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Sample records for critical limb-threatening ischemia

  1. Endovascular recanalization techniques for popliteal arterial occlusive injury with limb-threatening ischemia secondary to trauma.

    PubMed

    Mine, Takahiko; Murata, Satoru; Yasui, Daisuke; Tajima, Hiroyuki; Kawamata, Hiroshi; Yokota, Hiroyuki; Kumita, Shin-Ichiro

    2014-01-01

    To date, no ideal endovascular strategy has been established for traumatic arterial occlusion. Here, we report the outcomes of a combination of endovascular recanalization techniques applied in two patients with high risk of leg amputation. A 33-year-old man with popliteal artery occlusion due to blunt trauma was treated by balloon angioplasty with long inflation time and aspiration thrombectomy. A 74-year-old woman with popliteal artery occlusion after total knee replacement was treated by aspiration thrombectomy and stent placement. In both cases, we achieved satisfactory recanalization, and peripheral ischemia was absent even 1 year later.

  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. Limb-threatening ischemia secondary to a congenital acromioclavicular remnant.

    PubMed

    Enlow, Jonathan M; McGregor, Walter E

    2009-07-01

    Upper extremity vascular compromise from thoracic outlet syndrome is rare and is usually the result of a "cervical rib," anterior scalene muscle abnormality, or clavicular trauma. We report a case of acute axillary artery thrombosis secondary to a congenital acromioclavicular remnant in a 40-year-old woman.

  4. [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.

  5. 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

  6. 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.

  7. [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.

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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

  20. [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.

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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.

  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. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. 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

  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. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

    2017-02-27

    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.

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. Myocardial Ischemia

    MedlinePlus

    ... typically on the left side of the body (angina pectoris). Other signs and symptoms — which might be experienced ... ed. Philadelphia, Pa.: Saunders Elsevier; 2014. Podrid PJ. Angina pectoris: Chest pain caused by myocardial ischemia. www.uptodate. ...

  15. 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.

  16. 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.

  17. 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

  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. 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.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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

  7. 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

  8. A prospective feasibility study of duplex ultrasound arterial mapping, digital-subtraction angiography, and magnetic resonance angiography in management of critical lower limb ischemia by endovascular revascularization.

    PubMed

    Lowery, A J; Hynes, N; Manning, B J; Mahendran, M; Tawfik, S; Sultan, S

    2007-07-01

    Duplex ultrasound arterial mapping (DUAM) allows precise evaluation of peripheral vascular disease (PVD). However, magnetic resonance angiography (MRA) and digital-subtraction angiography (DSA) are the diagnostic tools used most frequently prior to intervention. Our aim was to compare clinical pragmatism, hemodynamic outcomes, and cost-effectiveness when using DUAM alone compared to DSA or MRA as preoperative assessment tools for endovascular revascularization (EvR) in critical lower limb ischemia (CLI). From 2002 through 2005, 465 patients were referred with PVD. Of these, 199 had CLI and 137 required EvR. Preoperative diagnostic evaluation included DUAM (n = 41), DSA (n = 50), or MRA (n = 46). EvR was aortoiliac in 27% of cases and infrainguinal in 73%. Patients were assessed at day 1, 6 weeks, 3 months, and 6 months. Composite end points were relief of rest pain, ulcer/gangrene healing, and increase in perfusion pressure, as measured by ankle-brachial index (ABI) and digital pressures. Patency by DUAM, limb salvage, morbidity, mortality, length of stay, and cost-effectiveness were compared between groups using nonparametric t-test, analysis of variance, and Kaplan-Meier analysis. The three groups were comparable in terms of age, sex, comorbidity, and Society for Vascular Surgery/International Society of Cardiovascular Surgery clinical classification. Six-month mean improvement in ABI in the DUAM group was comparable to that in the DSA group (P = 0.25) and significantly better than that in the MRA group (P < 0.05). Six-month patency rates for the DUAM group were comparable to those in the DSA group (P = 0.68, relative risk [RR] = 0.74, 95% confidence interval [CI] 0.18-2.99) and superior to that in the MRA group (P = 0.022, RR = 0.255, 95% CI 0.09-0.71). Length of hospital stay was lower in the DUAM group compared with the DSA group (P < 0.0001) and the MRA group (P = 0.0003). The cost of DUAM is lower than that of both DSA and MRA. DUAM accurately identified the

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. [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.

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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

  4. [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.

  5. 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

  6. [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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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.

  19. [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.

  20. 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.

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. [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.

  11. 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

  12. [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.

  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. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. 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.

  9. [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.

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  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.

  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. 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

  2. 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

  3. 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.

  4. [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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. 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.

  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. 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

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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…

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. 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 ...

  9. 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

  10. 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…

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. Arterial surgery for arm ischemia. A survey of 136 patients.

    PubMed Central

    Holleman, J H; Hardy, J D; Williamson, J W; Raju, S; Neely, W A

    1980-01-01

    A series of 136 patients with upper extremity ischemia requiring operative correction is presented. Causes of the ischemia included trauma, atherosclerosis, embolism, iatrogenic causes, radiation injury, and cervical rib syndrome. Operations included primary repair, various bypass grafts and embolectomy. Illustrative case reports are used to emphasize important points. The subclavian, axillary and brachial arteries have been considered separately. In general, ischemia of the arm caused by a discrete lesion is amenable to surgical correction with an excellent change of success. Images Fig. 1. Figs. 5a and b. Fig. 7. Fig. 8. Fig. 9. PMID:7387235

  17. 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…

  18. 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…

  19. 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…

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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).

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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

  16. [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.

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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.

  6. Critical thinking.

    PubMed

    Price, A; Price, B

    1996-05-01

    Critical thinking is a process applied to midwifery theory, research and experience. It is a positive activity, responsive to context, drawing on negative and positive triggers and emotions to suggest ways of acting in future. Practice-based and reflective midwifery assignments should reflect the midwifery goals of critical thinking. This may require adjustments in assessment criteria and a questioning of standard academic conventions.

  7. Critical Muralism

    ERIC Educational Resources Information Center

    Rosette, Arturo

    2009-01-01

    This study focuses on the development and practices of Critical Muralists--community-educator-artist-leader-activists--and situates these specifically in relation to the Mexican mural tradition of los Tres Grandes and in relation to the history of public art more generally. The study examines how Critical Muralists address artistic and…

  8. 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

  9. 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.

  10. 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

  11. Biphasic modulation of the mitochondrial electron transport chain in myocardial ischemia and reperfusion.

    PubMed

    Lee, Hsin-Ling; Chen, Chwen-Lih; Yeh, Steve T; Zweier, Jay L; Chen, Yeong-Renn

    2012-04-01

    Mitochondrial electron transport chain (ETC) is the major source of reactive oxygen species during myocardial ischemia-reperfusion (I/R) injury. Ischemic defect and reperfusion-induced injury to ETC are critical in the disease pathogenesis of postischemic heart. The properties of ETC were investigated in an isolated heart model of global I/R. Rat hearts were subjected to ischemia for 30 min followed by reperfusion for 1 h. Studies of mitochondrial function indicated a biphasic modulation of electron transfer activity (ETA) and ETC protein expression during I/R. Analysis of ETAs in the isolated mitochondria indicated that complexes I, II, III, and IV activities were diminished after 30 min of ischemia but increased upon restoration of flow. Immunoblotting analysis and ultrastructural analysis with transmission electron microscopy further revealed marked downregulation of ETC in the ischemic heart and then upregulation of ETC upon reperfusion. No significant difference in the mRNA expression level of ETC was detected between ischemic and postischemic hearts. However, reperfusion-induced ETC biosynthesis in myocardium can be inhibited by cycloheximide, indicating the involvement of translational control. Immunoblotting analysis of tissue homogenates revealed a similar profile in peroxisome proliferator-activated receptor-γ coactivator-1α expression, suggesting its essential role as an upstream regulator in controlling ETC biosynthesis during I/R. Significant impairment caused by ischemic and postischemic injury was observed in the complexes I- III. Analysis of NADH ferricyanide reductase activity indicated that injury of flavoprotein subcomplex accounts for 50% decline of intact complex I activity from ischemic heart. Taken together, our findings provide a new insight into the molecular mechanism of I/R-induced mitochondrial dysfunction.

