exercise on Motor Function Recovery and Brain-derived Neurotrophic Factor Expression after Focal Cerebral Ischemia in Rats.

    PubMed

    Kim, Gyeyeop; Kim, Eunjung

    2013-05-01

    [Purpose] In the present study, we investigated the effect of antecedent exercise on functional recovery and brain-derived neurotrophic factor (BDNF) expression following focal cerebral ischemia injury. [Subjects] The rat middle cerebral artery occlusion (MCAO) model was employed. Adult male Sprague-Dawley rats were randomly divided into 4 groups. Group I included untreated normal rats (n=10); Group II included untreated rats with focal cerebral ischemia (n=10); Group III included rats that performed treadmill exercise (20 m/min) training after focal cerebral ischemia (n=10); and Group IV included rats that performed antecedent treadmill exercise (20 m/min) training before focal cerebral ischemia (n=10) as well as treadmill exercise after ischemia. At different time points (1, 7, 14, and 21 days) Garcia's score, and the hippocampal expressions level of BDNF were examined. [Results] In the antecedent exercise group, improvements in the motor behavior index (Garcia's score) were observed and hippocampal BDNF protein expression levels increased. [Conclusion] These results indicate that antecedent treadmill exercise, before permanent brain ischemia exerts a neuroprotective effect against ischemia brain injury by improving motor performance and increasing the level of BDNF expression. Furthermore, the antecedent treadmill exercise of appropriate intensity is critical for post-stroke rehabilitation.

  18. Tenoxicam exerts a neuroprotective action after cerebral ischemia in rats.

    PubMed

    Galvão, Rita I M; Diógenes, João P L; Maia, Graziela C L; Filho, Emídio A S; Vasconcelos, Silvânia M M; de Menezes, Dalgimar B; Cunha, Geanne M A; Viana, Glauce S B

    2005-01-01

    In this study we investigated the effects of Tenoxicam, a type 2 cyclooxygenase (COX-2) inhibitor, on brain damage induced by ischemia-reperfusion. Male Wistar rats (18-month old average) were anesthetized and submitted to ischemia occlusion of both common carotid arteries (BCAO) for 45 min. After 24 h of reperfusion, rats were decapitated and hippocampi removed for further assays. Animals were divided into sham-operated, ischemia, ischemia + Tenoxicam 2.5 mg/kg, and ischemia + Tenoxicam 10 mg/kg groups. Tenoxicam was administered intraperitoneally immediately after BCAO. Histological analyses show that ischemia produced significant striatal as well as hippocampal lesions which were reversed by the Tenoxicam treatment. Tenoxicam also significantly reduced, to control levels, the increased myeloperoxidase activity in hippocampus homogenates observed after ischemia. However, nitrite concentrations showed only a tendency to decrease in the ischemia + Tenoxicam groups, as compared to that of ischemia alone. On the other hand, hippocampal glutamate and aspartate levels were not altered by Tenoxicam. In conclusion, we showed that ischemia is certainly related to inflammation and to increased free radical production, and selective COX-2 inhibitors might be neuroprotective agents of potential benefit in the treatment of cerebral brain ischemia.

  19. Acute mesenteric ischemia: current multidisciplinary approach.

    PubMed

    Savlania, Ajay; Tripathi, Ramesh K

    2017-04-01

    The aim of this review was to describe and discuss the mechanisms of acute mesenteric ischemia (AMI) and the rationale and conduct of currently available endovascular and open surgical techniques in its management. We also propose an algorithm to support the current multidisciplinary approach in decision-making for mesenteric revascularization to manage this high-risk entity.

  20. [Myocardial ischemia-reperfusion injury and melatonin].

    PubMed

    Sahna, Engin; Deniz, Esra; Aksulu, Hakki Engin

    2006-06-01

    It is believed that myocardial ischemia-reperfusion injury is related to increased free radical generated and intracellular calcium overload especially during the period of reperfusion. The pineal secretory product, melatonin, is known to be a potent free radical scavenger, antioxidant and can inhibit the intracellular calcium overload. In this review, we have summarized the fundamental of cardiac ischemia-reperfusion injury and the effects of melatonin on myocardial damage that related to cardiac ischemia-reperfusion injury. The total antioxidant capacity of human serum is related to melatonin levels. Incidence of sudden cardiac death is high in the morning hours. It has been shown that melatonin levels are significantly low at these times and patients with coronary heart disease have lower than normal individuals. These findings thought that melatonin would be valuable to test in clinical trials for prevention of possible ischemia-reperfusion-induced injury, especially life threatening arrhythmias and infarct size, effecting life quality, associated with thrombolysis, angioplasty, coronary artery spasm or coronary bypass surgery.

  1. Nitric oxide during ischemia attenuates oxidant stress and cell death during ischemia and reperfusion in cardiomyocytes.

    PubMed

    Iwase, Hirotaro; Robin, Emmanuel; Guzy, Robert D; Mungai, Paul T; Vanden Hoek, Terry L; Chandel, Navdeep S; Levraut, Jacques; Schumacker, Paul T

    2007-08-15

    Nitric oxide (NO) has been implicated as a cardioprotective agent during ischemia/reperfusion (I/R), but the mechanism of protection is unknown. Oxidant stress contributes to cell death in I/R, so we tested whether NO protects by attenuating oxidant stress. Cardiomyocytes and murine embryonic fibroblasts were administered NO (10-1200 nM) during simulated ischemia, and cell death was assessed during reperfusion without NO. In each case, NO abrogated cell death during reperfusion. Cells overexpressing endothelial NO synthase (NOS) exhibited a similar protection, which was abolished by the NOS inhibitor N(omega)-nitro-l-arginine methyl ester. Protection was not mediated by guanylate cyclase or the mitochondrial K(ATP) channel, as inhibitors of these systems failed to abolish protection. NO did not prevent decreases in mitochondrial potential, but cells protected with NO demonstrated recovery of potential at reperfusion. Measurements using C11-BODIPY reveal that NO attenuates lipid peroxidation during ischemia and reperfusion. Measurements of oxidant stress using the ratiometric redox sensor HSP-FRET demonstrate that NO attenuates protein oxidation during ischemia. These findings reveal that physiological levels of NO during ischemia can attenuate oxidant stress both during ischemia and during reperfusion. This response is associated with a remarkable attenuation of cell death, suggesting that ischemic cell death may be a regulated event.

  2. Unilateral Renal Ischemia-Reperfusion as a Robust Model for Acute to Chronic Kidney Injury in Mice

    PubMed Central

    Le Clef, Nathalie; Verhulst, Anja; D’Haese, Patrick C.; Vervaet, Benjamin A.

    2016-01-01

    Acute kidney injury (AKI) is an underestimated, yet important risk factor for development of chronic kidney disease (CKD). Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD). Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis) is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFβ, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care) with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data. PMID:27007127

  3. Unilateral Renal Ischemia-Reperfusion as a Robust Model for Acute to Chronic Kidney Injury in Mice.

    PubMed

    Le Clef, Nathalie; Verhulst, Anja; D'Haese, Patrick C; Vervaet, Benjamin A

    2016-01-01

    Acute kidney injury (AKI) is an underestimated, yet important risk factor for development of chronic kidney disease (CKD). Even after initial total recovery of renal function, some patients develop progressive and persistent deterioration of renal function and these patients are more likely to progress to end-stage renal disease (ESRD). Animal models are indispensable for unravelling the mechanisms underlying this progression towards CKD and ESRD and for the development of new therapeutic strategies in its prevention or treatment. Ischemia (i.e. hypoperfusion after surgery, bleeding, dehydration, shock, or sepsis) is a major aetiology in human AKI, yet unilateral ischemia-reperfusion is a rarely used animal model for research on CKD and fibrosis. Here, we demonstrate in C57Bl/6J mice, by both histology and gene expression, that unilateral ischemia-reperfusion without contralateral nephrectomy is a very robust model to study the progression from acute renal injury to long-term tubulo-interstitial fibrosis, i.e. the histopathological hallmark of CKD. Furthermore, we report that the extent of renal fibrosis, in terms of Col I, TGFβ, CCN2 and CCN3 expression and collagen I immunostaining, increases with increasing body temperature during ischemia and ischemia-time. Thus, varying these two main determinants of ischemic injury allows tuning the extent of the long-term fibrotic outcome in this model. Finally, in order to cover the whole practical finesse of ischemia-reperfusion and allow model and data transfer, we provide a referenced overview on crucial technical issues (incl. anaesthesia, analgesia, and pre- and post-operative care) with the specific aim of putting starters in the right direction of implementing ischemia in their research and stimulate them, as well as the community, to have a critical view on ischemic literature data.

  4. Pharmacological treatment of chronic pelvic ischemia.

    PubMed

    Andersson, Karl-Erik; Nomiya, Masanori; Sawada, Norifumi; Yamaguchi, Osamu

    2014-06-01

    Epidemiological studies have shown that lower urinary tract symptoms, including overactive bladder, commonly occur in both men and women, with an age-related increase in both sexes. Vascular endothelial dysfunction and urological symptoms are common in the metabolic syndrome; they also occur during the human ageing process and are independent risk factors for the development of atherosclerosis and hypertension. Pelvic arterial insufficiency may lead to impaired lower urinary tract perfusion and play an important role in the development of bladder dysfunction such as detrusor overactivity and overactive bladder. It seems reasonable, but has not been definitely established clinically, that chronic ischemia-related bladder dysfunction will progress to bladder underactivity. Studies in experimental models in rabbits and rats have shown that pelvic arterial insufficiency may result in significant bladder ischemia with reduced bladder wall oxygen tension, oxidative stress, increased muscarinic receptor activity, ultrastructural damage, and neurodegeneration. Several types of drug may be able to prevent some of these changes. Even if the α1-adrenoceptor blocker, silodosin, the phosphodiesterase type 5 inhibitor, tadalafil, the β3-α1-adrenoceptor agonist, mirabegron, and the free radical scavenger, melatonin, were unable to prevent the development of neointimal hyperplasia and consequent luminal occlusion in animal models, they all exerted a protecting effect on urodynamic parameters, and on the functional and morphological changes of the bladder demonstrable in vitro. The different mechanisms of action of the drugs suggest that many factors are involved in the pathogenesis of chronic ischemia-induced bladder dysfunction and can be targets for intervention. Since several of the agents tested are used clinically and effectively for relieving lower urinary tract symptoms, the results from animal models of chronic bladder ischemia seem to have translational value

  5. Collateralization and ischemia in hemodynamic cerebrovascular insufficiency.

    PubMed

    Czabanka, Marcus; Acker, Gueliz; Jussen, Daniel; Finger, Tobias; Pena-Tapia, Pablo; Schubert, Gerrit A; Scharf, Johann; Martus, Peter; Schmiedek, Peter; Vajkoczy, Peter

    2014-11-01

    Moyamoya disease and atherosclerotic cerebrovascular occlusive disease lead to hemodynamic impairment of cerebral blood flow. One major differentiation between both disease entities lies in the collateralization pathways. The clinical implications of the collateralization pathways for the development of hemodynamic ischemia remain unknown. The aim was to characterize collateralization and ischemia patterns in patients with chronic hemodynamic compromise. Hemodynamic compromise was verified using acetazolamide-stimulated xenon-CT or SPECT in 54 patients [30 moyamoya and 24 atherosclerotic cerebrovascular disease (ACVD)]. All patients received MRI to differentiate hemodynamic ischemia into anterior/posterior cortical border zone infarction (CBI), inferior border zone infarction (IBI) or territorial infarction (TI). Digital subtraction angiography was applied to evaluate collateralization. Collateralization was compared and correlated with the localization of ischemia and number of vascular territories with impaired cerebrovascular reserve capacity (CVRC). MM patients showed collateralization significantly more often via pericallosal anastomosis and the posterior communicating artery (flow in the anterior-posterior direction; MM: 95%/95% vs. ACVD: 23%/12%, p < 0.05). ACVD patients demonstrated collateralization via the anterior and posterior communicating arteries (flow in the posterior-anterior direction, MM: 6%/5% vs. ACVD: 62%/88%, p < 0.05). Patterns of infarction were comparable (aCBI: MM: 36% vs. ACVD: 35%; pCBI: MM: 10% vs. ACVD: 20%; IBI: MM: 35% vs. ACVD: 41%; TI: MM: 13% vs. ACVD: 18%). The number and localization of vascular territories with impaired CVRC were comparable. Despite significant differences in collateralization, the infarct patterns and severity of CVRC impairment do not differ between MMV and ACVD patients. Cerebral collateralization does not allow reaching conclusions about the localization of cerebral ischemia or severity of impaired

  6. Bromelain ameliorates hepatic microcirculation after warm ischemia.

    PubMed

    Bahde, Ralf; Palmes, Daniel; Minin, Evgeni; Stratmann, Udo; Diller, Ricarda; Haier, Jörg; Spiegel, Hans-Ullrich

    2007-05-01

    Because of its immunomodulatory action, the protease bromelain represents a novel strategy for the treatment of hepatic ischemia/reperfusion (I/R) injury. A dose-response study was performed to investigate the effect of bromelain on liver function, microcirculation, and leukocyte-endothelium interactions in hepatic I/R injury. One hundred forty rats were randomized to 8 short-term or 12 long-term groups (n=7 each). A 30 min normothermic hepatic ischemia was induced by Pringle maneuver with a portocaval shunt. Animals were treated 60 min prior to ischemia with either no therapy, 0.1, 1.0, or 10 mg/kg b.w. bromelain i.v. In the short-term experiments, microcirculation was investigated 30 min after sham operation or ischemia using intravital microscopy. In the long-term experiments AST, ALT, and bradykinin levels were determined for 14 d after central venous catheter (CVC) placement only, sham operation, or ischemia. Additionally, apoptosis rate, Kupffer cell activation, endothelial cell damage, and eNOS expression were analyzed. In sham-operated animals, treatment with 10 mg/kg b.w. bromelain led to a disturbed microcirculation with increased leukocyte adherence, apoptosis rate, Kupffer cell activation, and endothelial cell damage. Six h after CVC placement and administration of 10 mg/kg b.w. bromelain, AST and ALT levels were significantly increased. After I/R, rats treated with 0.1 mg/kg b.w. bromelain showed an improved microcirculation, reduction in leukocyte adhesion, apoptosis rates, Kupffer cell activation and endothelial cell damage, increased eNOS expression, and significantly lower AST levels compared with untreated animals. Bromelain represents a novel approach to the treatment of hepatic I/R injury with a limited therapeutic window.

  7. Therapeutic benefit of intrathecal injection of marrow stromal cells on ischemia-injured spinal cord.

    PubMed

    Shi, Enyi; Kazui, Teruhisa; Jiang, Xiaojing; Washiyama, Naoki; Yamashita, Katsushi; Terada, Hitoshi; Bashar, Abul Hasan Muhammad

    2007-04-01

    Prophylactic transplantation of marrow stromal cells (MSCs) before spinal cord ischemia has been shown to attenuate neurologic injures. We sought to investigate the therapeutic effect of MSCs on ischemia-injured spinal cord. Marrow stromal cells were expanded in vitro and prelabeled with bromodeoxyuridine. Spinal cord ischemia was induced in rabbits by infrarenal aortic occlusion for 30 minutes. Four groups were enrolled. About 1 x 10(8) MSCs were intrathecally injected 2 hours (group MSC-2h), 24 hours (group MSC-24h), or 48 hours (group MSC-48h) after spinal cord ischemia, respectively. The control group received intrathecal injection of medium alone. Hind-limb motor function was assessed during a 28-day recovery period with Tarlov criteria, and then histologic examination was performed. Marrow stromal cells still could be found in the spinal cord 4 weeks after transplantation. The capillary density in the ventral gray matter was significantly increased in the three MSC-treated groups (p < 0.01 versus control group, respectively). After a 28-day recovery, marked functional improvement was detected in group MSC-2h (from day 1 to 28, p < 0.05, versus control group, respectively) and group MSC-24h (from day 14 to 28, p < 0.05, versus control group, respectively), but not in group MSC-48h. The number of intact motor neurons was much greater in group MSC-2h (p < 0.05, versus control group). Intrathecal injection of MSCs enhances angiogenesis in the host spinal cord and improves the motor functional recovery after spinal cord ischemia. The therapeutic time window is critical for the therapeutic effect of MSCs.