  12. Collateral blood flow in different cerebrovascular hierarchy provides endogenous protection in cerebral ischemia.

    PubMed

    Luo, Chuanming; Liang, Fengyin; Ren, Huixia; Yao, Xiaoli; Liu, Qiang; Li, Mingyue; Qin, Dajiang; Yuan, Ti-Fei; Pei, Zhong; Su, Huanxing

    2016-11-15

    Collateral blood flow as vascular adaptions to focal cerebral ischemia is well recognized. However, few studies directly investigate the dynamics of collateral vessel recruitment in vivo and little is known about the effect of collateral blood flow in different cerebrovascular hierarchy on the neuropathology after focal ischemic stroke. Here, we report that collateral blood flow is critically involved in blood vessel compensations following regional ischemia. We occluded a pial arteriole using femtosecond laser ablating under the intact thinned skull and documented the changes of collateral flow around the surface communication network and between the surface communication network and subsurface microcirculation network using in vivo two photon microscopy imaging. Occlusion of the pial arteriole apparently increased the diameter and collateral blood flow of its leptomeningeal anastomoses, which significantly reduced the cortical infarction size. This result suggests that the collateral flow via surface communicating network connected with leptomeningeal anastomoses could greatly impact on the extent of infarction. We then further occluded the target pial arteriole and all of its leptomeningeal anastomoses. Notably, this type of occlusion led to reversals of blood flow in the penetrating arterioles mainly proximal to the occluded pial arteriole in a direction from the subsurface microcirculation network to surface arterioles. Interesting, the cell death in the area of ischemic penumbra was accelerated when we performed occlusion to cease the reversed blood flow in those penetrating arterioles, suggesting that the collateral blood flow from subsurface microcirculation network exerts protective roles in delaying cell death in the ischemic penumbra. In conclusion, we provide the first experimental evidence that collateral blood vessels at different cerebrovascular hierarchy are endogenously compensatory mechanisms in brain ischemia. This article is protected by

  13. 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 major causes of AKI and is characterized by uncontrolled renal inflammation and tubular epithelial cell death. Our recent studies demonstrated that regulatory T cells (Tregs) protect the kidney from ischemia reperfusion-induced inflammation and injury. Blockade of programmed death-1 (PD-1) on the surface of Tregs, prior to adoptive transfer, negates their ability to protect against ischemic kidney injury. The present study was designed to investigate the role of the known PD-1 ligands, PD-L1 and PD-L2, in kidney IRI. Administration of PD-L1 or PD-L2 blocking Abs prior to mild or moderate kidney IRI significantly exacerbated the loss of renal function, renal inflammation, and acute tubular necrosis compared with mice receiving isotype control Abs. Interestingly, blockade of both PD-1 ligands resulted in worse injury, dysfunction, and inflammation than did blocking either ligand alone. Genetic deficiency of either PD-1 ligand also exacerbated kidney dysfunction and acute tubular necrosis after subthreshold ischemia. Bone marrow chimeric studies revealed that PD-L1 expressed on non-bone marrow-derived cells is critical for this resistance to IRI. Finally, blockade of either PD-1 ligand negated the protective ability of adoptively transferred Tregs in IRI. These findings suggest that PD-L1 and PD-L2 are nonredundant aspects of the natural protective response to ischemic injury and may be novel therapeutic targets for AKI.

  14. 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

  15. Critics and Criticism of Education

    ERIC Educational Resources Information Center

    Ornstein, Allan C.

    1977-01-01

    Radical educational critics, such as Edgar Friedenberg, Paul Goodman, A. S. Neill, John Holt, Jonathan Kozol, Herbert Kohl, James Herndon, and Ivan Illich, have few constructive goals, no strategy for broad change, and a disdain for modernization and compromise. Additionally, these critics, says the author, fail to consider social factors related…

  16. Outcomes of lower extremity bypass performed for acute limb ischemia

    PubMed Central

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

    2013-01-01

    Objective Acute limb ischemia remains one of the most challenging emergencies in vascular surgery. Historically, outcomes following interventions for acute limb ischemia have been associated with high rates of morbidity and mortality. The purpose of this study was to determine contemporary outcomes following lower extremity bypass performed for acute limb ischemia. Methods All patients undergoing infrainguinal lower extremity bypass between 2003 and 2011 within hospitals comprising the Vascular Study Group of New England were identified. Patients were stratified according to whether or not the indication for lower extremity bypass was acute limb ischemia. Primary end points included bypass graft occlusion, major amputation, and mortality at 1 year postoperatively as determined by Kaplan-Meier life table analysis. Multivariable Cox proportional hazards models were constructed to evaluate independent predictors of mortality and major amputation at 1 year. Results Of 5712 lower extremity bypass procedures, 323 (5.7%) were performed for acute limb ischemia. Patients undergoing lower extremity bypass for acute limb ischemia were similar in age (66 vs 67; P = .084) and sex (68% male vs 69% male; P = .617) compared with chronic ischemia patients, but were less likely to be on aspirin (63% vs 75%; P < .0001) or a statin (55% vs 68%; P < .0001). Patients with acute limb ischemia were more likely to be current smokers (49% vs 39%; P < .0001), to have had a prior ipsilateral bypass (33% vs 24%; P = .004) or a prior ipsilateral percutaneous intervention (41% vs 29%; P = .001). Bypasses performed for acute limb ischemia were longer in duration (270 vs 244 minutes; P = .007), had greater blood loss (363 vs 272 mL; P < .0001), and more commonly utilized prosthetic conduits (41% vs 33%; P = .003). Acute limb ischemia patients experienced increased in-hospital major adverse events (20% vs 12%; P < .0001) including myocardial infarction, congestive heart failure exacerbation

  17. TGF-β1 prevents simulated ischemia/reperfusion-induced cardiac fibroblast apoptosis by activation of both canonical and non-canonical signaling pathways.

    PubMed

    Vivar, Raúl; Humeres, Claudio; Ayala, Pedro; Olmedo, Ivonne; Catalán, Mabel; García, Lorena; Lavandero, Sergio; Díaz-Araya, Guillermo

    2013-06-01

    Ischemia/reperfusion injury is a major cause of myocardial death. In the heart, cardiac fibroblasts play a critical role in healing post myocardial infarction. TGF-β1 has shown cardioprotective effects in cardiac damage; however, if TGF-β1 can prevent cardiac fibroblast death triggered by ischemia/reperfusion is unknown. Therefore, we test this hypothesis, and whether the canonical and/or non-canonical TGF-β1 signaling pathways are involved in this protective effect. Cultured rat cardiac fibroblasts were subjected to simulated ischemia/reperfusion. Cell viability was analyzed by trypan blue exclusion and propidium iodide by flow cytometry. The processing of procaspases 8, 9 and 3 to their active forms was assessed by Western blot, whereas subG1 population was evaluated by flow cytometry. Levels of total and phosphorylated forms of ERK1/2, Akt and Smad2/3 were determined by Western blot. The role of these signaling pathways on the protective effect of TGF-β1 was studied using specific chemical inhibitors. Simulated ischemia over 8h triggers a significant cardiac fibroblast death, which increased by reperfusion, with apoptosis actively involved. These effects were only prevented by the addition of TGF-β1 during reperfusion. TGF-β1 pretreatment increased the levels of phosphorylated forms of ERK1/2, Akt and Smad2/3. The inhibition of ERK1/2, Akt and Smad3 also blocked the preventive effects of TGF-β1 on cardiac fibroblast apoptosis induced by simulated ischemia/reperfusion. Overall, our data suggest that TGF-β1 prevents cardiac fibroblast apoptosis induced by simulated ischemia-reperfusion through the canonical (Smad3) and non canonical (ERK1/2 and Akt) signaling pathways.

  18. Critical Careers.

    ERIC Educational Resources Information Center

    Bowles, Roger A.

    2001-01-01

    Reports the critical shortage of qualified equipment technicians, especially in biomedical equipment. Cites the importance of encouraging careers in this field and describes a source of occupational information. (SK)

  19. Diastolic dysfunction in the critically ill patient.

    PubMed

    Suárez, J C; López, P; Mancebo, J; Zapata, L

    2016-11-01

    Left ventricular diastolic dysfunction is a common finding in critically ill patients. It is characterized by a progressive deterioration of the relaxation and the compliance of the left ventricle. Two-dimensional and Doppler echocardiography is a cornerstone in its diagnosis. Acute pulmonary edema associated with hypertensive crisis is the most frequent presentation of diastolic dysfunction critically ill patients. Myocardial ischemia, sepsis and weaning failure from mechanical ventilation also may be associated with diastolic dysfunction. The treatment is based on the reduction of pulmonary congestion and left ventricular filling pressures. Some studies have found a prognostic role of diastolic dysfunction in some diseases such as sepsis. The present review aims to analyze thoroughly the echocardiographic diagnosis and the most frequent scenarios in critically ill patients in whom diastolic dysfunction plays a key role.

  20. Treatment of Digital Ischemia with Liposomal Bupivacaine

    PubMed Central

    Raul Soberón, José; Duncan, Scott F.; Sternbergh, W. Charles

    2014-01-01

    Objective. This report describes a case in which the off-label use of liposomal bupivacaine (Exparel) in a peripheral nerve block resulted in marked improvement of a patient's vasoocclusive symptoms. The vasodilating and analgesic properties of liposomal bupivacaine in patients with ischemic symptoms are unknown, but our clinical experience suggests a role in the management of patients suffering from vasoocclusive disease. Case Report. A 45-year-old African American female was admitted to the hospital with severe digital ischemic pain. She was not a candidate for any vascular surgical or procedural interventions. Two continuous supraclavicular nerve blocks were placed with modest clinical improvement. These effects were also short-lived, with the benefits resolving after the discontinuation of the peripheral nerve blocks. She continued to report severe pain and was on multiple anticoagulant medications, so a decision was made to perform an axillary nerve block using liposomal bupivacaine (Exparel) given the compressibility of the site as well as the superficial nature of the target structures. Conclusions. This case report describes the successful off-label usage of liposomal bupivacaine (Exparel) in a patient with digital ischemia. Liposomal bupivacaine (Exparel) is currently FDA approved only for wound infiltration use at this time. PMID:24653844

  1. [Neurologically critical patient. Nurses' care].

    PubMed

    López Díaz, Cristina

    2009-12-01

    Handling a neurologically critical patient requires some necessary knowledge and aptitudes in order to avoid risks and complications which could worsen a patient's prognosis. To that end, in this article the author deals with two important points nursing personnel need to bear in mind: the distinct methods and catheters which can be used to monitor intracranial pressure, obtaining an important parameter for evaluation purposes and therapeutic follow-up on these patients, placing special emphasis on ventricular drainage and nursing care, and the operations nurses take when dealing with patients who present a risk of intracranial hypertension, setting up a protocol based on seven necessities in the Virginia Henderson model: breathing, elimination, temperature, hygiene and skin, feeding and hydration, mobility and safety. In each of these necessities, the author studies the problems these patients present, identifying them with a series of diagnoses according to NANDA (North American Nursing Diagnosis Association), and defining the care or nursing activities for each of them, which will prove essential to prevent cerebral ischemia after suffering a primary cerebral injury due to a "TCE"(Cranial Encephalic Trauma) hemorrhage, etc. Nurses' role in caring for neurologically critical patients proves to be of vital importance since these professionals must be capable of evaluating, preventing, controlling and identifying those risk situations which neurologically critical patients could present, avoiding possible complications, aiding their recuperation, and providing quality health care.

  2. Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage

    NASA Astrophysics Data System (ADS)

    Webb, Andrew; Bond, Richard; McLean, Peter; Uppal, Rakesh; Benjamin, Nigel; Ahluwalia, Amrita

    2004-09-01

    Nitric oxide (NO) is thought to protect against the damaging effects of myocardial ischemia-reperfusion injury, whereas xanthine oxidoreductase (XOR) normally causes damage through the generation of reactive oxygen species. In the heart, inorganic nitrite has the potential to act as an endogenous store of NO, liberated specifically during ischemia. Using a detection method that we developed, we report that under ischemic conditions both rat and human homogenized myocardium and the isolated perfused rat heart (Langendorff preparation) generate NO from in a reaction that depends on XOR activity. Functional studies of rat hearts in the Langendorff apparatus showed that nitrite (10 and 100 µM) reduced infarct size from 47.3 ± 2.8% (mean percent of control ± SEM) to 17.9 ± 4.2% and 17.4 ± 1.0%, respectively (P < 0.001), and was associated with comparable improvements in recovery of left ventricular function. This protective effect was completely blocked by the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide (carboxy-PTIO). In summary, the generation of NO from •, rather than damaging.

  3. PARP Inhibition Attenuates Histopathological Lesion in Ischemia/Reperfusion Renal Mouse Model after Cold Prolonged Ischemia

    PubMed Central

    del Moral, Raimundo M. G.; Gómez-Morales, Mercedes; Aguilar, David; Caballero, Trinidad; Aneiros-Fernández, Jose; Caba-Molina, Mercedes; Rodríguez-Martínez, Mª  Dolores; Peralta, Andreina; Galindo-Moreno, Pablo; Osuna, Antonio; Oliver, F. Javier

    2013-01-01

    We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN) and other renal lesions related to prolonged cold ischemia/reperfusion (IR) in kidneys preserved at 4°C in University of Wisconsin (UW) solution. Material and Methods. We used 30 male Parp1+/+ wild-type and 15 male Parp10/0 knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ). We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp10/0 knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation. PMID:24319370

  4. [Changes in the receptor function of Na,K-ATPase during hypoxia and ischemia].

    PubMed

    Lakunina, V A; Burnysheva, K M; Mitkevich, V A; Makarov, A A; Petrushanko, I Y

    2017-01-01

    Na,K-ATPase maintains sodium and potassium homeostasis. It is the only known receptor for cardiotonic steroids such as ouabain. Binding of ouabain to Na,K-ATPase leads to the activation of Src kinase and the subsequent initiation of intracellular signaling pathways, including the induction of apoptosis. Changes in Na,K-ATPase activity is one of the earliest responses to hypoxia and is most critical for cell survival. However, it is not known how the hypoxia affects the functioning of Na,K-ATPase as a receptor. We have shown that, under the conditions of hypoxia and ischemia, ouabain is less toxic for murine fibroblast cells (SC-1 cell line) and ouabain does not cause an increase in the level of reactive oxygen species, which is typically observed at 20% pO2. Under hypoxia, the treatment of cells with ouabain also does not lead to the activation of Na,K-ATPase-associated Src kinase. Thus, at low oxygen content, the receptor function of Na,K-ATPase is altered, and cells become less sensitive to cardiotonic steroids. The decrease in sensitivity to cardiotonic steroids, which is evident at hypoxic conditions, should be taken into account in clinical practice. At the same time, in the presence of ouabain the cells are less sensitive to hypoxia, which indicates that cardiotonic steroids can be protective in acute ischemia.

  5. MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain.

    PubMed

    Qu, Yi; Shi, Jing; Tang, Ying; Zhao, Fengyan; Li, Shiping; Meng, Junjie; Tang, Jun; Lin, Xuemei; Peng, Xiaodong; Mu, Dezhi

    2016-05-01

    Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain.