  8. ARRB1/β-arrestin-1 mediates neuroprotection through coordination of BECN1-dependent autophagy in cerebral ischemia

    PubMed Central

    Wang, Pei; Xu, Tian-Ying; Wei, Kai; Guan, Yun-Feng; Wang, Xia; Xu, Hui; Su, Ding-Feng; Pei, Gang; Miao, Chao-Yu

    2014-01-01

    Autophagy, a highly conserved process conferring cytoprotection against stress, contributes to the progression of cerebral ischemia. β-arrestins are multifunctional proteins that mediate receptor desensitization and serve as important signaling scaffolds involved in numerous physiopathological processes. Here, we show that both ARRB1 (arrestin, β 1) and ARRB2 (arrestin, β 2) were upregulated by cerebral ischemic stress. Knockout of Arrb1, but not Arrb2, aggravated the mortality, brain infarction, and neurological deficit in a mouse model of cerebral ischemia. Accordingly, Arrb1-deficient neurons exhibited enhanced cell injury upon oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Deletion of Arrb1 did not affect the cerebral ischemia-induced inflammation, oxidative stress, and nicotinamide phosphoribosyltransferase upregulation, but markedly suppressed autophagy and induced neuronal apoptosis/necrosis in vivo and in vitro. Additionally, we found that ARRB1 interacted with BECN1/Beclin 1 and PIK3C3/Vps34, 2 major components of the BECN1 autophagic core complex, under the OGD condition but not normal conditions in neurons. Finally, deletion of Arrb1 impaired the interaction between BECN1 and PIK3C3, which is a critical event for autophagosome formation upon ischemic stress, and markedly reduced the kinase activity of PIK3C3. These findings reveal a neuroprotective role for ARRB1, in the context of cerebral ischemia, centered on the regulation of BECN1-dependent autophagosome formation. PMID:24988431

  9. Delayed minocycline treatment reduces long-term functional deficits and histological injury in a rodent model of focal ischemia.

    PubMed

    Hewlett, K A; Corbett, D

    2006-08-11

    The absence of effective treatments for stroke presents a critical need for novel strategies that can reduce ischemic injury. Neuroinflammation following focal ischemia induces secondary injury in the region surrounding the insult, thus anti-inflammatory agents are potential neuroprotectants. Minocycline is one such agent possessing neuroprotective properties, however many studies examining minocycline after ischemia have used minimal delays between ischemia and treatment, short survival periods, and lack measures of functional outcome. Such studies do not distinguish whether minocycline provides sustained protection or merely delays cell death. This study was designed to address some of these concerns. Male Sprague-Dawley rats were treated with multiple doses of minocycline (45 mg/kg i.p.) or vehicle beginning 2.5 h after endothelin-1-induced focal ischemia. Measures of forelimb asymmetry and skilled reaching (staircase test) were used to determine functional outcome 7, 15 and 28 days after ischemia. Long-term functional assessment indicates that minocycline provides limited benefit in the staircase test, but confers long-term benefit in the forelimb asymmetry test. Subcortical and whole hemisphere infarct volumes were reduced by 41 and 39% respectively in minocycline-treated animals. Further analysis revealed that minocycline attenuated long-term white matter damage adjacent to the striatal injury core, which correlated with sustained functional benefits. This study indicates that delayed minocycline treatment improves long-term functional outcome which is linked to protection of both white and gray matter.

  10. Myocardial ischemia and angiotensin-converting enzyme inhibition: comparison of ischemia during mental and physical stress.

    PubMed

    Ramadan, Ronnie; Quyyumi, Arshed A; Zafari, A Maziar; Binongo, Jose N; Sheps, David S

    2013-01-01

    Mental stress provokes myocardial ischemia in many patients with stable coronary artery disease (CAD). Mental stress-induced myocardial ischemia (MSIMI) portends a worse prognosis, independent of standard cardiac risk factors or outcome of traditional physical stress testing. Angiotensin II plays a significant role in the physiological response to stress, but its role in MSIMI remains unknown. Our aim was to evaluate whether the use of angiotensin-converting enzyme inhibitors (ACEIs) is associated with a differential effect on the incidence of MSIMI compared with ischemia during physical stress. Retrospective analysis of 218 patients with stable CAD, including 110 on ACEI, was performed. 99m-Tc-sestamibi myocardial perfusion imaging was used to define ischemia during mental stress, induced by a standardized public speaking task, and during physical stress, induced by either exercise or adenosine. Overall, 40 patients (18%) developed MSIMI and 80 patients (37%) developed ischemia during physical stress. MSIMI occurred less frequently in patients receiving ACEIs (13%) compared with those not on ACEIs (24%; p = .030, adjusted odds ratio = 0.42, 95% confidence interval = 0.19-0.91). In contrast, the frequency of myocardial ischemia during physical stress testing was similar in both groups (39% versus 35% in those on and not on ACEIs, respectively); adjusted odds ratio = 0.91, 95% confidence interval = 0.48-1.73). In this retrospective study, patients using ACEI therapy displayed less than half the risk of developing ischemia during mental stress but not physical stress. This possible beneficial effect of ACEIs on MSIMI may be contributing to their salutary effects in CAD.

  11. Detrimental or beneficial: the role of TRPM2 in ischemia/reperfusion injury.

    PubMed

    Zhan, Kai-yu; Yu, Pei-lin; Liu, Chun-hui; Luo, Jian-hong; Yang, Wei

    2016-01-01

    Ischemia/reperfusion (I/R) injury is the main cause of tissue damage and dysfunction. I/R injury is characterized by Ca(2+) overload and production of reactive oxygen species (ROS), which play critical roles in the process of I/R injury to the brain, heart and kidney, but the underlying mechanisms are largely elusive. Recent evidence demonstrates that TRPM2, a Ca(2+)-permeable cationic channel and ROS sensor, is involved in I/R injury, but whether TRPM2 plays a protective or detrimental role in this process remains controversial. In this review, we discuss the recent progress in understanding the role of TRPM2 in reperfusion process after brain, heart and kidney ischemia and the potential of targeting TRPM2 for the development of therapeutic drugs to treat I/R injury.

  12. [Prostaglandin E1 in the treatment of chronic ischemia of the extremities].

    PubMed

    Kowal-Gierczak, B; Kurzawska-Mielecka, M; Czarnacki, M

    1990-11-01

    The authors observed the effect of prostaglandin E1 (Prostavasine) on the blood flow in the lower extremities in 25 patients with chronic ischemia caused by thrombo-angitis obliterans and arteriosclerosis obliterans (clinical stage III and IV). The blood flow in the lower extremities and the effects of prostaglandin E1 were assessed by means of rheo-angiographic and Doppler-testing investigations. The parameters A (amplitude), S (area) and WOT (index) of rheo-angiographic curves showed significant increased. No significant changes were found in the determined Doppler's indexes. The observed differences of values the parameters of rheo-angiographic curves suggests that prostaglandin E1 evident improvement the tissue blood flow in patients with critical ischemia of the lower extremities. The authors found that prostaglandin E1 was without any significant effect dilating the great vessels, but an evident improvement was observed in rheo-angiographic records which reflect rather the blood flow values in the small vessels.

  13. Kappa Opioid Receptor Agonist and Brain Ischemia

    PubMed Central

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury. PMID:25574482

  14. Spinal cord ischemia secondary to hypovolemic shock.

    PubMed

    Oh, Jacob Yl; Kapoor, Siddhant; Koh, Roy Km; Yang, Eugene Wr; Hee, Hwan-Tak

    2014-12-01

    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.

  15. Kappa Opioid Receptor Agonist and Brain Ischemia.

    PubMed

    Chunhua, Chen; Chunhua, Xi; Megumi, Sugita; Renyu, Liu

    2014-01-01

    Opioid receptors, especially Kappa opioid receptor (KOR) play an important role in the pathophysiological process of cerebral ischemia reperfusion injury. Previously accepted KOR agonists activity has included anti-nociception, cardiovascular, anti-pruritic, diuretic, and antitussive effects, while compelling evidence from various ischemic animal models indicate that KOR agonist have neuroprotective effects through various mechanisms. In this review, we aimed to demonstrate the property of KOR agonist and its role in global and focal cerebral ischemia. Based on current preclinical research, the KOR agonists may be useful as a neuroprotective agent. The recent discovery of salvinorin A, highly selective non-opioid KOR agonist, offers a new tool to study the role of KOR in brain HI injury and the protective effects of KOR agonist. The unique pharmacological profile of salvinorin A along with the long history of human usage provides its high candidacy as a potential alternative medication for brain HI injury.

  16. Caffeine reduces dipyridamole-induced myocardial ischemia

    SciTech Connect

    Smits, P.; Aengevaeren, W.R.; Corstens, F.H.; Thien, T. )

    1989-10-01

    The mechanism of action of coronary vasodilation after dipyridamole may be based on inhibition of cellular uptake of circulating endogenous adenosine. Since caffeine has been reported to be a competitive antagonist of adenosine we studied the effect of caffeine on the outcome of dipiridamole-{sup 201}Tl cardiac imaging in one patient. During caffeine abstinence dipyridamole induced myocardial ischemia with down-slope ST depressions on the ECG, and reversible perfusion defects on the scintigrams. When the test was repeated 1 wk later on similar conditions, but now shortly after infusion of caffeine (4 mg/kg), the ECG showed nodepressions, and the scintigrams only slight signs of ischemia. We conclude that when caffeine abstinence is not sufficient, the widespread use of coffee and related products may be responsible for false-negative findings in dipyridamole-201Tl cardiac imaging.

  17. Exercise-induced hyperemia unmasks regional blood flow deficit in experimental hindlimb ischemia.

    PubMed

    Brevetti, L S; Paek, R; Brady, S E; Hoffman, J I; Sarkar, R; Messina, L M

    2001-06-01

    /min/g after 10D, and 0.13 ml/min/g after 24D. The mean BF rate in normal muscle of unoperated controls was 0.16 ml/min/g (P > 0.05). However, the exercise-induced hyperemia in the skeletal muscle was significantly blunted in all of the ischemic groups. The unoperated control TA had a greater than 10-fold increase in BF to 1.95 ml/min/g in response to exercise while the ischemic TA had no increase in BF at 3D, 2-fold increase at 10D, and a 5-fold increase at 24D. Parallel findings were noted in the GC muscles. There was no significant difference in the BF rate in the skin. The accuracy of this microsphere technique in measuring very low BF rates found in ischemic muscle was supported by the significant correlation coefficient (r = 0.99) comparing two quantities of microspheres injected simultaneously. Despite clinical signs of severe hindlimb ischemia, resting BF rates in the ischemic groups were not significantly decreased. Peroneal nerve stimulation resulted in up to 10-fold increase in BF rate and unmasked a severe deficit in vascular reserve in the ischemic groups. Resting BF rate is not always an accurate reflection of the flow deficit in models of critical limb ischemia, and this model of exercise-induced hindlimb hyperemia may allow better long-term evaluation of angiogenic therapies designed to reverse critical limb ischemia. Copyright 2001 Academic Press.

  18. Urticarial Vasculitis-Associated Intestinal Ischemia

    PubMed Central

    Wong, Uni; Yfantis, Harris; Xie, Guofeng

    2016-01-01

    Urticarial vasculitis (UV) is a rare small vessel vasculitis. UV is often idiopathic but can also present in the context of autoimmune disorders such as systemic lupus erythematosus, drug reactions, infections, or a paraneoplastic syndrome. Extracutaneous complications include intestinal ischemic injuries, in UV patients with nonspecific gastrointestinal symptoms such as abdominal pain and nausea. Prompt recognition and treatment can minimize morbidity and mortality. This paper describes a case of urticarial vasculitis-associated intestinal ischemia. PMID:27190661

  19. Steroid-induced recurrent myocardial ischemia.

    PubMed

    Yildirim, Ufuk; Gulel, Okan; Soylu, Korhan; Yuksel, Serkan; Sahin, Mahmut

    2014-01-01

    We report the case of a female patient under oral prednisolone therapy due to a diagnosis of idiopathic intracranial hypertension with papilledema. Unfortunately, short-term treatment with prednisolone caused an unusual complication in the patient, i.e., recurrent myocardial ischemia. Possible mechanisms leading to this complication were evaluated in the light of current knowledge. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  20. Outcomes after endarterectomy for chronic mesenteric ischemia.

    PubMed

    Mell, Matthew W; Acher, Charles W; Hoch, John R; Tefera, Girma; Turnipseed, William D

    2008-11-01

    A retrospective study was performed to identify optimal factors affecting outcomes after open revascularization for chronic mesenteric ischemia. All patients who underwent open surgery for chronic mesenteric ischemia from 1987 to 2006 were reviewed. Patients with acute mesenteric ischemia or median arcuate ligament syndrome were excluded. Mortality, recurrent stenosis, and symptomatic recurrence were analyzed using logistic regression, and univariate and multivariate analysis. We identified 80 patients (69% women, 31% men). Mean age was 64 years (range, 31-86 years). Acute-on-chronic symptoms were present in 26%. Presenting symptoms included postprandial pain (91%), weight loss (69%), and food fear and diarrhea (25%). Preoperative imaging demonstrated severe (>70%) stenosis of the superior mesenteric artery in 75 patients (24 occluded), the celiac axis in 63 (20 occluded), and the inferior mesenteric artery in 53 (20 occluded). Multivessel disease was present in 72 patients (90%), and 40 (50%) underwent multivessel reconstruction. Revascularization was achieved by endarterectomy in 37 patients, mesenteric bypass in 29, and combined procedures in 14. Concurrent aortic reconstruction was required in 13 patients (16%). Three hospital deaths occurred (3.8%). Mean follow-up was 3.8 years (range, 0-17.2 years). One- and 5-year survival was 92.2% and 64.5%. Mortality was associated with age (P = .019) and renal insufficiency (P = .007), but not by clinical presentation. Symptom-free survival was 89.7% and 82.1% at 1 and 5 years, respectively. Symptoms requiring reintervention occurred in nine patients (11%) at a mean of 29 months (range, 5-127 months). Multivariate analysis showed that freedom from recurrent symptoms correlated with endarterectomy for revascularization (5.2% vs 27.6%; hazard ratio, 0.20; 95% confidence interval, 0.04-0.92; P = .02). For open surgical candidates, endarterectomy appears to provide the most durable long-term symptom relief in patients with

  1. In Vivo Ischemia Detection by Luminescent Nanothermometers.

    PubMed

    Ximendes, Erving Clayton; Rocha, Uéslen; Del Rosal, Blanca; Vaquero, Alberto; Sanz-Rodríguez, Francisco; Monge, Luis; Ren, Fuqiang; Vetrone, Fiorenzo; Ma, Dongling; García-Solé, José; Jacinto, Carlos; Jaque, Daniel; Fernández, Nuria

    2017-02-01

    There is an urgent need to develop new diagnosis tools for real in vivo detection of first stages of ischemia for the early treatment of cardiovascular diseases and accidents. However, traditional approaches show low sensitivity and a limited penetration into tissues, so they are only applicable for the detection of surface lesions. Here, it is shown how the superior thermal sensing capabilities of near infrared-emitting quantum dots (NIR-QDs) can be efficiently used for in vivo detection of subcutaneous ischemic tissues. In particular, NIR-QDs make possible ischemia detection by high penetration transient thermometry studies in a murine ischemic hindlimb model. NIR-QDs nanothermometers are able to identify ischemic tissues by means of their faster thermal dynamics. In addition, they have shown to be capable of monitoring both the revascularization and damage recovery processes of ischemic tissues. This work demonstrates the applicability of fluorescence nanothermometry for ischemia detection and treatment, as well as a tool for early diagnosis of cardiovascular disease.

  2. Breath hydrogen reflects canine intestinal ischemia.

    PubMed

    Perman, J A; Waters, L A; Harrison, M R; Yee, E S; Heldt, G P

    1981-09-01

    The relationship between breath hydrogen excretion and intestinal ischemia was investigated in nine mechanically ventilated dogs under pentobarbital anesthesia. An ileal segment was isolated in situ, ligated at each end, and insufflated with hydrogen. Expired air was collected at intervals. Blood volume was reduced 30% by three successive equivalent hemorrhages 10 min apart. Local bowel ischemia was produced by clamping the blood supply to the isolated segment for 10 min. Graded hemorrhage produced step-wise reductions in breath hydrogen concentration, to 77 +/- 13, 66 +/- 15, and 35 +/- 8% (mean +/- S.E.) of baseline after the first, second, and third hemorrhages, respectively. These reductions correlated highly (r = 0.84; P less than 0.01) with declines in mean aortic blood pressure. Occlusion of blood supply caused a significant (P less than 0.025) decrease in breath hydrogen concentration and excretion to 39 +/- 14% of baseline. Termination of occlusion was followed within 2 min by a 7-fold increase in breath H2 concentration above the original baseline, probably reflecting reactive hyperemia. Breath hydrogen measurements appear to reflect functional (hemorrhagic shock-induced) and mechanical (vascular occlusion induced) enteric ischemia in dogs.

  3. 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

  4. Isoflurane administration before ischemia and during reperfusion attenuates ischemia/reperfusion-induced injury of isolated rabbit lungs.

    PubMed

    Liu, R; Ishibe, Y; Ueda, M; Hang, Y

    1999-09-01

    To investigate the effects of isoflurane on ischemia/ reperfusion (IR)-induced lung injury, we administered isoflurane before ischemia or during reperfusion. Isolated rabbit lungs were divided into the following groups: control (n = 6), perfused and ventilated for 120 min without ischemia; ISO-control (n = 6), 1 minimum alveolar anesthetic concentration (MAC) isoflurane was administered for 30 min before 120 min continuous perfusion; IR (n = 6), ischemia for 60 min, followed by 60 min reperfusion; IR-ISO1 and IR-ISO2, ischemia followed by reperfusion and 1 MAC (n = 6) or 2 MAC (n = 6) isoflurane for 60 min; ISO-IR (n = 6), 1 MAC isoflurane was administered for 30 min before ischemia, followed by IR. During these maneuvers, we measured total pulmonary vascular resistance (Rt), coefficient of filtration (Kfc), and lung wet to dry ratio (W/D). The results indicated that administration of isoflurane during reperfusion inhibited an IR-induced increase in Kfc and W/D ratio. Furthermore, isoflurane at 2 MAC, but not 1 MAC, significantly inhibited an IR-induced increase in Rt. The administration of isoflurane before ischemia significantly attenuated the increase in IR-induced Kfc, W/D, and Rt. Our results suggest that the administration of isoflurane before ischemia and during reperfusion protects against ischemia-reperfusion-induced injury in isolated rabbit lungs.