  6. The protein kinase 2 inhibitor tetrabromobenzotriazole protects against renal ischemia reperfusion injury

    PubMed Central

    Ka, Sun-O; Hwang, Hong Pil; Jang, Jong-Hwa; Hyuk Bang, In; Bae, Ui-Jin; Yu, Hee Chul; Cho, Baik Hwan; Park, Byung-Hyun

    2015-01-01

    Protein kinase 2 (CK2) activation was reported to enhance reactive oxygen species production and activate the nuclear factor κB (NF-κB) pathway. Because oxidative stress and inflammation are critical events for tissue destruction during ischemia reperfusion (I/R), we sought to determine whether CK2 was important in the renal response to I/R. Mice underwent 25 min of renal ischemia and were then reperfused. We confirmed an increased expression of CK2α during the reperfusion period, while expression of CK2β remained consistent. We administered tetrabromobenzotriazole (TBBt), a selective CK2α inhibitor before inducing I/R injury. Mice subjected to I/R injury showed typical patterns of acute kidney injury; blood urea nitrogen and serum creatinine levels, tubular necrosis and apoptosis, inflammatory cell infiltration and proinflammatory cytokine production, and oxidative stress were markedly increased when compared to sham mice. However, pretreatment with TBBt abolished these changes and improved renal function and architecture. Similar renoprotective effects of CK2α inhibition were observed for emodin. Renoprotective effects of CK2α inhibition were associated with suppression of NF-κB and mitogen activated protein kinase (MAPK) pathways. Taken together, these results suggest that CK2α mediates proapoptotic and proinflammatory signaling, thus the CK2α inhibitor may be used to prevent renal I/R injuries observed in clinical settings. PMID:26423352

  7. Fluorometry of ischemia reperfusion injury in rat lungs in vivo

    NASA Astrophysics Data System (ADS)

    Sepehr, R.; Staniszewski, K.; Jacobs, E. R.; Audi, S.; Ranji, Mahsa

    2013-02-01

    Previously we demonstrated the utility of optical fluorometry to evaluate lung tissue mitochondrial redox state in isolated perfused rats lungs under various chemically-induced respiratory states. The objective of this study was to evaluate the effect of acute ischemia on lung tissue mitochondrial redox state in vivo using optical fluorometry. Under ischemic conditions, insufficient oxygen supply to the mitochondrial chain should reduce the mitochondrial redox state calculated from the ratio of the auto-fluorescent mitochondrial metabolic coenzymes NADH (Nicotinamide Adenine Dinucleotide) and FAD (Flavoprotein Adenine Dinucleotide). The chest of anesthetized, and mechanically ventilated Sprague-Dawley rat was opened to induce acute ischemia by clamping the left hilum to block both blood flow and ventilation to one lung for approximately 10 minutes. NADH and FAD fluorescent signals were recorded continuously in a dark room via a fluorometer probe placed on the pleural surface of the left lung. Acute ischemia caused a decrease in FAD and an increase in NADH, which resulted in an increase in the mitochondrial redox ratio (RR=NADH/FAD). Restoration of blood flow and ventilation by unclamping the left hilum returned the RR back to its baseline. These results (increase in RR under ischemia) show promise for the fluorometer to be used in a clinical setting for evaluating the effect of pulmonary ischemia-reperfusion on lung tissue mitochondrial redox state in real time.

  8. How much ischemia can the liver tolerate during resection?

    PubMed Central

    van Riel, Wouter G.; van Golen, Rowan F.; Reiniers, Megan J.; Heger, Michal

    2016-01-01

    The use of vascular inflow occlusion (VIO, also known as the Pringle maneuver) during liver surgery prevents severe blood loss and the need for blood transfusion. The most commonly used technique for VIO entails clamping of the portal triad, which simultaneously occludes the proper hepatic artery and portal vein. Although VIO is an effective technique to reduce intraoperative blood loss, it also inevitably inflicts hepatic ischemia/reperfusion (I/R) injury as a side effect. I/R injury induces formation of reactive oxygen species that cause oxidative stress and cell death, ultimately leading to a sterile inflammatory response that causes hepatocellular damage and liver dysfunction that can result in acute liver failure in most severe cases. Since the duration of ischemia correlates positively with the severity of liver injury, there is a need to find the balance between preventing severe blood loss and inducing liver damage through the use of VIO. Although research on the maximum duration of hepatic ischemia has intensified since the beginning of the 1980s, there still is no consensus on the tolerable upper limit. Based on the available literature, it is concluded that intermittent and continuous VIO can both be used safely when ischemia times do not exceed 120 min. However, intermittent VIO should be the preferred technique in cases that require >120 min duration of ischemia. PMID:26904558

  9. Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy

    PubMed Central

    Papadakis, Michalis; Hadley, Gina; Xilouri, Maria; Hoyte, Lisa C.; Nagel, Simon; McMenamin, M Mary; Tsaknakis, Grigorios; Watt, Suzanne M.; Drakesmith, Cynthia Wright; Chen, Ruoli; Wood, Matthew J A; Zhao, Zonghang; Kessler, Benedikt; Vekrellis, Kostas; Buchan, Alastair M.

    2013-01-01

    Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke1. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia2 and the tolerance conferred by ischemic preconditioning (IPC)3, would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism. PMID:23435171

  10. Intestinal Injury Currents Associated with Mesenteric Ischemia and Reperfusion

    NASA Astrophysics Data System (ADS)

    Cordova, T.; Bradshaw, L. A.; O'Mahony, G. P.; Gallucci, M. R.; Berch, B.; Richards, W. O.

    2006-09-01

    A non-invasive method of detecting mesenteric ischemia is presented. The aim of this study was to evaluate the effect of arterial reperfusion on these injury currents. The small bowel of New Zealand white rabbits was exteriorized and the mesenteric blood flow interrupted. Experiments were conducted in three groups, control (n = 3), ischemia (n = 6) and reperfusion following ischemia (n = 5). The subject's position was modulated in and out of the biological field detection range of a SQUID magnetometer. The changes in magnetic field amplitude for the experimental groups were 9.3% and 31.0% for the control and the ischemia groups respectively. The reperfusion group first exhibited a decrease of 17.4% from pre-ischemic to the ischemic period followed by an increase of 13.9% of the ischemic value after re-establishing perfusion. It is concluded that injury currents in GI smooth muscle that appear during ischemia are reduced to pre-ischemic levels during reperfusion.

  11. The divergent roles of autophagy in ischemia and preconditioning

    PubMed Central

    Sheng, Rui; Qin, Zheng-hong

    2015-01-01

    Autophagy is an evolutionarily conserved and lysosome-dependent process for degrading and recycling cellular constituents. Autophagy is activated following an ischemic insult or preconditioning, but it may exert dual roles in cell death or survival during these two processes. Preconditioning or lethal ischemia may trigger autophagy via multiple signaling pathways involving endoplasmic reticulum (ER) stress, AMPK/TSC/mTOR, Beclin 1/BNIP3/SPK2, and FoxO/NF-κB transcription factors, etc. Autophagy then interacts with apoptotic and necrotic signaling pathways to regulate cell death. Autophagy may also maintain cell function by removing protein aggregates or damaged mitochondria. To date, the dual roles of autophagy in ischemia and preconditioning have not been fully clarified. The purpose of the present review is to summarize the recent progress in the mechanisms underlying autophagy activation during ischemia and preconditioning. A better understanding of the dual effects of autophagy in ischemia and preconditioning could help to develop new strategies for the preventive treatment of ischemia. PMID:25832421

  12. Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy.

    PubMed

    Papadakis, Michalis; Hadley, Gina; Xilouri, Maria; Hoyte, Lisa C; Nagel, Simon; McMenamin, M Mary; Tsaknakis, Grigorios; Watt, Suzanne M; Drakesmith, Cynthia Wright; Chen, Ruoli; Wood, Matthew J A; Zhao, Zonghang; Kessler, Benedikt; Vekrellis, Kostas; Buchan, Alastair M

    2013-03-01

    Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism.

  13. Primary Infrainguinal Subintimal Angioplasty in Diabetic Patients

    SciTech Connect

    Bargellini, Irene Petruzzi, Pasquale; Scatena, Alessia; Cioni, Roberto; Cicorelli, Antonio; Vignali, Claudio; Rizzo, Loredana; Piaggesi, Alberto; Bartolozzi, Carlo

    2008-07-15

    The aim of this study was to prospectively evaluate technical and clinical results of infrainguinal subintimal angioplasty in a series of diabetic patients with limb-threatening ischemia. From July 2003 to December 2007, 60 consecutive diabetic patients (M/F = 41/19; mean age, 69.4 {+-} 9.4 years) with Fontaine stage IV critical limb ischemia, not suitable for surgical recanalization, underwent primary infrainguinal subintimal angioplasty. The technical success, perioperative morbidity and mortality, and clinical success (defined by ulcer healing) were evaluated. Kaplan-Meier life-table analysis was obtained for cumulative clinical success, limb salvage, and survival rates. The procedure was technically successful in 55 of 60 (91.7%) patients; in 5 cases we were not able to achieve a reentry. Periprocedural mortality was 5% (3 patients); three patients (5%) required major amputation periprocedurally. Mean follow-up was 23 months (range, 0-48 months). On an intention-to-treat basis, the limb salvage rate was 93.3% (56/60 patients); ulcer healing was observed in 45 of 60 (75%) patients and it was significantly (p < 0.05) associated with serum creatinine and HbA1c levels, diabetes duration, and infrapopliteal recanalization. One- and three-year cumulative survival rates were 91.5% and 83.1%, respectively; serum creatinine levels, patient age, and clinical success were significant predictors of survival. In conclusion, infrainguinal primary subintimal angioplasty is a safe and effective treatment in diabetic patients with limb-threatening ischemia not suitable for surgical recanalization. This procedure is aimed to create a 'temporary bypass' that facilitates ulcer healing.

  14. Effect of Polyphenols on Oxidative Stress and Mitochondrial Dysfunction in Neuronal Death and Brain Edema in Cerebral Ischemia

    PubMed Central

    Panickar, Kiran S.; Anderson, Richard A.

    2011-01-01

    Polyphenols are natural substances with variable phenolic structures and are elevated in vegetables, fruits, grains, bark, roots, tea, and wine. There are over 8000 polyphenolic structures identified in plants, but edible plants contain only several hundred polyphenolic structures. In addition to their well-known antioxidant effects, select polyphenols also have insulin-potentiating, anti-inflammatory, anti-carcinogenic, anti-viral, anti-ulcer, and anti-apoptotic properties. One important consequence of ischemia is neuronal death and oxidative stress plays a key role in neuronal viability. In addition, neuronal death may be initiated by the activation of mitochondria-associated cell death pathways. Another consequence of ischemia that is possibly mediated by oxidative stress and mitochondrial dysfunction is glial swelling, a component of cytotoxic brain edema. The purpose of this article is to review the current literature on the contribution of oxidative stress and mitochondrial dysfunction to neuronal death, cell swelling, and brain edema in ischemia. A review of currently known mechanisms underlying neuronal death and edema/cell swelling will be undertaken and the potential of dietary polyphenols to reduce such neural damage will be critically reviewed. PMID:22174658

  15. PARK2-dependent mitophagy induced by acidic postconditioning protects against focal cerebral ischemia and extends the reperfusion window

    PubMed Central

    Shen, Zhe; Zheng, Yanrong; Wu, Jiaying; Chen, Ying; Wu, Xiaoli; Zhou, Yiting; Yuan, Yang; Lu, Shousheng; Jiang, Lei; Qin, Zhenghong; Chen, Zhong; Hu, Weiwei; Zhang, Xiangnan

    2017-01-01

    ABSTRACT Prompt reperfusion after cerebral ischemia is critical for neuronal survival. Any strategies that extend the limited reperfusion window will be of great importance. Acidic postconditioning (APC) is a mild acidosis treatment that involves inhaling CO2 during reperfusion following ischemia. APC attenuates ischemic brain injury although the underlying mechanisms have not been elucidated. Here we report that APC reinforces ischemia-reperfusion-induced mitophagy in middle cortical artery occlusion (MCAO)-treated mice, and in oxygen-glucose deprivation (OGD)-treated brain slices and neurons. Inhibition of mitophagy compromises neuroprotection conferred by APC. Furthermore, mitophagy and neuroprotection are abolished in Park2 knockout mice, indicating that APC-induced mitophagy is facilitated by the recruitment of PARK2 to mitochondria. Importantly, in MCAO mice, APC treatment extended the effective reperfusion window from 2 to 4 h, and this window was further extended to 6 h by exogenously expressing PARK2. Taken together, we found that PARK2-dependent APC-induced mitophagy renders the brain resistant to ischemic injury. APC treatment could be a favorable strategy to extend the thrombolytic time window for stroke therapy. PMID:28103118

  16. Targeting Glial Mitochondrial Function for Protection from Cerebral Ischemia: Relevance, Mechanisms, and the Role of MicroRNAs

    PubMed Central

    Li, Le

    2016-01-01

    Astrocytes and microglia play crucial roles in the response to cerebral ischemia and are effective targets for stroke therapy in animal models. MicroRNAs (miRs) are important posttranscriptional regulators of gene expression that function by inhibiting the translation of select target genes. In astrocytes, miR expression patterns regulate mitochondrial function in response to oxidative stress via targeting of Bcl2 and heat shock protein 70 family members. Mitochondria play an active role in microglial activation, and miRs regulate the microglial neuroinflammatory response. As endogenous miR expression patterns can be altered with exogenous mimics and inhibitors, miR-targeted therapies represent a viable intervention to optimize glial mitochondrial function and improve clinical outcome following cerebral ischemia. In the present article, we review the role that astrocytes and microglia play in neuronal function and fate following ischemic stress, discuss the relevance of mitochondria in the glial response to injury, and present current evidence implicating miRs as critical regulators in the glial mitochondrial response to cerebral ischemia. PMID:27777645

  17. [Painless myocardial ischemia in patient with extensive constrictive atherosclerosis of coronary arteries].

    PubMed

    Oshchepkova, E V; Lazareva, N V

    2012-01-01

    We describe in this article a clinical case of a patient with arterial hypertension, painless myocardial ischemia and extensive constrictive atherosclerosis of coronary arteries. Coronary heart disease (painless ischemia) was suspected basing on results of transesophageal electrostimulation coupled with stress echocardiography and was confirmed by coronary angiography. This description is followed by discussion of possibilities of different instrumental methods in diagnostics of painless ischemia, classification of painless ischemia, treatment, and prognosis.

  18. In Vivo Detection of Macrophage Recruitment in Hind-Limb Ischemia Using a Targeted Near-Infrared Fluorophore

    PubMed Central

    Yoo, Jung Sun; Das, Raj Kumar; Jow, Zhi Yen; Chang, Young-Tae

    2014-01-01

    Macrophages are an essential component of the immune system and have protective and pathogenic functions in various diseases. Imaging of macrophages in vivo could furnish new tools to advance evaluation of disease and therapies. Critical limb ischemia is a disease in which macrophages have considerable pathogenic roles, and are potential targets for cell-based immunotherapy. We sought to develop a new near-infrared fluorescence (NIRF) imaging probe to target macrophages specifically in vivo in various pathological states, including hind-limb ischemia. We rapidly screened the photostable cyanine-based NIRF library against different blood cell lines. The identified monocyte/macrophage-selective hit was tested in vitro in live-cell labeling assay. Non-invasive NIRF imaging was performed with murine models of paw inflammation by lipopolysaccharide challenge and hind-limb ischemia with femoral artery ligation. in vivo macrophage targeting was further evaluated using intravital microscopy with Csf1r-EGFP transgenic mice and immunofluorescent staining with macrophage-specific markers. We discovered MF800, a Macrophage-specific near-infrared Fluorophore, which showed selective live-cell imaging performance in a panel of cell lines and primary human blood samples. MF800 outperforms the clinically-available NIRF contrast agent ICG for in vivo specificity in paw inflammation and hind-limb ischemia models. We observed a marked overlap of MF800-labeled cells and EGFP-expressing macrophages in intravital imaging of Csf1r-EGFP transgenic mice. In the histologic analysis, MF800-positive cells also expressed the macrophage markers CD68 and CD169. NIRF imaging showcased the potential of using MF800 to understand macrophage behavior in vivo, characterize macrophage-associated diseases, and may help in assessing therapeutic responses in the clinic. PMID:25072508