  5. CT perfusion during delayed cerebral ischemia after subarachnoid hemorrhage: distinction between reversible ischemia and ischemia progressing to infarction.

    PubMed

    Cremers, Charlotte H P; Vos, Pieter C; van der Schaaf, Irene C; Velthuis, Birgitta K; Vergouwen, Mervyn D I; Rinkel, Gabriel J E; Dankbaar, Jan Willem

    2015-09-01

    Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) can be reversible or progress to cerebral infarction. In patients with a deterioration clinically diagnosed as DCI, we investigated whether CT perfusion (CTP) can distinguish between reversible ischemia and ischemia progressing to cerebral infarction. From a prospectively collected series of aSAH patients, we included those with DCI, CTP on the day of clinical deterioration, and follow-up imaging. In qualitative CTP analyses (visual assessment), we calculated positive and negative predictive value (PPV and NPV) with 95% confidence intervals (95%CI) of a perfusion deficit for infarction on follow-up imaging. In quantitative analyses, we compared perfusion values of the least perfused brain tissue between patients with and without infarction by using receiver-operator characteristic curves and calculated a threshold value with PPV and NPV for the perfusion parameter with the highest area under the curve. In qualitative analyses of 33 included patients, 15 of 17 patients (88%) with and 6 of 16 patients (38%) without infarction on follow-up imaging had a perfusion deficit during clinical deterioration (p = 0.002). Presence of a perfusion deficit had a PPV of 71% (95%CI: 48-89%) and NPV of 83% (95%CI: 52-98%) for infarction on follow-up. Quantitative analyses showed that an absolute minimal cerebral blood flow (CBF) threshold of 17.7 mL/100 g/min had a PPV of 63% (95%CI: 41-81%) and a NPV of 78% (95%CI: 40-97%) for infarction. CTP may differ between patients with DCI who develop infarction and those who do not. For this purpose, qualitative evaluation may perform marginally better than quantitative evaluation.

  6. Factors influencing outcome following limb-threatening lower limb trauma: lessons learned from the Lower Extremity Assessment Project (LEAP).

    PubMed

    MacKenzie, Ellen J; Bosse, Michael J

    2006-01-01

    The Lower Extremity Assessment Project (LEAP) is a multicenter study of severe lower extremity trauma in the US civilian population. At 2- and 7-year follow-ups, the LEAP study found no difference in functional outcome between patients who underwent either limb salvage surgery or amputation. However, outcomes on average were poor for both groups. This study and others provide evidence of wide-ranging variations in outcome following major limb trauma, with a substantial proportion of patients experiencing long-term disability. In addition, outcomes often are more affected by the patient's economic, social, and personal resources than by the initial treatment of the injury--specifically, amputation or reconstruction and level of amputation. A conceptual framework for examining outcomes after injury may be used to identify opportunities for interventions that would improve outcomes. Because of essential differences between the civilian and military populations, the findings of the LEAP study may correlate only roughly with combat casualty outcomes.

  7. Mesenteric ischemia: the importance of differential diagnosis for the surgeon.

    PubMed

    Reginelli, Alfonso; Iacobellis, Francesca; Berritto, Daniela; Gagliardi, Giuliano; Di Grezia, Graziella; Rossi, Michele; Fonio, Paolo; Grassi, Roberto

    2013-01-01

    Intestinal ischemia is an abdominal emergency that accounts for approximately 2% of gastrointestinal illnesses. It represents a complex of diseases caused by impaired blood perfusion to the small and/or large bowel including acute arterial mesenteric ischemia (AAMI), acute venous mesenteric ischemia (AVMI), non occlusive mesenteric ischemia (NOMI), ischemia/reperfusion injury (I/R), ischemic colitis (IC). In this study different study methods (US, CT) will be correlated in the detection of mesenteric ischemia imaging findings due to various etiologies. Basing on our institutions experience, 163 cases of mesenteric ischemia/infarction from various cases, investigated with CT and undergone surgical treatment were retrospectively evaluated, in particular trought the following findings: presence/absence of arterial/venous obstruction, bowel wall thickness and enhancement, presence/absence of spastic reflex ileus, hypotonic reflex ileus or paralitic ileus, mural and/or portal/mesenteric pneumatosis, abdominal free fluid, parenchymal ischemia/infarction (liver, kidney, spleen). To make an early diagnosis useful to ensure a correct therapeutic approach, it is very important to differentiate between occlusive (arterial, venous) and non occlusive causes (NOMI). The typical findings of each forms of mesenteric ischemia are explained in the text. The radiological findings of mesenteric ischemia have different course in case of different etiology. In venous etiology the progression of damage results faster than arterial even if the symptomatology is less acute; bowel wall thickening is an early finding and easy to detect, simplifying the diagnosis. In arterial etiology the damage progression is slower than in venous ischemia, bowel wall thinning is typical but difficult to recognize so diagnosis may be hard. In the NOMI before/without reperfusion the ischemic damage is similar to AAMI with additional involvement of large bowel parenchymatous organs. In reperfusion after NOMI

  8. Cerebral ischemia produces laddered DNA fragments distinct from cardiac ischemia and archetypal apoptosis.

    PubMed

    MacManus, J P; Fliss, H; Preston, E; Rasquinha, I; Tuor, U

    1999-05-01

    The electrophoretic pattern of laddered DNA fragments which has been observed after cerebral ischemia is considered to indicate that neurons are dying by apoptosis. Herein the authors directly demonstrate using ligation-mediated polymerase chain reaction methods that 99% of the DNA fragments produced after either global or focal ischemia in adult rats, or produced after hypoxia-ischemia in neonatal rats, have staggered ends with a 3' recess of approximately 8 to 10 nucleotides. This is in contrast to archetypal apoptosis in which the DNA fragments are blunt ended as seen during developmental programmed cell death in dying cortical neurons, neuroblastoma, or thymic lymphocytes. It is not simply ischemia that results in staggered ends in DNA fragments because ischemic myocardium is similar to archetypal apoptosis with a vast majority of blunt-ended fragments. It is concluded that the endonucleases that produce this staggered fragmentation of the DNA backbone in ischemic brain must be different than those of classic or type I apoptosis.

  9. DAP12 expression in lung macrophages mediates ischemia reperfusion injury by promoting neutrophil extravasation

    PubMed Central

    Spahn, Jessica H.; Li, Wenjun; Bribriesco, Alejandro C.; Liu, Jie; Shen, Hua; Ibricevic, Aida; Pan, Jiehong; Zinselmeyer, Bernd H.; Brody, Steven L.; Goldstein, Daniel R.; Krupnick, Alexander S.; Gelman, Andrew E.; Miller, Mark J.; Kreisel, Daniel

    2015-01-01

    Neutrophils are critical mediators of innate immune responses and contribute to tissue injury. However, immune pathways that regulate neutrophil recruitment to injured tissues during noninfectious inflammation remain poorly understood. DAP12 is a cell-membrane associated protein that is expressed in myeloid cells and can either augment or dampen innate inflammatory responses during infections. To elucidate the role of DAP12 in pulmonary ischemia-reperfusion injury, we took advantage of a clinically relevant mouse model of transplant-mediated lung ischemia reperfusion injury. This technique allowed us to dissect the importance of DAP12 in tissue-resident cells and those that infiltrate injured tissue from the periphery during noninfectious inflammation. Macrophages in both mouse and human lungs that have been subjected to cold ischemic storage express DAP12. We found that donor, but not recipient deficiency in DAP12 protected against pulmonary ischemia reperfusion injury. Analysis of the immune response showed that DAP12 promotes the survival of tissue-resident alveolar macrophages and contributes to local production of neutrophil chemoattractants. Intravital imaging demonstrated a transendothelial migration defect into DAP12-deficient lungs, which can be rescued by local administration of the neutrophil chemokine CXCL2. We have uncovered a previously unrecognized role for DAP12 expression in tissue-resident alveolar macrophages in mediating acute noninfectious tissue injury through regulation of neutrophil trafficking. PMID:25762783

  10. Targeted photocoagulation of peripheral ischemia to treat rebound edema.

    PubMed

    Singer, Michael A; Tan, Colin S; Surapaneni, Krishna R; Sadda, Srinivas R

    2015-01-01

    Peripheral retinal ischemia not detectable by conventional fluorescein angiography has been proposed to be a driving force for rebound edema in retinal vein occlusions. In this report, we examine the treatment of peripheral retinal ischemia with targeted retinal photocoagulation (TRP) to manage a patient's rebound edema. To assess the extent of peripheral nonperfusion, an Optos 200Tx device was used. To target the treatment to peripheral ischemia areas, a Navilas Panretinal Laser was used. A 64-year-old male with a central retinal vein occlusion and a visual acuity 20/300, and central macular thickness 318 μm presented with rubeosis. Angiography revealed extensive peripheral nonperfusion. Despite TRP to areas of irreversible ischemia, after 2 months, he continued show rubeosis and rebound edema. Additional TRP laser was repeatedly added more posteriorly to areas of reversible nonperfusion, resulting in eventual resolution of rubeosis and edema. In this study, we demonstrate the use of widefield imaging with targeted photo-coagulation of peripheral ischemia to treat rebound edema, while preserving most peripheral vision. In order to treat rebound edema, extensive TRP, across reversible and nonreversible areas of ischemia, had to be performed - not just in areas of nonreversible peripheral ischemia. These areas need to be mapped during episodes of rebound edema, when ischemia is at its maximum. In this way, by doing the most TRP possible, the cycle of rebound edema can be broken.

  11. Glibenclamide in cerebral ischemia and stroke.

    PubMed

    Simard, J Marc; Sheth, Kevin N; Kimberly, W Taylor; Stern, Barney J; del Zoppo, Gregory J; Jacobson, Sven; Gerzanich, Volodymyr

    2014-04-01

    The sulfonylurea receptor 1 (Sur1)-transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and "accidental necrotic cell death." Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1-2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.

  12. Anterior Segment Ischemia after Strabismus Surgery

    PubMed Central

    Göçmen, Emine Seyhan; Atalay, Yonca; Evren Kemer, Özlem; Sarıkatipoğlu, Hikmet Yavuz

    2017-01-01

    A 46-year-old male patient was referred to our clinic with complaints of diplopia and esotropia in his right eye that developed after a car accident. The patient had right esotropia in primary position and abduction of the right eye was totally limited. Primary deviation was over 40 prism diopters at near and distance. The patient was diagnosed with sixth nerve palsy and 18 months after trauma, he underwent right medial rectus muscle recession. Ten months after the first operation, full-thickness tendon transposition of the superior and inferior rectus muscles (with Foster suture) was performed. On the first postoperative day, slit-lamp examination revealed corneal edema, 3+ cells in the anterior chamber and an irregular pupil. According to these findings, the diagnosis was anterior segment ischemia. Treatment with 0.1/5 mL topical dexamethasone drops (16 times/day), cyclopentolate hydrochloride drops (3 times/day) and 20 mg oral fluocortolone (3 times/day) was initiated. After 1 week of treatment, corneal edema regressed and the anterior chamber was clean. Topical and systemic steroid treatment was gradually discontinued. At postoperative 1 month, the patient was orthophoric and there were no pathologic symptoms besides the irregular pupil. Anterior segment ischemia is one of the most serious complications of strabismus surgery. Despite the fact that in most cases the only remaining sequel is an irregular pupil, serious circulation deficits could lead to phthisis bulbi. Clinical properties of anterior segment ischemia should be well recognized and in especially risky cases, preventative measures should be taken. PMID:28182149

  13. Casein Kinase 1 Suppresses Activation of REST in Insulted Hippocampal Neurons and Halts Ischemia-Induced Neuronal Death

    PubMed Central

    Kaneko, Naoki; Hwang, Jee-Yeon; Gertner, Michael; Pontarelli, Fabrizio

    2014-01-01

    Repressor Element-1 (RE1) Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF) is a gene-silencing factor that is widely expressed during embryogenesis and plays a strategic role in neuronal differentiation. Recent studies indicate that REST can be activated in differentiated neurons during a critical window of time in postnatal development and in adult neurons in response to neuronal insults such as seizures and ischemia. However, the mechanism by which REST is regulated in neurons is as yet unknown. Here, we show that REST is controlled at the level of protein stability via β-TrCP-dependent, ubiquitin-based proteasomal degradation in differentiated neurons under physiological conditions and identify Casein Kinase 1 (CK1) as an upstream effector that bidirectionally regulates REST cellular abundance. CK1 associates with and phosphorylates REST at two neighboring, but distinct, motifs within the C terminus of REST critical for binding of β-TrCP and targeting of REST for proteasomal degradation. We further show that global ischemia in rats in vivo triggers a decrease in CK1 and an increase in REST in selectively vulnerable hippocampal CA1 neurons. Administration of the CK1 activator pyrvinium pamoate by in vivo injection immediately after ischemia restores CK1 activity, suppresses REST expression, and rescues neurons destined to die. Our results identify a novel and previously unappreciated role for CK1 as a brake on REST stability and abundance in adult neurons and reveal that loss of CK1 is causally related to ischemia-induced neuronal death. These findings point to CK1 as a potential therapeutic target for the amelioration of hippocampal injury and cognitive deficits associated with global ischemia. PMID:24760862

  14. Maturation Phenomenon in Cerebral Ischemia IV

    DTIC Science & Technology

    2001-01-01

    of gonads and/or neurons. This study evaluated the existence of age-related changes in transcriptional expression of HSC70, HSP72 , and c-fos mRNA...young animals compared with that in adult animals showed: (1) more rapid and /or prolonged expression of HSC70, HSP72 , and c-fos mRNAs; (2) a marked...induction of HSP72 protein; and (3) enhanced pyramidal cell survival. The observed endogenous ’tolerance’ of CA1 neurons in young gerbils to ischemia/reperfusion injury may be related to the expression of HSC70, HSP72 and c-fos.

  15. Acute bowel ischemia after heart operations.

    PubMed

    Lorusso, Roberto; Mariscalco, Giovanni; Vizzardi, Enrico; Bonadei, Ivano; Renzulli, Attilio; Gelsomino, Sandro

    2014-06-01

    Acute bowel ischemia is a perioperative complication that is frequently unrecognized as a cause of death after cardiac surgical procedures, with an in-hospital mortality of 50% to 100%. In recent years, controversy regarding the most appropriate approach to resolve clinical or laboratory suspicion and the limited therapeutic options have led to very little improvement in patient prognosis. This article reviews the related literature examining the actual prevalence, pathophysiologic mechanisms, predisposing factors, diagnostic tests, and therapeutic approaches providing a glance at new promising tools in diagnostic workup. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

  16. Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia.

    PubMed

    Braithwaite, Steven P; Xu, Jian; Leung, John; Urfer, Roman; Nikolich, Karoly; Oksenberg, Donna; Lombroso, Paul J; Shamloo, Mehrdad

    2008-05-01

    Striatal enriched protein tyrosine phosphatase (STEP) acts in the central nervous system to dephosphorylate a number of important proteins involved in synaptic function including ERK and NMDA receptor subunits. These proteins are also linked to stroke, in which cerebral ischemia triggers a complex cascade of events. Here we demonstrate that STEP is regulated at both the transcriptional and the post-transcriptional levels in rat models of cerebral ischemia and that its regulation may play a role in the outcome of ischemic insults. After transient middle cerebral artery occlusion, there are profound decreases in the levels of STEP mRNA, whilst in global ischemia STEP mRNA is selectively down-regulated in areas susceptible to ischemic damage. In a neuroprotective preconditioning paradigm, and in regions of the brain that are relatively resistant to ischemic damage, STEP mRNA levels are increased. Furthermore, there is a significant processing of STEP after ischemia to generate a novel species, STEP(33), resulting in a redistribution of STEP from membrane-bound to soluble compartments. Concomitant with the cleavage of mature forms of STEP, there are changes in the phosphorylation state of ERK. We show that the cleavage of STEP leads to a catalytically active form, but this cleaved form no longer binds to and dephosphorylates its substrate pERK. Therefore, in response to ischemic insults, there are profound reductions in both the amount and the activity of STEP, its localization, as well as the activity of one of its key substrates, pERK. These changes in STEP may reflect a critical role in the outcomes of ischemic brain injury.