  19. Exercise preconditioning exhibits neuroprotective effects on hippocampal CA1 neuronal damage after cerebral ischemia

    PubMed Central

    Shamsaei, Nabi; Khaksari, Mehdi; Erfani, Sohaila; Rajabi, Hamid; Aboutaleb, Nahid

    2015-01-01

    Recent evidence has suggested the neuroprotective effects of physical exercise on cerebral ischemic injury. However, the role of physical exercise in cerebral ischemia-induced hippocampal damage remains controversial. The aim of the present study was to evaluate the effects of pre-ischemia treadmill training on hippocampal CA1 neuronal damage after cerebral ischemia. Male adult rats were randomly divided into control, ischemia and exercise + ischemia groups. In the exercise + ischemia group, rats were subjected to running on a treadmill in a designated time schedule (5 days per week for 4 weeks). Then rats underwent cerebral ischemia induction through occlusion of common carotids followed by reperfusion. At 4 days after cerebral ischemia, rat learning and memory abilities were evaluated using passive avoidance memory test and rat hippocampal neuronal damage was detected using Nissl and TUNEL staining. Pre-ischemic exercise significantly reduced the number of TUNEL-positive cells and necrotic cell death in the hippocampal CA1 region as compared to the ischemia group. Moreover, pre-ischemic exercise significantly prevented ischemia-induced memory dysfunction. Pre-ischemic exercise mighct prevent memory deficits after cerebral ischemia through rescuing hippocampal CA1 neurons from ischemia-induced degeneration. PMID:26487851

  20. Evaluation of cold ischemia for preservation of testicular function during partial orchiectomy in the rat model

    PubMed Central

    McNamara, Erin R.; Madden-Fuentes, Ramiro J.; Routh, Jonathan C.; Rouse, Douglas; Madden, John F.; Wiener, John S.; Rushton, Harry G.; Ross, Sherry S.

    2015-01-01

    Objective We hypothesized that cold ischemia during partial orchiectomy would lead to higher serum testosterone levels and preservation of testicular architecture than warm ischemia in a prepubescent rat model. Materials and methods Eighteen prepubescent male Sprague–Dawley rats were randomized to three different surgical groups: sham surgery, bilateral partial orchiectomy with 30 min of cord compression with cold ischemia, or bilateral partial orchiectomy with 30 min of cord compression with warm ischemia. Animals were killed at puberty, and serum, sperm, and testicles were collected. Histological tissue injury was graded by standardized methodology. Results Mean serum testosterone levels were 1445 ± 590 pg/mL for the sham group, 449 ± 268 pg/mL for the cold ischemia group and 879 ± 631 pg/mL for the warm ischemia group (p = 0.12). Mean sperm counts were 2.1 × 107 for sham, 4.4 × 106 for cold ischemia, and 9.9 × 106 for the warm ischemia groups (p = 0.48). Histological evaluation revealed significant difference in tissue injury grading with more injury in the cold ischemia than in the warm ischemia group (p = 0.01). Conclusions In our preclinical rat model, we found no benefit for cold ischemia over warm ischemia at 30 min. PMID:25128916

  1. [Neuroprotective mechanisms of cannabinoids in brain ischemia and neurodegenerative disorders].

    PubMed

    Osuna-Zazuetal, Marcela Amparo; Ponce-Gómez, Juan Antonio; Pérez-Neri, Iván

    2015-06-01

    One of the most important causes of morbidity and mortality is neurologic dysfunction; its high incidence has led to an intense research of the mechanisms that protect the central nervous system from hypoxia and ischemia. The mayor challenge is to block the biochemical events leading to neuronal death. This may be achieved by neuroprotective mechanisms that avoid the metabolic and immunologic cascades that follow a neurological damage. When it occurs, several pathophysiological events develop including cytokine release, oxidative stress and excitotoxicity. Neuroprotective effects of cannabinoids to all those mechanisms have been reported in animal models of brain ischemia, excitotoxicity, brain trauma and neurodegenerative disorders. Some endocannabinoid analogs are being tested in clinical studies (I-III phase) for acute disorders involving neuronal death (brain trauma and ischemia). The study of the cannabinoid system may allow the discovery of effective neuroprotective drugs for the treatment of neurological disorders.

  2. Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia

    PubMed Central

    Zhang, Yonghua; Kimelberg, Harold K.

    2005-01-01

    Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top killers worldwide, and intensive studies have been performed to reduce neural cell death after cerebral ischemia. Alpha 2-adrenergic agonists have been shown to improve the histomorphological and neurological outcome after cerebral ischemic injury when administered during ischemia, and recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain from ischemia/reperfusion injury. Thus, alpha 2-adrenergic agonists are promising potential drugs in preventing cerebral ischemic injury, but the mechanisms by which alpha 2-adrenergic agonists exert their neuroprotective effect are unclear. Activation of both the alpha 2-adrenergic receptor and imidazoline receptor may be involved. This mini review examines the recent progress in alpha 2-adrenergic agonists - induced neuroprotection and its proposed mechanisms in cerebral ischemic injury. PMID:18369397

  3. Activation of p38MAPK in microglia after ischemia.

    PubMed

    Walton, K M; DiRocco, R; Bartlett, B A; Koury, E; Marcy, V R; Jarvis, B; Schaefer, E M; Bhat, R V

    1998-04-01

    p38MAPK has been implicated in the regulation of proinflammatory cytokines and apoptosis in vitro. To understand its role in neurodegeneration, we determined the time course and localization of the dually phosphorylated active form of p38MAPK in hippocampus after global forebrain ischemia. Phosphorylated p38MAPK and mitogen-activated protein kinase-activated protein 2 activity increased over 4 days after ischemia. Phosphorylated p38MAPK immunoreactivity was observed in microglia in regions adjacent to, but not in, the dying CA1 neurons. In contrast, neither c-Jun N-terminal kinase 1 nor p42/p44MAPK activity was altered after ischemia. These results provide the first evidence for localization of activated p38MAPK in the CNS and support a role for p38MAPK in the microglial response to stress.

  4. Reformulated meat products protect against ischemia-induced cardiac damage.

    PubMed

    Asensio-Lopez, M C; Lax, A; Sanchez-Mas, J; Avellaneda, A; Planes, J; Pascual-Figal, D A

    2016-02-01

    The protective effects of the antioxidants present in food are of great relevance for cardiovascular health. This study evaluates whether the extracts from reformulated meat products with a reduction in fat and/or sodium content exert a cardioprotective effect against ischemia-induced oxidative stress in cardiomyocytes, compared with non-meat foods. Ischemic damage caused loss of cell viability, increased reactive oxygen species and lipid peroxidation and decreased the antioxidant activity. Pretreatment for 24 h with digested or non-digested extracts from reformulated meat products led to protection against ischemia-induced oxidative damage: increased cell viability, reduced oxidative stress and restored the antioxidant activity. Similar results were obtained using extracts from tuna fish, but not with the extracts of green peas, salad or white beans. These results suggest that reformulated meat products have a beneficial impact in protecting cardiac cells against ischemia, and they may represent a source of natural antioxidants with benefits for cardiovascular health.

  5. Glutamate transporters in brain ischemia: to modulate or not?

    PubMed Central

    Krzyżanowska, Weronika; Pomierny, Bartosz; Filip, Małgorzata; Pera, Joanna

    2014-01-01

    In this review, we briefly describe glutamate (Glu) metabolism and its specific transports and receptors in the central nervous system (CNS). Thereafter, we focus on excitatory amino acid transporters, cystine/glutamate antiporters (system xc-) and vesicular glutamate transporters, specifically addressing their location and roles in CNS and the molecular mechanisms underlying the regulation of Glu transporters. We provide evidence from in vitro or in vivo studies concerning alterations in Glu transporter expression in response to hypoxia or ischemia, including limited human data that supports the role of Glu transporters in stroke patients. Moreover, the potential to induce brain tolerance to ischemia through modulation of the expression and/or activities of Glu transporters is also discussed. Finally we present strategies involving the application of ischemic preconditioning and pharmacological agents, eg β-lactam antibiotics, amitriptyline, riluzole and N-acetylcysteine, which result in the significant protection of nervous tissues against ischemia. PMID:24681894

  6. Myocardial perfusion imaging for detection of silent myocardial ischemia

    SciTech Connect

    Beller, G.A.

    1988-04-21

    Despite the widespread use of the exercise stress test in diagnosing asymptomatic myocardial ischemia, exercise radionuclide imaging remains useful for detecting silent ischemia in numerous patient populations, including those who are totally asymptomatic, those who have chronic stable angina, those who have recovered from an episode of unstable angina or an uncomplicated myocardial infarction, and those who have undergone angioplasty or received thrombolytic therapy. Studies show that thallium scintigraphy is more sensitive than exercise electrocardiography in detecting ischemia, i.e., in part, because perfusion defects occur more frequently than ST depression and before angina in the ischemic cascade. Thallium-201 scintigraphy can be performed to differentiate a true- from a false-positive exercise electrocardiographic test in patients with exercise-induced ST depression and no angina. The development of technetium-labeled isonitriles may improve the accuracy of myocardial perfusion imaging. 11 references.

  7. Conflicts of interest in the management of silent ischemia.

    PubMed

    Graboys, T B

    1989-04-14

    Nonclinical factors that may pressure physicians to intervene when a patient presents with so-called silent ischemia, and that may compel a management course not necessarily in the patient's best interest, are explored. These factors include the public's "obsession" with cardiac health, the enormous potential market for pharmaceuticals and medical devices, the funding of ischemia research by drug and medical device companies, the growth of "interventional cardiology" as a subspecialty, the increasingly entrepreneurial approach to medical care on the part of physicians and hospitals, and the fear of malpractice litigation. Given the financial advantage to health facilities and practitioners in recommending an interventionist rather than a conservative approach to silent ischemia, Graboys questions whether studies to determine the optimal management of this condition will ever be undertaken.

  8. Angina and Mental Stress-Induced Myocardial Ischemia

    PubMed Central

    Pimple, Pratik; Shah, Amit J.; Rooks, Cherie; Bremner, J. Douglas; Nye, Jonathon; Ibeanu, Ijeoma; Raggi, Paolo; Vaccarino, Viola

    2015-01-01

    Objective Mental stress-induced myocardial ischemia is a common phenomenon in patients with coronary artery disease (CAD) and an emerging prognostic factor. Mental stress ischemia is correlated with ambulatory ischemia. However, whether it is related to angina symptoms during daily life has not been examined. Methods We assessed angina-frequency (past month) in 98 post-myocardial infarction (MI) subjects (age 18-60 years) using the Seattle Angina Questionnaire. Patients underwent [99mTc]sestamibi SPECT perfusion imaging at rest, after mental stress, and after exercise/pharmacological stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed-difference score (SDS), the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. Results The mean age was 50 years, 50% were female and 60% were non-white. After adjustment for age, sex, smoking, CAD-severity, depressive, anger and anxiety symptoms, each 1-point increase in mental-stress SDS was associated with 1.73-unit increase in the angina-frequency score (95% CI: 0.09-3.37) and 17% higher odds of being in a higher angina-frequency category (OR: 1.17, 95% CI: 1.00-1.38). Depressive symptoms were associated with 12% higher odds of being in a higher angina-frequency category (OR: 1.12, 95% CI: 1.03-1.21). In contrast, exercise/pharmacological stress-induced SDS was not associated with angina-frequency. Conclusion Among young and middle-aged post-MI patients, myocardial ischemia induced by mental stress in the lab, but not by exercise/pharmacological stress, is associated with higher frequency of retrospectively reported angina during the day. Psychosocial stressors related to mental stress ischemia may be important contributory factor to daily angina. PMID:25727240

  9. Tetramethylpyrazine inhibits neutrophil activation following permanent cerebral ischemia in rats.

    PubMed

    Chang, Cheng-Yi; Kao, Tsung-Kuei; Chen, Wen-Ying; Ou, Yen-Chuan; Li, Jian-Ri; Liao, Su-Lan; Raung, Shue-Ling; Chen, Chun-Jung

    2015-07-31

    Experimental studies have demonstrated the beneficial effects of tetramethylpyrazine (TMP) against ischemic stroke and highlighted its crucial role in anti-inflammatory activity. This study provides evidence of an alternative target for TMP and sheds light on the mechanism of its anti-inflammatory action against ischemic brain injury. We report a global inhibitory effect of TMP on inflammatory cell intracerebral activation and infiltration in a rat model of permanent cerebral ischemia. The results of immunohistochemistry, enzymatic assay, flow cytometric analysis, and cytological analysis revealed that intraperitoneal TMP administration reduced neuronal loss, macrophage/microglia activation, brain parenchyma infiltrative neutrophils, and circulating neutrophils after cerebral ischemia. Biochemical studies of cultured neutrophils further demonstrated that TMP attenuated neutrophil migration, endothelium adhesion, spontaneous nitric oxide (NO) production, and stimuli-activated NO production after cerebral ischemia. In parallel with these anti-neutrophil phenomena, TMP also attenuated the activities of ischemia-induced inflammation-associated signaling molecules, including plasma high-mobility group box-1 protein (HMGB1) and neutrophil toll-like receptor-4 (TLR4), Akt, extracellular signal-regulated kinase (ERK), and inducible nitric oxide synthase. Another finding in this study was that the anti-neutrophil effect of TMP was accompanied by a further elevated expression of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in neutrophils after cerebral ischemia. Taken together, our results suggest that both the promotion of endogenous anti-inflammatory defense capacity and the attenuation of pro-inflammatory responses via targeting of circulating neutrophils by elevating Nrf2/HO-1 expression and inhibiting HMGB1/TLR4, Akt, and ERK signaling might actively contribute to TMP-mediated neuroprotection against cerebral ischemia.

  10. Extracorporeal Free Flap Perfusion in Case of Prolonged Ischemia Time.

    PubMed

    Taeger, C D; Präbst, K; Beier, J P; Meyer, A; Horch, R E

    2016-04-01

    In free flap surgery, a clinically established concept still has to be found for the reduction of ischemia-related cell damage in the case of prolonged ischemia. Although promising results using extracorporeal free flap perfusion in the laboratory have been published in the past, until now this concept has not yet paved its way into clinical routine. This might be due to the complexity of perfusion systems and a lack of standardized tools. Here, we want to present the results of the first extracorporeal free flap perfusion in a clinical setting using a simple approach without the application of a complex perfusion machinery.