  17. Prolonged ischemia elicits acute allograft rejection involved in CXCR3 activation in rat kidney transplants.

    PubMed

    Zou, Xun-feng; Song, Bin; Duan, Ji-hui; Hu, Zhan-dong; Cui, Zi-lin; Gu, Chuan

    2015-10-01

    Acute rejection is a major obstacle in patients with prolonged ischemia in deceased-donor renal transplantation. Chemokines and their receptors play a critical role in leukocyte trafficking, resulting in allograft rejection; therefore, the role of chemokine receptor CXCR3 in acute rejection induced by prolonged ischemia in rat kidney transplantation models was evaluated. Syngeneic and allogeneic renal transplantations were performed. For cold ischemia, grafts were stored in 4.0°C University of Wisconsin solution for 12 or 16 h. Serum and renal tissues were harvested 7.0 d after surgery and serum TNF-α, IL-6, and renal function were measured. Graft histology was stained with periodic acid-Schiff and immunohistochemical staining and further evaluated for signs of acute rejection. CXCR3 proteins were quantified by Western blot. The transplanted rats were divided into 4 groups as follows: iso-12-h = isogeneic transplant with 12-h CIT graft; iso-16-h = isogeneic kidney transplant with 16-h CIT graft; allo-12-h = allogeneic renal transplant with 12-h CIT graft; allo-16 h = allogeneic renal transplant with 16-h CIT graft; and 16 h+T = allogeneic 16-h CIT graft received tacrolimus. Prolonged cold ischemia time (CIT; 16 h) enhanced acute glomerular damage, interstitial inflammation, and tubulointerstitial cellular infiltration in allografts with and without immunosuppressant tacrolimus; but it was not apparent in the isografts. The expression of CXCR3 protein and the proportion of CXCR3-positive cells were significantly higher in the allo-16 h and 16 h +T groups than that in the allo-12 h group 7d post-surgery. CIT triggered acute rejection in allogeneic, but not in isogeneic, kidney transplants, accompanied by an elevation of leukocyte recruitment and damaged graft function. The upregulated expression of chemokine receptor CXCR3 promoted inflammatory infiltration and acute allograft rejection. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. Ischemia reperfusion injury, ischemic conditioning and diabetes mellitus.

    PubMed

    Lejay, Anne; Fang, Fei; John, Rohan; Van, Julie A D; Barr, Meredith; Thaveau, Fabien; Chakfe, Nabil; Geny, Bernard; Scholey, James W

    2016-02-01

    Ischemia/reperfusion, which is characterized by deficient oxygen supply and subsequent restoration of blood flow, can cause irreversible damages to tissue. Mechanisms contributing to the pathogenesis of ischemia reperfusion injury are complex, multifactorial and highly integrated. Extensive research has focused on increasing organ tolerance to ischemia reperfusion injury, especially through the use of ischemic conditioning strategies. Of morbidities that potentially compromise the protective mechanisms of the heart, diabetes mellitus appears primarily important to study. Diabetes mellitus increases myocardial susceptibility to ischemia reperfusion injury and also modifies myocardial responses to ischemic conditioning strategies by disruption of intracellular signaling responsible for enhancement of resistance to cell death. The purpose of this review is twofold: first, to summarize mechanisms underlying ischemia reperfusion injury and the signal transduction pathways underlying ischemic conditioning cardioprotection; and second, to focus on diabetes mellitus and mechanisms that may be responsible for the lack of effect of ischemic conditioning strategies in diabetes.

  19. Altered Calcium Handling and Ventricular Arrhythmias in Acute Ischemia

    PubMed Central

    Baumeister, Peter; Quinn, T. Alexander

    2016-01-01

    Acute ischemia results in deadly cardiac arrhythmias that are a major contributor to sudden cardiac death (SCD). The electrophysiological changes involved have been extensively studied, yet the mechanisms of ventricular arrhythmias during acute ischemia remain unclear. What is known is that during acute ischemia both focal (ectopic excitation) and nonfocal (reentry) arrhythmias occur, due to an interaction of altered electrical, mechanical, and biochemical properties of the myocardium. There is particular interest in the role that alterations in intracellular calcium handling, which cause changes in intracellular calcium concentration and to the calcium transient, play in ischemia-induced arrhythmias. In this review, we briefly summarize the known contributors to ventricular arrhythmias during acute ischemia, followed by an in-depth examination of the potential contribution of altered intracellular calcium handling, which may include novel targets for antiarrhythmic therapy. PMID:28008297

  20. Enhanced fibrinolysis protects against lung ischemia-reperfusion injury.

    PubMed

    Lau, Christine L; Zhao, Yunge; Kim, Jiyoun; Kron, Irving L; Sharma, Ashish; Yang, Zequan; Laubach, Victor E; Linden, Joel; Ailawadi, Gorav; Pinsky, David J

    2009-05-01

    Ischemia-reperfusion injury continues to plague the field of lung transplantation, resulting in suboptimal outcomes. In acute lung injury, processes such as ventilator-induced injury, sepsis, or acute respiratory distress syndrome, extravascular fibrin has been shown to promote lung dysfunction and the acute inflammatory response. This study investigates the role of the fibrinolytic cascade in lung ischemia-reperfusion injury and investigates the interplay between the fibrinolytic system and the inflammatory response. Mice lacking the plasminogen activator inhibitor-1 gene (PAI-1 knock out, PAI-1 KO; and thus increased lysis of endogenous fibrin) and wild-type mice underwent in situ left lung ischemia and reperfusion. Fibrin content in the lung was evaluated by immunoblotting. Reperfusion injury was assessed by histologic and physiologic parameters. Proinflammatory mediators were measured in bronchoalveolar lavage fluid and plasma using enzyme-linked immunosorbent assays. Ischemia-reperfusion causes fibrin deposition in murine lungs. Less fibrin was seen in PAI-1 KO mice than in wild-type mice subjected to the same ischemia-reperfusion conditions. By histologic criteria, more evidence of ischemia-reperfusion injury was noted (thickening of the interstium, cellular infiltration in the alveoli) in the wild-type than in PAI-1 KO mice. Physiologic parameters also revealed more ischemia-reperfusion injury in the wild-type than in PAI-1 KO mice. Cytokine and chemokines were elevated more in the wild-type group than the PAI-1 KO group. Lung ischemia-reperfusion injury triggers fibrin deposition in the murine lungs and fibrin creates a proinflammatory environment. Preventing fibrin deposition may reduce ischemia-reperfusion injury and inflammation. This finding may lead to novel treatment strategies for ischemia-reperfusion.

  1. Effect of ischemia preconditioning and leech therapy on cutaneous pedicle flaps subjected to prolonged ischemia in a mouse model.

    PubMed

    Moosavian, Hamid Reza; Mirghazanfari, Sayid Mahdi; Moghaddam, Katayoun Gohari

    2014-10-01

    We sought to determine the effect of ischemic preconditioning (IPC) and hirudotherapy (leech therapy) on cutaneous pedicle flaps after they underwent prolonged ischemia (global ischemia) in a mouse model. Twenty cutaneous pedicle flaps were elevated in 20 mice, and the animals were randomized into four groups: sham, control, IPC and leech (5 flaps in each group). Except in the sham group, all flaps were subjected to global ischemia for 5 h via pedicle clamping. The control group did not receive any treatment before or after global ischemia. In the IPC group, global ischemia was preceded by three 10-min episodes of ischemia, each followed by 10 min of reperfusion. In the leech therapy group, after global ischemia, hirudotherapy was performed. Flap survival area and histopathological changes were evaluated on the 10th day after surgery. Flap survival areas were significantly higher in both the IPC and leech groups than in the control group and were significantly higher in the leech group than in the IPC group (p < 0.05). In conclusion IPC and hirudotherapy had definite effects on the survival area of cutaneous pedicle flaps that underwent prolonged ischemia in a mouse model.

  2. Vascular adhesion protein-1 enhances neutrophil infiltration by generation of hydrogen peroxide in renal ischemia/reperfusion injury.

    PubMed

    Tanaka, Shinji; Tanaka, Tetsuhiro; Kawakami, Takahisa; Takano, Hideki; Sugahara, Mai; Saito, Hisako; Higashijima, Yoshiki; Yamaguchi, Junna; Inagi, Reiko; Nangaku, Masaomi

    2017-07-01

    Vascular adhesion protein-1 (VAP-1) is a unique molecule since it acts as an adhesion molecule as well as an ectoenzyme catalyzing oxidative deamination of primary amines and generates hydrogen peroxide in the extracellular space. While VAP-1 is implicated in various inflammatory diseases, its role in acute kidney injury is less characterized. Here we studied VAP-1 expression in the kidney and the effect of its inhibition in a rat model of renal ischemia/reperfusion injury. VAP-1 was predominantly expressed in pericytes, which released enzymatically active enzyme. In vivo, a specific VAP-1 inhibitor, RTU-1096, significantly ameliorated rat renal ischemia/reperfusion injury and decreased neutrophil infiltration measured 12 hours after injury without altering macrophage or T lymphocyte populations. The protective effect of VAP-1 inhibition was lost in neutrophil-depleted rats, suggesting its inhibition ameliorated renal ischemia/reperfusion injury by suppressing neutrophil infiltration. To investigate whether hydrogen peroxide generated by VAP-1 enzyme reaction enhances neutrophil infiltration, we conducted an under-agarose migration assay with purified human neutrophils. Recombinant human VAP-1 significantly induced neutrophil migration, which was almost completely inhibited by RTU-1096 or catalase. Thus, VAP-1 plays a critical role in the pathophysiology of renal ischemia/reperfusion injury by enhancement of neutrophil infiltration generating a local hydrogen peroxide gradient. Hence, VAP-1 inhibition may be a novel therapy in ischemic acute kidney injury. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  3. Procaspase-9 induces its cleavage by transnitrosylating XIAP via the Thioredoxin system during cerebral ischemia-reperfusion in rats

    PubMed Central

    Zhang, Dengyue; Zhao, Ningjun; Ma, Bin; Wang, Yan; Zhang, Gongliang; Yan, Xianliang; Hu, Shuqun; Xu, Tie

    2016-01-01

    Transnitrosylation is an important mechanism by which nitric oxide (NO) modulates cell signaling pathways. For instance, SNO-caspase-3 can transnitrosylate the X-linked inhibitor of apoptosis (XIAP) to enhance apoptosis. XIAP is a potent antagonist of caspase apoptotic activity. Decrease in XIAP activity via nitrosylation results in SNO-XIAP-mediated caspase activation. Considering the functional liaison of procaspase-9 and XIAP, we hypothesized that procaspase-9 nitrosylates XIAP directly. Our data confirmed that cerebral ischemia-reperfusion induced XIAP nitrosylation, procaspase-9 denitrosylation and cleavage. Interestingly, the time courses of the nitrosylation of procaspase-9 and XIAP were negatively correlated, which was more prominent after cerebral ischemia-reperfusion, suggesting a direct interaction. The nitrosylation of XIAP, as well as the denitrosylation and cleavage of procaspase-9, were inhibited by DNCB, TrxR1 AS-ODNs, or TAT-AVPY treatment. Meanwhile, DNCB, TrxR1 AS-ODNs, or TAT-AVPY also inhibited the decrease in hippocampal CA1 neurons induced by ischemia-reperfusion in rats. The denitrosylation and cleavage of procaspase-9 induced by OGD/reoxygenation in SH-SY5Y cells were inhibited when cells were co-transfected with wild-type procaspase-9 and XIAP mutant (C449G). These data suggest that cerebral ischemia-reperfusion induces a transnitrosylation from procaspase-9 to XIAP via the Trx system to consequently cause apoptosis. Additionally, Cys325 is a critical S-nitrosylation site of procaspase-9. PMID:27052476

  4. The E-Selectin Ligand Basigin/CD147 Is Responsible for Neutrophil Recruitment in Renal Ischemia/Reperfusion

    PubMed Central

    Kato, Noritoshi; Yuzawa, Yukio; Kosugi, Tomoki; Hobo, Akinori; Sato, Waichi; Miwa, Yuko; Sakamoto, Kazuma; Matsuo, Seiichi; Kadomatsu, Kenji

    2009-01-01

    E-selectin and its ligands are essential for extravasation of leukocytes in inflammation. Here, we report that basigin (Bsg)/CD147 is a ligand for E-selectin that promotes renal inflammation in ischemia/reperfusion. Compared with wild-type mice, Bsg-deficient (Bsg−/−) mice demonstrated striking suppression of neutrophil infiltration in the kidney after renal ischemia/reperfusion. Although E-selectin expression increased similarly between the two genotypes, Bsg−/− mice exhibited less renal damage, suggesting that Bsg on neutrophils contribute to renal injury in this model. Neutrophils expressed Bsg with N-linked polylactosamine chains and Bsg−/− neutrophils showed reduced binding to E-selectin. Bsg isolated from HL-60 cells bound to E-selectin, and tunicamycin treatment to abolish N-linked glycans from Bsg abrogated this binding. Furthermore, Bsg−/− neutrophils exhibited reduced E-selectin-dependent adherence to human umbilical vein endothelial cells in vitro. Injection of labeled neutrophils into mice showed that Bsg−/− neutrophils were less readily recruited to the kidney after renal ischemia/reperfusion than Bsg+/+ neutrophils, regardless of the recipient's genotype. Taken together, these results indicate that Bsg is a physiologic ligand for E-selectin that plays a critical role in the renal damage induced by ischemia/reperfusion. PMID:19443639

  5. Effects of carbon monoxide on myocardial ischemia

    SciTech Connect

    Allred, E.N.; Pagano, M. ); Bleecker, E.R.; Walden, S.M. ); Chaitman, B.R.; Dahms, T.E. ); Hackney, J.D.; Selvester, R.H. ); Warren, J. ); Gottlieb, S.O.

    1991-02-01

    The purpose of this study was to determine whether low doses of carbon monoxide (CO) exacerbate myocardial ischemia during a progressive exercise test. The effect of CO exposure was evaluated using the objective measure of time to development of electrocardiographic changes indicative of ischemia and the subjective measure of time to onset of angina. Sixty-three male subjects (41-75 years) with well-documented coronary artery disease, who had exertional angina pectoris and ischemic ST-segment changes in their electrocardiograms, were studied. Results from three randomized, double-blind test visits (room air, low and high CO) were compared. The effect of CO exposure was determined from the percent difference in the end points obtained on exercise tests performed before and after a 1-hr exposure to room air or CO. A significant dose-response relationship was found for the individual differences in the time to ST end point and angina for the pre-versus postexposure exercise test at the three carboxyhemoglobin levels. These findings demonstrate that low doses of CO produce significant effects on cardiac function during exercise in subjects with coronary artery disease.

  6. Autophagy and Liver Ischemia-Reperfusion Injury

    PubMed Central

    2015-01-01

    Liver ischemia-reperfusion (I-R) injury occurs during liver resection, liver transplantation, and hemorrhagic shock. The main mode of liver cell death after warm and/or cold liver I-R is necrosis, but other modes of cell death, as apoptosis and autophagy, are also involved. Autophagy is an intracellular self-digesting pathway responsible for removal of long-lived proteins, damaged organelles, and malformed proteins during biosynthesis by lysosomes. Autophagy is found in normal and diseased liver. Although depending on the type of ischemia, warm and/or cold, the dynamic process of liver I-R results mainly in adenosine triphosphate depletion and in production of reactive oxygen species (ROS), leads to both, a local ischemic insult and an acute inflammatory-mediated reperfusion injury, and results finally in cell death. This process can induce liver dysfunction and can increase patient morbidity and mortality after liver surgery and hemorrhagic shock. Whether autophagy protects from or promotes liver injury following warm and/or cold I-R remains to be elucidated. The present review aims to summarize the current knowledge in liver I-R injury focusing on both the beneficial and the detrimental effects of liver autophagy following warm and/or cold liver I-R. PMID:25861623

  7. Focal embolic cerebral ischemia in the rat

    PubMed Central

    Zhang, Li; Zhang, Rui Lan; Jiang, Quan; Ding, Guangliang; Chopp, Michael; Zhang, Zheng Gang

    2015-01-01

    Animal models of focal cerebral ischemia are well accepted for investigating the pathogenesis and potential treatment strategies for human stroke. Occlusion of the middle cerebral artery (MCA) with an endovascular filament is a widely used model to induce focal cerebral ischemia. However, this model is not amenable to thrombolytic therapies. As thrombolysis with recombinant tissue plasminogen activator (rtPA) is a standard of care within 4.5 hours of human stroke onset, suitable animal models that mimic cellular and molecular mechanisms of thrombosis and thrombolysis of stroke are required. By occluding the MCA with a fibrin-rich allogeneic clot, we have developed an embolic model of MCA occlusion in the rat, which recapitulates the key components of thrombotic development and of thrombolytic therapy of rtPA observed from human ischemic stroke. The surgical procedures of our model can be typically completed within approximately 30 min and are highly adaptable to other strains of rats as well as mice for both genders. Thus, this model provides a powerful tool for translational stroke research. PMID:25741989

  8. Worsening of preoperative foot ischemia after occlusion of polytetrafluoroethylene femorotibial grafts: a comparison with saphenous vein grafts.

    PubMed

    Cavallaro, Antonino; Sterpetti, Antonio V; DiMarzo, Luca; Sapienza, Paolo

    2013-07-01

    The aim of this study was to determine the hemodynamic and clinical changes after occlusion of polytetrafluoroethylene (PTFE) femorotibial grafts. Twenty-seven patients were randomly selected from all patients who underwent femorotibial bypass grafting in our department. In 10 patients, the reversed autologous saphenous vein was used as graft, and in 17 patients a PTFE prosthesis was used. Out of the latter 17 patients, 10 began long-term aspirin therapy and 7 began oral anticoagulation with warfarin. Nine out of the 10 patients with occluded PTFE grafts and who received only aspirin therapy had a critical ischemia after occlusion of the graft, and 4 underwent major amputation. Among the 10 patients with occluded autologous vein bypass, critical ischemia was present in only 4 patients, and only 2 required some form of surgical therapy with no case of major amputation. After occlusion of a PTFE femorotibial graft, there is a condition of critical ischemia that is less common after occlusion of a vein graft. Oral anticoagulation seems to prevent these negative changes. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Marked difference in tumor necrosis factor-alpha expression in warm ischemia- and cold ischemia-reperfusion of the rat liver.

    PubMed

    Lutterová, M; Szatmáry, Z; Kukan, M; Kuba, D; Vajdová, K

    2000-12-01

    Although tumor necrosis factor-alpha has been implicated in liver injury after both warm ischemia- and cold ischemia-reperfusion, it is unclear whether reactivity of the liver to these stimuli is similar with regard to cytokine expression. Here we compare the effects of warm and cold ischemia on tumor necrosis factor-alpha expression and test the hypothesis that cold ischemia preceding warm ischemia causes overexpression of this cytokine. Rat livers were flushed out with University of Wisconsin solution and subjected to varying periods of warm ischemia, cold ischemia, or cold ischemia plus warm ischemia followed by reperfusion using a blood-free perfusion model. Tumor necrosis factor-alpha and interleukin-10 release into the perfusate and bile were measured by ELISA, and expression of these cytokines and that of c-fos, c-jun, and c-myc were studied by reverse-transcriptase polymerase chain reaction. We found high levels of tumor necrosis factor-alpha in the perfusates of livers subjected to warm ischemia-reperfusion, whereas minimal or no tumor necrosis factor-alpha was detected in livers subjected to cold ischemia-reperfusion or to cold ischemia plus warm ischemia-reperfusion. Reverse-transcriptase polymerase chain reaction confirmed the above findings and showed that immediate early genes were expressed in reperfused groups of livers. Measurements of cytokine release into bile showed that neither tumor necrosis factor-alpha nor interleukin-10 were upregulated by cold ischemia-reperfusion. The results suggest that (1) warm ischemia- and cold ischemia-reperfusion of rat liver lead to very different outcomes with regard to tumor necrosis factor-alpha expression and (2) cold ischemia preceding warm ischemia prevents upregulation of tumor necrosis factor-alpha. Copyright 2000 Academic Press.

  10. Blue light reduces organ injury from ischemia and reperfusion.

    PubMed

    Yuan, Du; Collage, Richard D; Huang, Hai; Zhang, Xianghong; Kautza, Benjamin C; Lewis, Anthony J; Zuckerbraun, Brian S; Tsung, Allan; Angus, Derek C; Rosengart, Matthew R

    2016-05-10

    Evidence suggests that light and circadian rhythms profoundly influence the physiologic capacity with which an organism responds to stress. However, the ramifications of light spectrum on the course of critical illness remain to be determined. Here, we show that acute exposure to bright blue spectrum light reduces organ injury by comparison with bright red spectrum or ambient white fluorescent light in two murine models of sterile insult: warm liver ischemia/reperfusion (I/R) and unilateral renal I/R. Exposure to bright blue light before I/R reduced hepatocellular injury and necrosis and reduced acute kidney injury and necrosis. In both models, blue light reduced neutrophil influx, as evidenced by reduced myeloperoxidase (MPO) within each organ, and reduced the release of high-mobility group box 1 (HMGB1), a neutrophil chemotactant and key mediator in the pathogenesis of I/R injury. The protective mechanism appeared to involve an optic pathway and was mediated, in part, by a sympathetic (β3 adrenergic) pathway that functioned independent of significant alterations in melatonin or corticosterone concentrations to regulate neutrophil recruitment. These data suggest that modifying the spectrum of light may offer therapeutic utility in sterile forms of cellular injury.

  11. Blue light reduces organ injury from ischemia and reperfusion

    PubMed Central

    Yuan, Du; Collage, Richard D.; Huang, Hai; Zhang, Xianghong; Kautza, Benjamin C.; Lewis, Anthony J.; Zuckerbraun, Brian S.; Tsung, Allan; Angus, Derek C.; Rosengart, Matthew R.

    2016-01-01

    Evidence suggests that light and circadian rhythms profoundly influence the physiologic capacity with which an organism responds to stress. However, the ramifications of light spectrum on the course of critical illness remain to be determined. Here, we show that acute exposure to bright blue spectrum light reduces organ injury by comparison with bright red spectrum or ambient white fluorescent light in two murine models of sterile insult: warm liver ischemia/reperfusion (I/R) and unilateral renal I/R. Exposure to bright blue light before I/R reduced hepatocellular injury and necrosis and reduced acute kidney injury and necrosis. In both models, blue light reduced neutrophil influx, as evidenced by reduced myeloperoxidase (MPO) within each organ, and reduced the release of high-mobility group box 1 (HMGB1), a neutrophil chemotactant and key mediator in the pathogenesis of I/R injury. The protective mechanism appeared to involve an optic pathway and was mediated, in part, by a sympathetic (β3 adrenergic) pathway that functioned independent of significant alterations in melatonin or corticosterone concentrations to regulate neutrophil recruitment. These data suggest that modifying the spectrum of light may offer therapeutic utility in sterile forms of cellular injury. PMID:27114521

  12. Thinking Critically about Critical Thinking

    ERIC Educational Resources Information Center

    Mulnix, Jennifer Wilson

    2012-01-01

    As a philosophy professor, one of my central goals is to teach students to think critically. However, one difficulty with determining whether critical thinking can be taught, or even measured, is that there is widespread disagreement over what critical thinking actually is. Here, I reflect on several conceptions of critical thinking, subjecting…

  13. Thinking Critically about Critical Thinking

    ERIC Educational Resources Information Center

    Mulnix, Jennifer Wilson

    2012-01-01

    As a philosophy professor, one of my central goals is to teach students to think critically. However, one difficulty with determining whether critical thinking can be taught, or even measured, is that there is widespread disagreement over what critical thinking actually is. Here, I reflect on several conceptions of critical thinking, subjecting…

  14. Ischemia/Reperfusion Induces Interferon-Stimulated Gene Expression in Microglia.

    PubMed

    McDonough, Ashley; Lee, Richard V; Noor, Shahani; Lee, Chungeun; Le, Thu; Iorga, Michael; Phillips, Jessica L H; Murphy, Sean; Möller, Thomas; Weinstein, Jonathan R

    2017-08-23

    death in the United States and is a leading cause of serious long-term disability worldwide. Innate immune responses are critical in stroke pathophysiology, and microglia are key cellular effectors in the CNS response to ischemia/reperfusion. Using a transcriptional analysis approach, we identified a robust interferon (IFN)-stimulated gene response within microglia exposed to ischemia/reperfusion in both in vitro and in vivo experimental paradigms. Using a number of complementary techniques, we have demonstrated that these responses are dependent on innate immune signaling components including Toll-like receptor-4 and type I IFNs. We have also elucidated several novel ischemia/reperfusion-induced microglial signaling mechanisms. Copyright © 2017 the authors 0270-6474/17/378292-17$15.00/0.

  15. An Evidence-Based Review of Related Metabolites and Metabolic Network Research on Cerebral Ischemia

    PubMed Central

    Liu, Mengting; Tang, Liying; Liu, Xin; Fang, Jing; Zhan, Hao; Wu, Hongwei; Yang, Hongjun

    2016-01-01

    In recent years, metabolomics analyses have been widely applied to cerebral ischemia research. This paper introduces the latest proceedings of metabolomics research on cerebral ischemia. The main techniques, models, animals, and biomarkers of cerebral ischemia will be discussed. With analysis help from the MBRole website and the KEGG database, the altered metabolites in rat cerebral ischemia were used for metabolic pathway enrichment analyses. Our results identify the main metabolic pathways that are related to cerebral ischemia and further construct a metabolic network. These results will provide useful information for elucidating the pathogenesis of cerebral ischemia, as well as the discovery of cerebral ischemia biomarkers. PMID:27274780

  16. Myocardial ischemia reperfusion injury: from basic science to clinical bedside.

    PubMed

    Frank, Anja; Bonney, Megan; Bonney, Stephanie; Weitzel, Lindsay; Koeppen, Michael; Eckle, Tobias

    2012-09-01

    Myocardial ischemia reperfusion injury contributes to adverse cardiovascular outcomes after myocardial ischemia, cardiac surgery or circulatory arrest. Primarily, no blood flow to the heart causes an imbalance between oxygen demand and supply, named ischemia (from the Greek isch, restriction; and haema, blood), resulting in damage or dysfunction of the cardiac tissue. Instinctively, early and fast restoration of blood flow has been established to be the treatment of choice to prevent further tissue injury. Indeed, the use of thrombolytic therapy or primary percutaneous coronary intervention is the most effective strategy for reducing the size of a myocardial infarct and improving the clinical outcome. Unfortunately, restoring blood flow to the ischemic myocardium, named reperfusion, can also induce injury. This phenomenon was therefore termed myocardial ischemia reperfusion injury. Subsequent studies in animal models of acute myocardial infarction suggest that myocardial ischemia reperfusion injury accounts for up to 50% of the final size of a myocardial infarct. Consequently, many researchers aim to understand the underlying molecular mechanism of myocardial ischemia reperfusion injury to find therapeutic strategies ultimately reducing the final infarct size. Despite the identification of numerous therapeutic strategies at the bench, many of them are just in the process of being translated to bedside. The current review discusses the most striking basic science findings made during the past decades that are currently under clinical evaluation, with the ultimate goal to treat patients who are suffering from myocardial ischemia reperfusion-associated tissue injury.

  17. Myocardial ischemia and ventricular fibrillation: pathophysiology and clinical implications.

    PubMed

    Luqman, Nazar; Sung, Ruey J; Wang, Chun-Li; Kuo, Chi-Tai

    2007-07-31

    Ventricular fibrillation (VF) and myocardial ischemia are inseparable. The first clinical manifestation of myocardial ischemia or infarction may be sudden cardiac death in 20-25% of patients. The occurrence of potentially lethal arrhythmia is the end result of a cascade of pathophysiological abnormalities that result from complex interactions between coronary vascular events, myocardial injury, and changes in autonomic tone, metabolic conditions and ionic state of the myocardium. It is also related to the time from the onset of ischemia. Within the first few minutes there is abundant ventricular arrhythmogenesis usually lasting for 30 min. Triggers for ischemic VF occur at the border zone or regionally ischemic heart. The border zone of ischemia is the predominant site of fragmentation. Acute ischemia opens K(ATP) channels and causes acidosis and hypoxia of myocardial cells leading to a large dispersion in repolarization across the border zone. Abnormalities of intracellular Ca2+ handling also occur in the first few minutes of acute myocardial ischemia and may be an important cause of arrhythmias in human coronary artery disease. Substrate on the other hand transforms triggers into VF and serves to maintain it through fragmentation of waves in the ischemic zone. Thrombin levels, stretch, catecholamine, genetic predisposition, etc. are some of these factors. Reentry models described are spiral wave reentry, 3 dimensional rotors, reentry around 'M' cells and figure-of-eight reentry. Continuing efforts to better understand these arrhythmias will help identify patients of myocardial ischemia prone to arrhythmias.

  18. Quercetin protects rat skeletal muscle from ischemia reperfusion injury.

    PubMed

    Ekinci Akdemir, Fazile Nur; Gülçin, İlhami; Karagöz, Berna; Soslu, Recep

    2016-01-01

    In this study, we investigated the potential beneficial effects of quercetin on skeletal muscle ischemia reperfusion injury. Twenty-four Sprague-Dawley type rats were randomly divided into four groups. In the sham group, only gastrocnemius muscle were removed and given no quercetin. In ischemia group, all the femoral artery, vein and collaterals were occluded in the left hindlimb by applying tourniquate under general anaesthesia for three hours but reperfusion was not done. In the Quercetin + Ischemia reperfusion group, quercetin (200 mg kg(-1) dose orally) was given during one-week reoperation and later ischemia reperfusion model was done. Finally, gastrocnemius muscle samples were removed to measure biochemical parameters. The biomarkers, MDA levels, SOD, CAT and GPx activities, were evaluated related to skeletal muscle ischemia reperfusion injury. MDA levels reduced and SOD, CAT and GPx activities increased significantly in Quercetin + Ischemia reperfusion group. Results clearly showed that Quercetin have a protective role against oxidative damage induced by ischemia reperfusion in rats.

  19. Met-enkephalin levels during PTCA-induced myocardial ischemia.

    PubMed

    Parlapiano, C; Borgia, M C; Tonnarini, G; Giancaspro, G; Pizzuto, F; Campana, E; Giovanniello, T; Pantone, P; Vincentelli, G M; Alegiani, F; Negri, M

    2001-07-01

    Met-enkephalin (Met-enk) has been demonstrated to modulate myocardial-ischemia mechanisms via the opioid receptors, but no studies are now available on Met-enk levels in the coronary circulation. In this experience Met-enk levels were evaluated in aortic root and in coronary sinus at baseline (T0), during PTCA induced transient ischemia (T1) and during reperfusion (T2). No significant differences were found at any time. Thus, it appears that there is no Met-enk extraction from the coronary circulation during provoked myocardial ischemia and no Met-enk release from the ischemic heart.

  20. Panretinal photocoagulation for radiation-induced ocular ischemia

    SciTech Connect

    Augsburger, J.J.; Roth, S.E.; Magargal, L.E.; Shields, J.A.

    1987-08-01

    We present preliminary findings on the effectiveness of panretinal photocoagulation in preventing neovascular glaucoma in eyes with radiation-induced ocular ischemia. Our study group consisted of 20 patients who developed radiation-induced ocular ischemia following cobalt-60 plaque radiotherapy for a choroidal or ciliary body melanoma. Eleven of the 20 patients were treated by panretinal photocoagulation shortly after the diagnosis of ocular ischemia, but nine patients were left untreated. In this non-randomized study, the rate of development of neovascular glaucoma was significantly lower (p = 0.024) for the 11 photocoagulated patients than for the nine who were left untreated.

  1. Role of cannabinoids and endocannabinoids in cerebral ischemia

    PubMed Central

    Hillard, Cecilia J.

    2008-01-01

    The human costs of stroke are very large and growing; it is the third largest cause of death in the United States and survivors are often faced with loss of ability to function independently. There is a large need for therapeutic approaches that act to protect neurons from the injury produced by ischemia and reperfusion. The goal of this review is to introduce and discuss the available data that endogenous cannabinoid signaling is altered during ischemia and that it contributes to the consequences of ischemia-induced injury. Overall, the available data suggest that inhibition of CB1 receptor activation together with increased CB2 receptor activation produces beneficial effects. PMID:18781985

  2. Critical Care

    MedlinePlus

    Critical care helps people with life-threatening injuries and illnesses. It might treat problems such as complications from surgery, ... attention by a team of specially-trained health care providers. Critical care usually takes place in an ...

  3. Archetypal Criticism.

    ERIC Educational Resources Information Center

    Chesebro, James W.; And Others

    1990-01-01

    Argues that archetypal criticism is a useful way of examining universal, historical, and cross-cultural symbols in classrooms. Identifies essential features of an archetype; outlines operational and critical procedures; illustrates archetypal criticism as applied to the cross as a symbol; and provides a synoptic placement for archetypal criticism…

  4. Real-Time Visualization of Tissue Ischemia

    NASA Technical Reports Server (NTRS)

    Bearman, Gregory H. (Inventor); Chrien, Thomas D. (Inventor); Eastwood, Michael L. (Inventor)

    2000-01-01

    A real-time display of tissue ischemia which comprises three CCD video cameras, each with a narrow bandwidth filter at the correct wavelength is discussed. The cameras simultaneously view an area of tissue suspected of having ischemic areas through beamsplitters. The output from each camera is adjusted to give the correct signal intensity for combining with, the others into an image for display. If necessary a digital signal processor (DSP) can implement algorithms for image enhancement prior to display. Current DSP engines are fast enough to give real-time display. Measurement at three, wavelengths, combined into a real-time Red-Green-Blue (RGB) video display with a digital signal processing (DSP) board to implement image algorithms, provides direct visualization of ischemic areas.

  5. Vitreal Ocygenation in Retinal Ischemia Reperfusion

    SciTech Connect

    Abdallab, Walid; AmeriMD, Hossein; Barron, Ernesto; ChaderPhD, Gerald; Greenbaum, Elias; Hinton, David E; Humayun, Mark S

    2011-01-01

    PURPOSE. To study the feasibility of anterior vitreal oxygenation for the treatment of acute retinal ischemia. METHODS. Twenty rabbits were randomized into an oxygenation group, a sham treatment group, and a no treatment group. Baseline electroretinography (ERG) and preretinal oxygen (PO2) measurements were obtained 3 to 5 days before surgery. Intraocular pressure was raised to 100 mm Hg for 90 minutes and then normalized. The oxygenation group underwent vitreal oxygenation for 30 minutes using intravitreal electrodes. The sham treatment group received inactive electrodes for 30 minutes while there was no intervention for the no treatment group. Preretinal PO2 in the posterior vitreous was measured 30 minutes after intervention or 30 minutes after reperfusion (no treatment group) and on postoperative days (d) 3, 6, 9, and 12. On d14, rabbits underwent ERG and were euthanatized.

  6. Leukotriene signaling in atherosclerosis and ischemia

    PubMed Central

    Bäck, Magnus

    2009-01-01

    Introduction The inflammatory process of atherosclerosis is associated with several pathophysiological reactions within the vascular wall. The arachidonic acid released by phospholipase A2 serves as substrate for the production of a group of lipid mediators known as the leukotrienes, which induce pro-inflammatory signaling through activation of specific BLT and CysLT receptors. Discussion Leukotriene signaling has been implicated in early lipid retention and foam cell accumulation, as well as in the development of intimal hyperplasia and advanced atherosclerotic lesions. Furthermore, the association of leukotrienes with degradation of extracellular matrix has suggested a role in atherosclerotic plaque rupture. Finally, studies of either myocardial or cerebral ischemia and reperfusion indicate that leukotriene signaling in addition may be involved in the development of ischemic injury. Conclusion Both leukotriene synthesis inhibitors and leukotriene receptor antagonists have been suggested to induce beneficial effects at different stages of the atherosclerosis process. PMID:18949546

  7. Does machine perfusion decrease ischemia reperfusion injury?

    PubMed

    Bon, D; Delpech, P-O; Chatauret, N; Hauet, T; Badet, L; Barrou, B

    2014-06-01

    In 1990's, use of machine perfusion for organ preservation has been abandoned because of improvement of preservation solutions, efficient without perfusion, easy to use and cheaper. Since the last 15 years, a renewed interest for machine perfusion emerged based on studies performed on preclinical model and seems to make consensus in case of expanded criteria donors or deceased after cardiac death donations. We present relevant studies highlighted the efficiency of preservation with hypothermic machine perfusion compared to static cold storage. Machines for organ preservation being in constant evolution, we also summarized recent developments included direct oxygenation of the perfusat. Machine perfusion technology also enables organ reconditioning during the last hours of preservation through a short period of perfusion on hypothermia, subnormothermia or normothermia. We present significant or low advantages for machine perfusion against ischemia reperfusion injuries regarding at least one primary parameter: risk of DFG, organ function or graft survival.

  8. Thoracic sympathectomy for upper extremity ischemia.

    PubMed

    Hoexum, Frank; Coveliers, Hans M; Lu, Joyce J; Jongkind, Vincent; Yeung, Kakkhee K; Wisselink, Willem

    2016-12-01

    Thoracic sympathectomy is performed in the management of a variety of disorders of the upper extremity. To evaluate the contemporary results of thoracic sympathectomy for upper extremity ischemia a systematic review of the literature was conducted. We performed a PubMed, EMBASE and Cochrane search of the literature written in the English language from January 1975 to December 2015. All articles presenting original patient data regarding the effect of treatment on symptoms or on the healing of ulcers were eligible for inclusion. Individual analyses for Primary Raynaud's Disease (PRD) and Secondary Raynaud's Phenomenon (SRP) were performed. We included 6 prospective and 23 retrospective series with a total of 753 patients and 1026 affected limbs. Early beneficial effects of thoracic sympathectomy were noticed in 63-100% (median 94%) of all patients, in 73-100% (median 98%) of PRD patients and in 63-100% (median 94%) of SRP patients. The beneficial effect was noted to lessen over time. Long-term beneficial effects were reported in 13-100% (median 75%) of all patients, in 22-100% (median 58%) of PRD patients, and in 13-100% (median 79%) of SRD patients. Complete or improved ulcer healing was achieved in 33-100% and 25-67% respectively, of all patients. Thoracic sympathectomy can be beneficial in the treatment of upper extremity ischemia in select patients. Although the effect in patients with PRD will lessen over time, it may still reduce the severity of symptoms. In SRD, effects are more often long-lasting. In addition, thoracic sympathectomy may maximize tissue preservation or prevent amputation in cases of digital ulceration.

  9. The treatment of chronic intestinal ischemia.

    PubMed

    Illuminati, G; Caliò, F G; D'Urso, A; Papaspyropoulos, V; Mancini, P; Ceccanei, G; Vietri, F

    2004-01-01

    Due to the rarity of the condition, large and prospective series defining the optimal method of digestive arteries revascularization, for the treatment of chronic intestinal ischemia, are lacking. The aim of this consecutive sample clinical study was to test the hypothesis that flexible application of different revascularization methods, according to individual cases, will yield the best results in the management of chronic intestinal ischemia. Eleven patients, of a mean age of 57 years, underwent revascularization of 11 digestive arteries for symptomatic chronic mesenteric occlusive disease. Eleven superior mesenteric arteries and one celiac axis were revascularized. The revascularization techniques included retrograde bypass grafting in 7 cases, antegrade bypass grafting in 2, percutaneous arterial angioplasty in 1, and arterial reimplantation in one case. The donor axis for either reimplantation or bypass grafting was the infrarenal aorta in 4 cases, an infrarenal Dacron graft in 4, and the celiac aorta in one case. Grafting materials included 5 polytetrafluoroethylene (PTFE) and 3 Dacron grafts. Concomitant procedures included 3 aorto-ilio-femoral grafts and one renal artery revascularization. Mean follow-up length was 31 months. There was no operative mortality. Cumulative survival rate was 88.9% at 36 months (SE 12.1%). Primary patency rate was 90% at 36 months (SE 11.6%). The symptom free rate was 90% at 36 months (SE 11.6%). Direct reimplantation, antegrade and retrograde bypass grafting, all allow good mid-term results: the choice of the optimal method depends on the anatomic and general patients status. Associated infrarenal and renal arterial lesions can be safely treated in the same time of digestive revascularization. Angioplasty alone yields poor results and should be limited to patients at poor risk for surgery.

  10. Vitreal Oxygenation in Retinal Ischemia Reperfusion

    PubMed Central

    Abdallah, Walid; Ameri, Hossein; Barron, Ernesto; Chader, Gerald J.; Greenbaum, Elias; Hinton, David R.

    2011-01-01

    Purpose. To study the feasibility of anterior vitreal oxygenation for the treatment of acute retinal ischemia. Methods. Twenty rabbits were randomized into an oxygenation group, a sham treatment group, and a no treatment group. Baseline electroretinography (ERG) and preretinal oxygen (Po2) measurements were obtained 3 to 5 days before surgery. Intraocular pressure was raised to 100 mm Hg for 90 minutes and then normalized. The oxygenation group underwent vitreal oxygenation for 30 minutes using intravitreal electrodes. The sham treatment group received inactive electrodes for 30 minutes while there was no intervention for the no treatment group. Preretinal Po2 in the posterior vitreous was measured 30 minutes after intervention or 30 minutes after reperfusion (no treatment group) and on postoperative days (d) 3, 6, 9, and 12. On d14, rabbits underwent ERG and were euthanatized. Results. Mean final (d12) Po2 was 10.64 ± 0.77 mm Hg for the oxygenation group, 2.14 ± 0.61 mm Hg for the sham group, and 1.98 ± 0.63 mm Hg for the no treatment group. On ERG, scotopic b-wave amplitude was significantly preserved in the oxygenation group compared with the other two groups. Superoxide dismutase assay showed higher activity in the operated eyes than in the nonoperated control eyes in the sham treatment group and no treatment group only. Histopathology showed preservation of retinal architecture and choroidal vasculature in the oxygenation group, whereas the sham-treated and nontreated groups showed retinal thinning and choroidal atrophy. Conclusions. In severe total ocular ischemia, anterior vitreal oxygenation supplies enough oxygen to penetrate the retinal thickness, resulting in rescue of the RPE/choriocapillaris that continues to perfuse, hence sparing the retinal tissue from damage. PMID:21051734

  11. Zero ischemia laparoscopic partial thulium laser nephrectomy.

    PubMed

    Thomas, Arun Z; Smyth, Lisa; Hennessey, Derek; O'Kelly, Fardod; Moran, Diarmaid; Lynch, Thomas H

    2013-11-01

    Laser technology presents a promising alternative to achieve tumor excision and renal hemostasis with or without hilar occlusion, yet its use in partial nephrectomy has not been significantly evaluated. We prospectively evaluated the thulium:yttrium-aluminum-garnet laser in laparoscopic partial nephrectomy (LPN) in our institution over a 1-year period. We used the thulium laser with a wavelength of 2013 nm in the infrared spectrum. Data were recorded prospectively. Tumor size, preoperative aspects and dimensions used for an anatomical classification (PADUA) score, operative time, warm ischemia time (WIT), and perioperative and postoperative morbidity were recorded. Blood loss, preoperative and postoperative creatinine level, and estimated glomerular filtration rate (eGFR) were also collected. A total of 15 patients underwent consecutive LPN. The mean tumour diameter was 2.85 (1.5-4). The mean PADUA score was 6.8 (6-9). The mean total operative time was 168 minutes (128-306 min). Mean blood loss was 341 mL (0-800 mL). Date of discharge was 3.2 days postoperatively (2-8 days). The renal vessels were not clamped, resulting in a WIT of 0 minutes in all cases. There was no statistical significant increase in serum creatinine level or decrease in eGFR postoperatively. Histologically, the majority of lesions (13/15 patients) were renal-cell carcinoma stage pT1a. In all cases, base margins had negative results for tumor. The 2013-nm thulium laser system offers excellent hemostasis and precise resection capability of the renal cortex during LPN of small partially exophytic renal tumors. Our series showed excellent perioperative functional and pathologic outcomes, including minimal blood loss, zero ischemia, negative tumor margins, and preservation of renal function.

  12. Cell Biology of Ischemia/Reperfusion Injury

    PubMed Central

    Kalogeris, Theodore; Baines, Christopher P.; Krenz, Maike; Korthuis, Ronald J.

    2014-01-01

    Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues. PMID:22878108

  13. Reliability of preoperative duplex scanning in designing a therapeutic strategy for chronic lower limb ischemia.

    PubMed

    Fontcuberta, Juan; Flores, Angel; Orgaz, Antonio; Doblas, Manuel; Gil, Jose; Leal, Ignacio; Rodriguez, Ruben; Benito, Jose Maria; Bermúdez, Maria Dolores

    2009-01-01

    The objective of this study was to compare the treatment plan designed on the basis of preoperative duplex scanning evaluation of the critical limb ischemia with the treatment plan finally carried out, after assessing the findings obtained during surgical or endovascular treatment. Over a period of 51 months a preoperative duplex scanning study was carried out in 335 consecutive patients with chronic critical ischemia, to design the best therapeutic strategy. Agreement between both plans were as follows: 80%, 82,7% and 59% in the examinations of the iliac arteries, femoropopliteal or tibial arteries respectively. The operation plan was more frequently modified due to a duplex scanning failure in procedures involving the the distal vessels(10 of 44 [22.7%], p < 0.01). In conclusion, duplex scanning evaluation of patients with occlusive arterial disease of the lower limbs permits the design of both a medical and a surgical or endovascular treatment plan with a high level of agreement with the findings obtained during the revascularization procedure.

  14. Multiple coronary arterial loops as a cause of myocardial ischemia

    NASA Technical Reports Server (NTRS)

    Bashour, Tali T.; Mansour, Nagi N.; Lee, Damon

    1993-01-01

    A case of long-standing angina with ischemia documented by exercise testing and thallium scintigraphy in a patient who had multiple proximal loops in all three major coronary arteries in the absence of luminal stenosis, is reported.

  15. Hippocampal neurogenesis in the new model of global cerebral ischemia

    NASA Astrophysics Data System (ADS)

    Kisel, A. A.; Chernysheva, G. A.; Smol'yakova, V. I.; Savchenko, R. R.; Plotnikov, M. B.; Khodanovich, M. Yu.

    2015-11-01

    The study aimed to evaluate the changes of hippocampal neurogenesis in a new model of global transient cerebral ischemia which was performed by the occlusion of the three main vessels (tr. brachiocephalicus, a. subclavia sinistra, and a. carotis communis sinistra) branching from the aortic arch and supplying the brain. Global transitory cerebral ischemia was modeled on male rats (weight = 250-300 g) under chloral hydrate with artificial lung ventilation. Animals after the same surgical operation without vessel occlusion served as sham-operated controls. The number of DCX-positive (doublecortin, the marker of immature neurons) cells in dentate gyrus (DG) and CA1-CA3 fields of hippocampus was counted at the 31st day after ischemia modeling. It was revealed that global cerebral ischemia decreased neurogenesis in dentate gyrus in comparison with the sham-operated group (P<0.05) while neurogenesis in CA1-CA3 fields was increased as compared to the control (P<0.05).

  16. Current technology in assessing painless and painful ischemia

    SciTech Connect

    Selwyn, A.P. )

    1990-09-01

    Recent technologic advances have yielded diverse techniques for studying myocardial ischemia, a useful functional expression of coronary artery disease. These techniques have revealed new characteristics and expanded our understanding of myocardial ischemia. In turn this has led to the establishment of more realistic and discriminating criteria on which to base diagnostic and management decisions. Many of the techniques are noninvasive and can be performed in the cardiologist's office. These include treadmill exercise testing; radioisotope techniques, including ejection fraction studies, stress thallium scintigraphy, and tomographic imaging; and ambulatory monitoring. Other, newer techniques include provocative tests that induce ischemia in patients who cannot exercise. These new noninvasive tests should be used to detect transient ischemia, estimate its severity, and thus record a measure of the patient's risk for adverse coronary events.

  17. The complement system in ischemia-reperfusion injuries.

    PubMed

    Gorsuch, William B; Chrysanthou, Elvina; Schwaeble, Wilhelm J; Stahl, Gregory L

    2012-11-01

    Tissue injury and inflammation following ischemia and reperfusion of various organs have been recognized for many years. Many reviews have been written over the last several decades outlining the role of complement in ischemia/reperfusion injury. This short review provides a current state of the art knowledge on the complement pathways activated, complement components involved and a review of the clinical biologics/inhibitors used in the clinical setting of ischemia/reperfusion. This is not a complete review of the complement system in ischemia and reperfusion injury but will give the reader an updated view point of the field, potential clinical use of complement inhibitors, and the future studies needed to advance the field.

  18. The Complement System in Ischemia-Reperfusion Injuries

    PubMed Central

    Gorsuch, William B.; Chrysanthou, Elvina; Schwaeble, Wilhelm J.; Stahl, Gregory L.

    2012-01-01

    Tissue injury and inflammation following ischemia and reperfusion of various organs has been recognized for many years. Many reviews have been written over the last several decades outlining the role of complement in ischemia/reperfusion injury. This short review provides a current state of the art knowledge on the complement pathways activated, complement components involved and a review of the clinical biologics/inhibitors used in the clinical setting of ischemia/reperfusion. This is not a complete review of the complement system in ischemia and reperfusion injury but will give the reader an updated view point of the field, potential clinical use of complement inhibitors, and the future studies needed to advance the field. PMID:22964228

  19. MiR-146b protects cardiomyocytes injury in myocardial ischemia/reperfusion by targeting Smad4

    PubMed Central

    Di, Yun-Feng; Li, De-Cai; Shen, Yan-Qing; Wang, Chun-Lei; Zhang, Da-Yong; Shang, An-Quan; Hu, Teng

    2017-01-01

    MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post-transcriptionally modulate the expression of their target genes, have been implicated as critical regulatory molecules in many cardiovascular diseases, including ischemia-/reperfusion-induced cardiac injury. In the present study, we report on the role of miR-146b in myocardial I/R injury and the underlying cardio-protective mechanism. Antagomir-146b was used to explore the effects of miR-146b on cardiac ischemia/reperfusion injury (30 min ischemia followed by 180 min reperfusion). As predicted, miR-146b overexpression significantly reduced the infarct size and cardiomyocytes apoptosis and release of creatine kinase and lactate dehydrogenase. In addition, miR-146b attenuated H9c2 cell apoptosis. Furthermore, Smad4 was predicted and verified as a potential miR-146b target using bioinformatics and luciferase assay. In summary, this study demonstrated that miR-146b plays a critical protective role in cardiac ischemic injury and may provide a new therapeutic approach for the treatment of myocardial I/R injury.

  20. Mesenteric ischemia: the importance of differential diagnosis for the surgeon

    PubMed Central

    2013-01-01

    Background Intestinal ischemia is an abdominal emergency that accounts for approximately 2% of gastrointestinal illnesses. It represents a complex of diseases caused by impaired blood perfusion to the small and/or large bowel including acute arterial mesenteric ischemia (AAMI), acute venous mesenteric ischemia (AVMI), non occlusive mesenteric ischemia (NOMI), ischemia/reperfusion injury (I/R), ischemic colitis (IC). In this study different study methods (US, CT) will be correlated in the detection of mesenteric ischemia imaging findings due to various etiologies. Methods Basing on our institutions experience, 163 cases of mesenteric ischemia/infarction from various cases, investigated with CT and undergone surgical treatment were retrospectively evaluated, in particular trought the following findings: presence/absence of arterial/venous obstruction, bowel wall thickness and enhancement, presence/absence of spastic reflex ileus, hypotonic reflex ileus or paralitic ileus, mural and/or portal/mesenteric pneumatosis, abdominal free fluid, parenchymal ischemia/infarction (liver, kidney, spleen). Results To make an early diagnosis useful to ensure a correct therapeutic approach, it is very important to differentiate between occlusive (arterial, venous) and non occlusive causes (NOMI). The typical findings of each forms of mesenteric ischemia are explained in the text. Conclusion The radiological findings of mesenteric ischemia have different course in case of different etiology. In venous etiology the progression of damage results faster than arterial even if the symptomatology is less acute; bowel wall thickening is an early finding and easy to detect, simplifying the diagnosis. In arterial etiology the damage progression is slower than in venous ischemia, bowel wall thinning is typical but difficult to recognize so diagnosis may be hard. In the NOMI before/without reperfusion the ischemic damage is similar to AAMI with additional involvement of large bowel

  1. How Critical Is Critical Thinking?

    ERIC Educational Resources Information Center

    Shaw, Ryan D.

    2014-01-01

    Recent educational discourse is full of references to the value of critical thinking as a 21st-century skill. In music education, critical thinking has been discussed in relation to problem solving and music listening, and some researchers suggest that training in critical thinking can improve students' responses to music. But what exactly is…

  2. Critical Thinking vs. Critical Consciousness

    ERIC Educational Resources Information Center

    Doughty, Howard A.

    2006-01-01

    This article explores four kinds of critical thinking. The first is found in Socratic dialogues, which employ critical thinking mainly to reveal logical fallacies in common opinions, thus cleansing superior minds of error and leaving philosophers free to contemplate universal verities. The second is critical interpretation (hermeneutics) which…

  3. Critically Thinking about Critical Thinking

    ERIC Educational Resources Information Center

    Weissberg, Robert

    2013-01-01

    In this article, the author states that "critical thinking" has mesmerized academics across the political spectrum and that even high school students are now being called upon to "think critically." He furthers adds that it is no exaggeration to say that "critical thinking" has quickly evolved into a scholarly…

  4. How Critical Is Critical Thinking?

    ERIC Educational Resources Information Center

    Shaw, Ryan D.

    2014-01-01

    Recent educational discourse is full of references to the value of critical thinking as a 21st-century skill. In music education, critical thinking has been discussed in relation to problem solving and music listening, and some researchers suggest that training in critical thinking can improve students' responses to music. But what exactly is…

  5. [Antioxidant effects of antihypoxic drugs in cerebral ischemia].

    PubMed

    Plotnikov, M B; Kobzeva, E A; Plotnikova, T M

    1992-05-01

    Cerebral ischemia in rats (both carotid arteries occlusion) during 30 min, 3 hours and recirculation (1 hour) after ischemia (30 min) stimulated diene conjugates and fluorescent products accumulation in brain tissue. Intraperitoneal injection of sodium hydroxybutyrate (100 mg/kg), bemitil (50 mg/kg), ethomersol (50 mg/kg) reduced brain lipid peroxidation and did not yield in this respect to emoxypin (5 mg/kg). In contrast to emoxypin, sodium hydroxybutyrate, bemitil and ethomersol had no antiradical activity.

  6. Neuroprotective Effects of Pregabalin on Cerebral Ischemia and Reperfusion.

    PubMed

    Aşcı, Sanem; Demirci, Serpil; Aşcı, Halil; Doğuç, Duygu Kumbul; Onaran, İbrahim

    2016-03-01

    Stroke is one of the most common causes of death and the leading cause of disability in adults. Cerebral ischemia/reperfusion injury causes cerebral edema, hemorrhage, and neuronal death. In post-ischemic reperfusion, free radical production causes brain tissue damage by oxidative stress. Pregabalin, an antiepileptic agent was shown to have antioxidant effects. The aim of this study was to evaluate the neuroprotective and antioxidant effects of pregabalin on ischemia and reperfusion in rat brain injury. Animal experimentation. Male Wistar rats weighing (250-300 g) were randomly divided into six groups, each consisting of 6 rats: control (C), pregabalin (P), ischemia (I), pregabalin + ischemia (PI), ischemia + reperfusion (IR) and ischemia + reperfusion + pregabalin (PIR). Rats were initially pre-treated with 50 mg/kg/d pregabalin orally for two days. Then, animals that applied ischemia in I, PI, IR and PIR groups were exposed to carotid clamping for 30 minutes and 20 minutes reperfusion was performed in the relevant reperfusion groups. NR2B receptor levels were significantly lower in the PIR group in comparison to the IR group. In the PIR group, Thiobarbituric acid reactive substance (TBARS) level had statistically significant decrease compared with IR group. Glutathione peroxidase (GSH-PX) levels were also significantly increased in the PIR group compared with I, IR and control groups. In the PI and PIR groups, catalase (CAT) levels were also significantly increased compared with I and IR groups (p=0.03 and p=0.07, respectively). Pregabalin may protect the damage of oxidative stress after ischemia + reperfusion. This result would illuminate clinical studies in the future.

  7. Neuroprotective Effects of Pregabalin on Cerebral Ischemia and Reperfusion

    PubMed Central

    Aşcı, Sanem; Demirci, Serpil; Aşcı, Halil; Doğuç, Duygu Kumbul; Onaran, İbrahim

    2016-01-01

    Background: Stroke is one of the most common causes of death and the leading cause of disability in adults. Cerebral ischemia/reperfusion injury causes cerebral edema, hemorrhage, and neuronal death. Aims: In post-ischemic reperfusion, free radical production causes brain tissue damage by oxidative stress. Pregabalin, an antiepileptic agent was shown to have antioxidant effects. The aim of this study was to evaluate the neuroprotective and antioxidant effects of pregabalin on ischemia and reperfusion in rat brain injury. Study Design: Animal experimentation. Methods: Male Wistar rats weighing (250–300 g) were randomly divided into six groups, each consisting of 6 rats: control (C), pregabalin (P), ischemia (I), pregabalin + ischemia (PI), ischemia + reperfusion (IR) and ischemia + reperfusion + pregabalin (PIR). Rats were initially pre-treated with 50 mg/kg/d pregabalin orally for two days. Then, animals that applied ischemia in I, PI, IR and PIR groups were exposed to carotid clamping for 30 minutes and 20 minutes reperfusion was performed in the relevant reperfusion groups. Results: NR2B receptor levels were significantly lower in the PIR group in comparison to the IR group. In the PIR group, Thiobarbituric acid reactive substance (TBARS) level had statistically significant decrease compared with IR group. Glutathione peroxidase (GSH-PX) levels were also significantly increased in the PIR group compared with I, IR and control groups. In the PI and PIR groups, catalase (CAT) levels were also significantly increased compared with I and IR groups (p=0.03 and p=0.07, respectively). Conclusion: Pregabalin may protect the damage of oxidative stress after ischemia + reperfusion. This result would illuminate clinical studies in the future. PMID:27403394

  8. Spinal cord ischemia following thoracotomy without epidural anesthesia.

    PubMed

    Raz, Aeyal; Avramovich, Aharon; Saraf-Lavi, Efrat; Saute, Milton; Eidelman, Leonid A

    2006-06-01

    Paraplegia is an uncommon yet devastating complication following thoracotomy, usually caused by compression or ischemia of the spinal cord. Ischemia without compression may be a result of global ischemia, vascular injury and other causes. Epidural anesthesia has been implicated as a major cause. This report highlights the fact that perioperative cord ischemia and paraplegia may be unrelated to epidural intervention. A 71-yr-old woman was admitted for a left upper lobectomy for resection of a non-small cell carcinoma of the lung. The patient refused epidural catheter placement and underwent a left T5-6 thoracotomy under general anesthesia. During surgery, she was hemodynamically stable and good oxygen saturation was maintained. Several hours following surgery the patient complained of loss of sensation in her legs. Neurological examination disclosed a complete motor and sensory block at the T5-6 level. Magnetic resonance imaging (MRI) revealed spinal cord ischemia. The patient received iv steroid treatment, but remained paraplegic. Five months following the surgery there was only partial improvement in her motor symptoms. A follow-up MRI study was consistent with a diagnosis of spinal cord ischemia. In this case of paraplegia following thoracic surgery for lung resection, epidural anesthesia/analgesia was not used. The MRI demonstrated evidence of spinal cord ischemia, and no evidence of cord compression. This case highlights that etiologies other than epidural intervention, such as injury to the spinal segmental arteries during thoracotomy, should be considered as potential causes of cord ischemia and resultant paraplegia in this surgical population.

  9. Association between Anger and Mental Stress-Induced Myocardial Ischemia

    PubMed Central

    Pimple, Pratik; Shah, Amit; Rooks, Cherie; Bremner, J. Douglas; Nye, Jonathon; Ibeanu, Ijeoma; Murrah, Nancy; Shallenberger, Lucy; Kelley, Mary; Raggi, Paolo; Vaccarino, Viola

    2014-01-01

    Background Mental stress-induced myocardial ischemia is associated with adverse prognosis in coronary artery disease patients. Anger is thought to be a trigger of acute coronary syndromes and is associated with increased cardiovascular risk; however, little direct evidence exists for a link between anger and myocardial ischemia. Methods [99mTc]sestamibi single-photon emission tomography was performed at rest, after mental stress (a social stressor with a speech task), and after exercise/pharmacological stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed difference score, the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. The Spielberger's State-Trait Anger Expression Inventory was used to assess different anger dimensions. Results The mean age was 50 years, 50% were female and 60% were non-white. After adjusting for demographic factors, smoking, coronary artery disease severity, depressive and anxiety symptoms, each interquartile range increment in state-anger score was associated with 0.36 units adjusted increase in ischemia as measured by the summed difference score (95% CI: 0.14-0.59); the corresponding association for trait-anger was 0.95 (95% CI: 0.21-1.69). Anger expression scales were not associated ischemia. None of the anger dimensions were related to ischemia during exercise/pharmacological stress. Conclusion Anger, both as an emotional state and as a personality trait, is significantly associated with propensity to develop myocardial ischemia during mental stress, but not during exercise/pharmacological stress. Patients with this psychological profile may be at increased risk for silent ischemia induced by emotional stress and this may translate into worse prognosis. PMID:25497256

  10. Ocular Sarcoidosis Limited to Retinal Vascular Ischemia and Neovascularization

    PubMed Central

    Dyer, Gawain; Shaikh, Saad

    2016-01-01

    A 59-year-old Caucasian male experienced progressive vision loss secondary to retinal vascular ischemia and neovascularization. At no time did he present with uveitis or vasculitis, and his serology tests were all negative. He was soon after diagnosed with sarcoidosis by hilar lymph node lung biopsy. Our patient demonstrates an atypical presentation of ocular sarcoidosis, manifesting solely as neovascularization and retinal vascular ischemia. Ophthalmologists should consider proliferative sarcoid retinopathy in patients with neovascularization. PMID:27928517

  11. Ischemia in Tumors Induces Early and Sustained Phosphorylation Changes in Stress Kinase Pathways but Does Not Affect Global Protein Levels*

    PubMed Central

    Mertins, Philipp; Yang, Feng; Liu, Tao; Mani, D. R.; Petyuk, Vladislav A.; Gillette, Michael A.; Clauser, Karl R.; Qiao, Jana W.; Gritsenko, Marina A.; Moore, Ronald J.; Levine, Douglas A.; Townsend, Reid; Erdmann-Gilmore, Petra; Snider, Jacqueline E.; Davies, Sherri R.; Ruggles, Kelly V.; Fenyo, David; Kitchens, R. Thomas; Li, Shunqiang; Olvera, Narciso; Dao, Fanny; Rodriguez, Henry; Chan, Daniel W.; Liebler, Daniel; White, Forest; Rodland, Karin D.; Mills, Gordon B.; Smith, Richard D.; Paulovich, Amanda G.; Ellis, Matthew; Carr, Steven A.

    2014-01-01

    Protein abundance and phosphorylation convey important information about pathway activity and molecular pathophysiology in diseases including cancer, providing biological insight, informing drug and diagnostic development, and guiding therapeutic intervention. Analyzed tissues are usually collected without tight regulation or documentation of ischemic time. To evaluate the impact of ischemia, we collected human ovarian tumor and breast cancer xenograft tissue without vascular interruption and performed quantitative proteomics and phosphoproteomics after defined ischemic intervals. Although the global expressed proteome and most of the >25,000 quantified phosphosites were unchanged after 60 min, rapid phosphorylation changes were observed in up to 24% of the phosphoproteome, representing activation of critical cancer pathways related to stress response, transcriptional regulation, and cell death. Both pan-tumor and tissue-specific changes were observed. The demonstrated impact of pre-analytical tissue ischemia on tumor biology mandates caution in interpreting stress-pathway activation in such samples and motivates reexamination of collection protocols for phosphoprotein analysis. PMID:24719451

  12. The protective role of heme oxygenase-1 in cerebral ischemia.

    PubMed

    Aztatzi-Santillán, Emmanuel; Nares-López, Felipe Eduardo; Márquez-Valadez, Berenice; Aguilera, Penélope; Chánez-Cárdenas, María Elena

    2010-12-01

    Cerebral ischemia is one of the leading causes of death and disability in industrialized countries, with no curative treatments to date. Identification of potential targets and elucidation of their physiological role under stress conditions may give support to the development of drugs and strategies to contend with this pathology. In the last years, Heme oxygenase-1 (HO-1) has been considered by many groups as a potential target in ischemic damage. HO-1 is the enzyme responsible for the conversion of the heme group to billiverdin, carbon monoxide and iron; a highly regulated cytoprotective enzyme able to respond to numerous chemical or physical stressors, many of which decrease oxygen availability and generate oxidative stress. The disruption of HO-1 activity has been widely associated with a bad outcome in many disorders, and a protective role through its heme catabolism products has been observed in transplantation, cardiac ischemia, limb ischemia/reperfusion and different alterations that involve ischemia and reperfusion events. Here, we review recent reports supporting the protective role of HO-1 in cerebral ischemia. Results on the endogenous HO-1 response, overexpression of HO-1 and compounds that reduce ischemic damage through the induction of HO-1 in cerebral ischemia in in vivo and in vitro models are analyzed.

  13. Rat model of focal cerebral ischemia in the dominant hemisphere

    PubMed Central

    Zhang, Hua; Shen, Yan; Wang, Wei; Gao, Huanmin

    2015-01-01

    In the human brain, the dominant hemisphere is more complex than the non-dominant hemisphere. Hence, cerebral ischemia of the dominant hemisphere often leads to serious consequences. This study aims to establish a rodent model of focal cerebral ischemia in the dominant hemisphere. The quadruped feeding test was used to screen 70 male Sprague Dawley rats. From this test, 48 rats with right paw preference were selected and randomly assigned numbers. Half were assigned to the dominant hemisphere ischemia (DHI) group, and the other half were assigned to the non-dominant hemisphere ischemia (NDHI) group. The middle cerebral artery was occluded 2 h before reperfusion. Neurological functions were tested. TTC and HE staining were performed. The volume of cerebral infarction was calculated. Rats in the DHI group had significantly worse neurological scores than rats in the NDHI group (P < 0.05). TTC staining indicated ischemia had more severe consequences in the dominant hemisphere than in the non-dominant hemisphere. The dominant hippocampus indicated severe neuronal loss and disorderly cellular arrangement. The volume of cerebral infarction was also greater in the DHI group compared to the NDHI group (P < 0.05). Compared to MCA occlusion in the non-dominant hemisphere, MCA occlusion in the dominant hemisphere caused greater impairment in neurological functions. The proposed rodent model is reliable and has high levels of reproducibility. Therefore, his model can be reliably for investigating the mechanism of focal cerebral ischemia in the dominant hemisphere of human brains. PMID:25785023

  14. A Program for Solving the Brain Ischemia Problem

    PubMed Central

    DeGracia, Donald J.

    2013-01-01

    Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of “master bifurcation diagrams” that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection. PMID:24961411

  15. Exercise-induced Myocardial Ischemia Detected by Cardiopulmonary Exercise Testing

    PubMed Central

    Chaudhry, Sundeep; Arena, Ross; Wasserman, Karlman; Hansen, James E.; Lewis, Gregory D.; Myers, Jonathan; Chronos, Nicolas; Boden, William E.

    2010-01-01

    Cardiopulmonary exercise testing (CPET) is a well-accepted physiologic evaluation technique in patients diagnosed with heart failure and in individuals presenting with unexplained dyspnea on exertion. Several variables obtained during CPET, including oxygen consumption relative to heart rate (VO2/HR or O2-pulse) and work rate (VO2/Watt) provide consistent, quantitative patterns of abnormal physiologic responses to graded exercise when left ventricular dysfunction is caused by myocardial ischemia. This concept paper describes both the methodology and clinical application of CPET associated with myocardial ischemia. Initial evidence indicates left ventricular dysfunction induced by myocardial ischemia may be accurately detected by an abnormal CPET response. CPET testing may complement current non-invasive testing modalities that elicit inducible ischemia. It provides a physiologic quantification of the work rate, heart rate and O2 uptake at which myocardial ischemia develops. In conclusion, the potential value of adding CPET with gas exchange measurements is likely to be of great value in diagnosing and quantifying both overt and occult myocardial ischemia and its reversibility with treatment. PMID:19231322

  16. The role of renal sympathetic nerves in ischemia reperfusion injury.

    PubMed

    Lambert, Elisabeth; Schlaich, Markus

    2017-05-01

    Decreased blood flow supply to the kidneys known as renal ischemia/reperfusion is a common occurrence during various clinical and surgical settings. This remains highly concerning as it is a major cause of acute kidney injury (AKI). The kidneys have a rich supply of efferent and afferent sympathetic nerves playing a crucial physiological role in regulation of renal function. Studies in animal models of renal ischemia/reperfusion injury have indicated that very early during an ischemic event, the sympathetic nerves are activated and in concert with decreased nitric oxide availability, increased angiotensin II and several other molecules results in renal damage. Renal sympathetic inhibition or denervation seems to prevent or decrease some of the renal damage induced by ischemia/reperfusion injury but the evidence at present is based on animal studies and remains to be confirmed in the clinical setting. Remote ischemic preconditioning (IPC) has gained a lot of interest as a strategy to limit ischemia/reperfusion damage with some recent evidence suggesting that intact sympathetic nerves may be relevant in mediating protective effects. In this article, we review the experimental studies and emerging clinical studies that have investigated the role of sympathetic nerves following ischemia/reperfusion injury and studies exploring the role of sympathetic nerves in IPC and preventing tissue dysfunction induced by renal ischemia/reperfusion. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Methods for Acute and Subacute Murine Hindlimb Ischemia

    PubMed Central

    Padgett, Michael E.; McCord, Timothy J.; McClung, Joseph M.; Kontos, Christopher D.

    2016-01-01

    Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality in developed countries, and animal models that reliably reproduce the human disease are necessary to develop new therapies for this disease. The mouse hindlimb ischemia model has been widely used for this purpose, but the standard practice of inducing acute limb ischemia by ligation of the femoral artery can result in substantial tissue necrosis, compromising investigators' ability to study the vascular and skeletal muscle tissue responses to ischemia. An alternative approach to femoral artery ligation is the induction of gradual femoral artery occlusion through the use of ameroid constrictors. When placed around the femoral artery in the same or different locations as the sites of femoral artery ligation, these devices occlude the artery over 1-3 days, resulting in more gradual, subacute ischemia. This results in less substantial skeletal muscle tissue necrosis, which may more closely mimic the responses seen in human PAD. Because genetic background influences outcomes in both the acute and subacute ischemia models, consideration of the mouse strain being studied is important in choosing the best model. This paper describes the proper procedure and anatomical placement of ligatures or ameroid constrictors on the mouse femoral artery to induce subacute or acute hindlimb ischemia in the mouse. PMID:27403963

  18. Anticerebral Ischemia-Reperfusion Injury Activity of Synthesized Puerarin Derivatives

    PubMed Central

    Ji, Yubin; Yan, Xinjia

    2016-01-01

    When cerebral ischemia-reperfusion injury happened in patients, multiple pathological processes occur, such as leukocyte infiltration, platelet, and complement activation, which would result in cognitive dysfunction and inflammation. Puerarin has shown protective effect on injury of neural cell. In order to enhance this protective effect of puerarin, puerarin derivatives with different log⁡P values were designed and synthesized. The original phenolic hydroxyl in the puerarin molecules was substituted in order to change the blood-brain barrier permeability and thus enhance the efficacy for preventing cerebral ischemia/reperfusion injury. And the structure of the newly synthesized molecules was confirmed by 1H NMR spectroscopy and mass spectrometry. The mouse model of cerebral artery ischemia/reperfusion injury was established to test the anticerebral ischemia-reperfusion injury activity of the puerarin derivatives. The assays of the water maze, Y maze, brain cortex Ca2+-Mg2+-ATP enzyme, and iNOS enzyme activity were performed in this mouse model. The results showed that puerarin derivative P1-EA and P2-EA were resulting in an increased lipophilicity that enabled the derivatives to pass more efficiently through the blood-brain barrier, thus, improving the protective effects against cerebral ischemia/reperfusion injury. Therefore, derivatives of puerarin may serve as promising approach to improve neuron function in ischemia-reperfusion brain injury-related disorders. PMID:27807543

  19. Neuroprotective effects of rutaecarpine on cerebral ischemia reperfusion injury

    PubMed Central

    Yan, Chunlin; Zhang, Ji; Wang, Shu; Xue, Guiping; Hou, Yong

    2013-01-01

    Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia reperfusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 μg/kg carpine were given to mice via intraperitoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutaecarpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neurological function following injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice. PMID:25206511

  20. Role of Histamine and Its Receptors in Cerebral Ischemia

    PubMed Central

    2012-01-01

    Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy. However, important questions about the molecular aspects and pathophysiology of histamine and related agents in cerebral ischemia remain to be answered to form a solid scientific basis for therapeutic application. PMID:22860191

  1. Improved renal ischemia tolerance in females influences kidney transplantation outcomes

    PubMed Central

    Aufhauser, David D.; Wang, Zhonglin; Murken, Douglas R.; Bhatti, Tricia R.; Wang, Yanfeng; Ge, Guanghui; Redfield, Robert R.; Abt, Peter L.; Wang, Liqing; Reese, Peter P.; Hancock, Wayne W.; Levine, Matthew H.

    2016-01-01

    Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor α–KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance. PMID:27088798

  2. Improved renal ischemia tolerance in females influences kidney transplantation outcomes.

    PubMed

    Aufhauser, David D; Wang, Zhonglin; Murken, Douglas R; Bhatti, Tricia R; Wang, Yanfeng; Ge, Guanghui; Redfield, Robert R; Abt, Peter L; Wang, Liqing; Svoronos, Nikolaos; Thomasson, Arwin; Reese, Peter P; Hancock, Wayne W; Levine, Matthew H

    2016-05-02

    Experimentally, females show an improved ability to recover from ischemia-reperfusion injury (IRI) compared with males; however, this sex-dependent response is less established in humans. Here, we developed a series of murine renal ischemia and transplant models to investigate sex-specific effects on recovery after IRI. We found that IRI tolerance is profoundly increased in female mice compared with that observed in male mice and discovered an intermediate phenotype after neutering of either sex. Transplantation of adult kidneys from either sex into a recipient of the opposite sex followed by ischemia at a remote time resulted in ischemia recovery that reflected the sex of the recipient, not the donor, revealing that the host sex determines recovery. Likewise, renal IRI was exacerbated in female estrogen receptor α-KO mice, while female mice receiving supplemental estrogen before ischemia were protected. We examined data from the United Network for Organ Sharing (UNOS) to determine whether there is an association between sex and delayed graft function (DGF) in patients who received deceased donor renal transplants. A multivariable logistic regression analysis determined that there was a greater association with DGF in male recipients than in female recipients. Together, our results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance.

  3. Polyadenylated mRNA staining reveals distinct neuronal phenotypes following endothelin 1, focal brain ischemia, and global brain ischemia/ reperfusion

    PubMed Central

    Jamison, Jill T.; Lewis, Monique K.; Kreipke, Christian W.; Rafols, Jose A.; DeGracia, Donald J.

    2011-01-01

    Objectives Most work on ischemia-induced neuronal death has revolved around the relative contributions of necrosis and apoptosis, but this work has not accounted for the role of ischemia-induced stress responses. An expanded view recognizes a competition between ischemia-induced damage mechanisms and stress responses in the genesis of ischemia-induced neuronal death. An important marker of post-ischemic stress responses is inhibition of neuronal protein synthesis, a morphological correlate of which is the compartmentalization of mRNA away from ribosomes in the form of cytoplasmic mRNA granules. Methods Here we assessed the generality of this mRNA granule response following either 10 or 15 minutes global brain ischemia and 1 hour reperfusion, 4 hours focal cerebral ischemia alone, and endothelin 1 intraventricular injection. Results Both global and focal ischemia led to prominent neuronal cytoplasmic mRNA granule formation in layer II cortical neurons. In addition, we report here new post-ischemic cellular phenotypes characterized by the loss of nuclear polyadenylated mRNA staining in cortical neurons following endothelin 1 treatment and 15 minutes global ischemia. Both mRNA granulation and loss of nuclear mRNAs occurred in non-shrunken post-ischemic neurons. Discussion Where cytoplasmic mRNA granules generally appear to mark a protective response in surviving cells, loss of nuclear mRNAs may mark cellular damage leading to cell atrophy/death. Hence, staining for total mRNA may reveal facets of the competition between stress responses and damage mechanisms at early stages in post-ischemic neurons. PMID:21499502

  4. Criticality Model

    SciTech Connect

    A. Alsaed

    2004-09-14

    The ''Disposal Criticality Analysis Methodology Topical Report'' (YMP 2003) presents the methodology for evaluating potential criticality situations in the monitored geologic repository. As stated in the referenced Topical Report, the detailed methodology for performing the disposal criticality analyses will be documented in model reports. Many of the models developed in support of the Topical Report differ from the definition of models as given in the Office of Civilian Radioactive Waste Management procedure AP-SIII.10Q, ''Models'', in that they are procedural, rather than mathematical. These model reports document the detailed methodology necessary to implement the approach presented in the Disposal Criticality Analysis Methodology Topical Report and provide calculations utilizing the methodology. Thus, the governing procedure for this type of report is AP-3.12Q, ''Design Calculations and Analyses''. The ''Criticality Model'' is of this latter type, providing a process evaluating the criticality potential of in-package and external configurations. The purpose of this analysis is to layout the process for calculating the criticality potential for various in-package and external configurations and to calculate lower-bound tolerance limit (LBTL) values and determine range of applicability (ROA) parameters. The LBTL calculations and the ROA determinations are performed using selected benchmark experiments that are applicable to various waste forms and various in-package and external configurations. The waste forms considered in this calculation are pressurized water reactor (PWR), boiling water reactor (BWR), Fast Flux Test Facility (FFTF), Training Research Isotope General Atomic (TRIGA), Enrico Fermi, Shippingport pressurized water reactor, Shippingport light water breeder reactor (LWBR), N-Reactor, Melt and Dilute, and Fort Saint Vrain Reactor spent nuclear fuel (SNF). The scope of this analysis is to document the criticality computational method. The criticality

  5. Impact of hyperthermia before and during ischemia-reperfusion on neuronal damage and gliosis in the gerbil hippocampus induced by transient cerebral ischemia.

    PubMed

    Kim, Min Joung; Cho, Jun Hwi; Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Tae, Hyun-Jin; Cho, Geum-Sil; Yan, Bing Chun; Hwang, In Koo; Lee, Choong Hyun; Bae, Eun Joo; Won, Moo-Ho; Lee, Jae-Chul

    2015-01-15

    Hyperthermia can exacerbate the brain damage produced by ischemia. In the present study, we investigated the effects of hyperthermia before and during ischemia-reperfusion on neuronal damage and glial changes in the gerbil hippocampus following transient cerebral ischemia using cresyl violet staining, NeuN immunohistochemistry and Fluoro-Jade B histofluorescence staining. The animals were randomly assigned to 4 groups: (1) sham-operated animals with normothermia (normothermia + sham group); (2) ischemia-operated animals with normothermia (normothermia + ischemia group); (3) sham-operated animals with hyperthermia (hyperthermia + sham group); and (4) ischemia-operated animals with hyperthermia (hyperthermia + ischemia group). Hyperthermia (39.5 ± 0.2°C) was induced by exposing the gerbils to a heating pad connected to a rectal thermistor for 30 min before and during ischemia-reperfusion. In the normothermia+ischemia groups, a significant delayed neuronal death was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) 5 days after ischemia-reperfusion. In the hyperthermia+ischemia groups, neuronal death in the SP of the CA1 occurred at 1 day post-ischemia, and neuronal death was observed in the SP of the CA2/3 region at 2 days post-ischemia. In addition, we examined activations of astrocytes and microglia using immunohistochemistry for anti-glial fibrillary acidic protein (GFAP) and anti-ionized calcium-binding adapter molecule 1 (Iba-1). GFAP-positive astrocytes and Iba-1-positive microglia in the ischemic hippocampus were activated much earlier and much more accelerated in the hyperthermia+ischemia groups than those in the normothermia+ischemia groups. Based on our findings, we suggest that an experimentally hyperthermic pre-condition before cerebral ischemic insult produces more extensive neuronal damage and glial activation in the ischemic hippocampus.

  6. 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

    2017-09-21

    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

  7. Effects of carbon monoxide on myocardial ischemia.

    PubMed Central

    Allred, E N; Bleecker, E R; Chaitman, B R; Dahms, T E; Gottlieb, S O; Hackney, J D; Pagano, M; Selvester, R H; Walden, S M; Warren, J

    1991-01-01

    The purpose of this study was to determine whether low doses of carbon monoxide (CO) exacerbate myocardial ischemia during a progressive exercise test. The effect of CO exposure was evaluated using the objective measure of time to development of electrocardiographic changes indicative of ischemia and the subjective measure of time to onset of angina. Sixty-three male subjects (41-75 years) with well-documented coronary artery disease, who had exertional angina pectoris and ischemic ST-segment changes in their electrocardiograms, were studied. Results from three randomized, double-blind test visits (room air, low and high CO) were compared. The effect of CO exposure was determined from the percent difference in the end points obtained on exercise tests performed before and after a 1-hr exposure to room air or CO. The exposures resulted in postexercise carboxyhemoglobin (COHb) levels of 0.6% +/- 0.3%, 2.0% +/- 0.1%, and 3.9% +/- 0.1%. The results obtained on the 2%-COHb day and 3.9%-COHb day were compared to those on the room air day. There were 5.1% (p = 0.01) and 12.1% (p less than or equal to 0.0001) decreases in the time to development of ischemic ST-segment changes after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. In addition, there were 4.2% (p = 0.027) and 7.1% (p = 0.002) decreases in time to the onset of angina after exposures producing 2.0 and 3.9% COHb, respectively, compared to the control day. A significant dose-response relationship was found for the individual differences in the time to ST end point and angina for the pre- versus postexposure exercise tests at the three carboxyhemoglobin levels. These findings demonstrate that low doses of CO produce significant effects on cardiac function during exercise in subjects with coronary artery disease. PMID:2040254

  8. Gastrin attenuates ischemia-reperfusion-induced intestinal injury in rats

    PubMed Central

    Liu, Zhihao; Luo, Yongli; Cheng, Yunjiu; Zou, Dezhi; Zeng, Aihong; Yang, Chunhua

    2016-01-01

    Intestinal ischemia-reperfusion (I/R) injury is a devastating complication when the blood supply is reflowed in ischemic organs. Gastrin has critical function in regulating acid secretion, proliferation, and differentiation in the gastric mucosa. We aimed to determine whether gastrin has an effect on intestinal I/R damage. Intestinal I/R injury was induced by 60-min occlusion of the superior mesenteric artery followed by 60-min reperfusion, and the rats were induced to be hypergastrinemic by pretreated with omeprazole or directly injected with gastrin. Some hypergastrinemic rats were injected with cholecystokinin-2 (CCK-2) receptor antagonist prior to I/R operation. After the animal surgery, the intestine was collected for histological analysis. Isolated intestinal epithelial cells or crypts were harvested for RNA and protein analysis. CCK-2 receptor expression, intestinal mucosal damage, cell apoptosis, and apoptotic protein caspase-3 activity were measured. We found that high gastrin in serum significantly reduced intestinal hemorrhage, alleviated extensive epithelial disruption, decreased disintegration of lamina propria, downregulated myeloperoxidase activity, tumor necrosis factor-α, and caspase-3 activity, and lead to low mortality in response to I/R injury. On the contrary, CCK-2 receptor antagonist L365260 could markedly impair intestinal protection by gastrin on intestinal I/R. Severe edema of mucosal villi with severe intestinal crypt injury and numerous intestinal villi disintegrated were observed again in the hypergastrinemic rats with L365260. The survival in the hypergastrinemic rats after intestinal I/R injury was shortened by L365260. Finally, gastrin could remarkably upregulated intestinal CCK-2 receptor expression. Our data suggest that gastrin by omeprazole remarkably attenuated I/R induced intestinal injury by enhancing CCK-2 receptor expression and gastrin could be a potential mitigator for intestinal I/R damage in the clinical setting. PMID

  9. Both PD-1 ligands protect the kidney from ischemia reperfusion injury.

    PubMed

    Jaworska, Katarzyna; Ratajczak, Joanna; Huang, Liping; Whalen, Kristen; Yang, Mana; Stevens, Brian K; Kinsey, Gilbert R

    2015-01-01

    Acute kidney injury (AKI) is a common problem in hospitalized patients that enhances morbidity and mortality and promotes the development of chronic and end-stage renal disease. Ischemia reperfusion injury (IRI) is one of the