  11. Ionic transporter activity in astrocytes, microglia, and oligodendrocytes during brain ischemia

    PubMed Central

    Annunziato, Lucio; Boscia, Francesca; Pignataro, Giuseppe

    2013-01-01

    Glial cells constitute a large percentage of cells in the nervous system. During recent years, a large number of studies have critically attributed to glia a new role which no longer reflects the long-held view that glia constitute solely a silent and passive supportive scaffolding for brain cells. Indeed, it has been hypothesized that glia, partnering neurons, have a much more actively participating role in brain function. Alteration of intraglial ionic homeostasis in response to ischemic injury has a crucial role in inducing and maintaining glial responses in the ischemic brain. Therefore, glial transporters as potential candidates in stroke intervention are becoming promising targets to enhance an effective and additional therapy for brain ischemia. In this review, we will describe in detail the role played by ionic transporters in influencing astrocyte, microglia, and oligodendrocyte activity and the implications that these transporters have in the progression of ischemic lesion. PMID:23549380

  12. Protection of mitochondrial and heart function by amino acids after ischemia and cardioplegia.

    PubMed

    Shug, A L; Madsen, D; Dobbie, R; Paulson, D J

    1994-01-01

    The effects of amino acids in protecting against ischemic/reperfusion injury were tested in two experimental models: the isolated perfused rat heart subjected to 21 min of zero flow ischemia (37 degrees) followed by 40 min of reperfusion and the isolated perfused rabbit heart subjected to 300 min of cardioplegic arrest (29 degrees) followed by 60 min of reperfusion. In both cases, the addition of amino acids to the perfusion medium significantly improved the recovery of cardiac contractile function. The protective effects of amino acids were associated with a preservation of mitochondrial respiratory activity. These findings suggest that amino acids by replenishing mitochondrial matrix levels of critical TCA cycle substrates, such as malate, stimulate mitochondrial respiration and thereby enhance the recovery of heart function.

  13. Arginase as a target for treatment of myocardial ischemia-reperfusion injury.

    PubMed

    Tratsiakovich, Yahor; Yang, Jiangning; Gonon, Adrian Thomas; Sjöquist, Per-Ove; Pernow, John

    2013-11-15

    Two distinct enzymes of arginase (1 and 2) are critically regulating nitric oxide (NO) bioavailability by competing with NO synthase for their common substrate l-arginine. Increased expression and activity of arginase is observed in atherosclerosis and myocardial ischemia-reperfusion (I/R). Several studies have demonstrated a key pathophysiological role of increased activity of arginase during I/R. Pharmacological inhibition of arginase results in restoration of NO availability and salvage of myocardium during I/R. Arginase inhibition might be a promising therapeutic strategy for the limitation of myocardial injury in acute myocardial infarction. Current understanding of the role of arginase and efficacy of arginase inhibition during myocardial I/R is reviewed in the present article.

  14. Critical Information at Critical Moments

    ERIC Educational Resources Information Center

    Fierman, Ben; Thrower, Raymond H., Jr.

    2011-01-01

    On a daily basis, administrators are reminded of the potential, perhaps the likelihood, of violence or natural crises on their campuses. Comprehensive studies have been conducted and point to recommendations and best practices for planning, preparing, responding to, and recovering from critical incidents. The International Association of Campus…

  15. Nrf2 activation protects the liver from ischemia/ reperfusion injury in mice

    PubMed Central

    Kudoh, Kazuhiro; Uchinami, Hiroshi; Yoshioka, Masato; Seki, Ekihiro; Yamamoto, Yuzo

    2014-01-01

    Objective To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury. Summary Background Data Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury. Methods Wild-type (WT) and Nrf2-deficient mice were treated with 15-deoxy-Δ12, 14-prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60 min hepatic 70% ischemia followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions. Results After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage, impaired GSTm1, NQO1, and GCLc inductions, disturbed redox state, and aggravated TNF-α mRNA expression in comparison to WT livers. 15d-PGJ2 treatment protected the livers of WT mice from I/R injury via increased expressions of GSTm1, NQO1 and GCLc, maintained redox status, and decreased TNF-α induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2−/− mice and were not annulled by PPARγ antagonist in Nrf2+/+ mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response. Conclusions Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery. PMID:24368646

  16. Angina and exertional myocardial ischemia in diabetic and nondiabetic patients: assessment by exercise thallium scintigraphy

    SciTech Connect

    Nesto, R.W.; Phillips, R.T.; Kett, K.G.; Hill, T.; Perper, E.; Young, E.; Leland, O.S. Jr.

    1988-02-01

    Patients with diabetes mellitus and coronary artery disease are thought to have painless myocardial ischemia more often than patients without diabetes. We studied 50 consecutive patients with diabetes and 50 consecutive patients without diabetes, all with ischemia, on exercise thallium scintigraphy to show the reliability of angina as a marker for exertional ischemia. The two groups had similar clinical characteristics, treadmill test results, and extent of infarction and ischemia, but only 7 patients with diabetes compared with 17 patients without diabetes had angina during exertional ischemia. In diabetic patients the extent of retinopathy, nephropathy, or peripheral neuropathy was similar in patients with and without angina. Angina is an unreliable index of myocardial ischemia in diabetic patients with coronary artery disease. Given the increased cardiac morbidity and mortality in such patients, periodic objective assessments of the extent of ischemia are warranted.

  17. Energy Drinks and Myocardial Ischemia: A Review of Case Reports.

    PubMed

    Lippi, Giuseppe; Cervellin, Gianfranco; Sanchis-Gomar, Fabian

    2016-07-01

    The use and abuse of energy drinks (EDs) is constantly increasing worldwide. We performed a systematic search in Medline, Scopus and Web of Science to identify evidence about the potential link between these beverages and myocardial ischemia. Overall, 8 case reports could be detected, all of which described a realistic association between large intake of EDs and episodes of myocardial ischemia. Interestingly, no additional triggers of myocardial ischemia other than energy drinks could be identified in the vast majority of cases. Some plausible explanations can be brought in support of this association. Most of the biological effects of EDs are seemingly mediated by a positive inotropic effect on cardiac function, which entails increase in heart rate, cardiac output and contractility, stroke volume and arterial blood pressure. Additional biological abnormalities reported after EDs intake include increased platelet aggregation, endothelial dysfunction, hyperglycemia as well as an increase in total cholesterol, triglycerides and low-density lipoprotein cholesterol. Although a causal relationship between large consumption of EDs and myocardial ischemia cannot be definitely established so far, concerns about the cardiovascular risk of excessive consumption of these beverages are seemingly justified.

  18. Encephaloduroarteriosynangiosis for cerebral proliferative angiopathy with cerebral ischemia.

    PubMed

    Kono, Kenichi; Terada, Tomoaki

    2014-12-01

    Cerebral proliferative angiopathy (CPA) is a rare clinical entity. This disorder is characterized by diffuse vascular abnormalities with intermingled normal brain parenchyma, and is differentiated from classic arteriovenous malformations. The management of CPA in patients presenting with nonhemorrhagic neurological deficits due to cerebral ischemia is challenging and controversial. The authors report a case of adult CPA with cerebral ischemia in which neurological deficits were improved after encephaloduroarteriosynangiosis (EDAS). A 28-year-old man presented with epilepsy. Magnetic resonance imaging and angiography showed a diffuse vascular network (CPA) in the right hemisphere. Antiepileptic medications were administered. Four years after the initial onset of epilepsy, the patient's left-hand grip strength gradually decreased over the course of 1 year. The MRI studies showed no infarcts, but technetium-99m-labeled ethyl cysteinate dimer ((99m)Tc-ECD) SPECT studies obtained with acetazolamide challenge demonstrated hypoperfusion and severely impaired cerebrovascular reactivity over the affected hemisphere. This suggested that the patient's neurological deficits were associated with cerebral ischemia. The authors performed EDAS for cerebral ischemia, and the patient's hand grip strength gradually improved after the operation. Follow-up angiography studies obtained 7 months after the operation showed profound neovascularization through the superficial temporal artery and the middle meningeal artery. A SPECT study showed slight improvement of hypoperfusion at the focal region around the right motor area, indicating clinical improvement from the operation. The authors conclude that EDAS may be a treatment option for CPA-related hypoperfusion.

  19. [Neuroprotection of herbs promoting EPO on cerebral ischemia].

    PubMed

    Li, Xu; Bai, Zhen-ya; Zhang, Fei-yan; Xu, Xiao-yu

    2015-06-01

    Amounts of researches show that EPO is characterized with neurotrophic and neuroprotective manner, especially in brain stroke, which attracts a large numbers of researchers to study it. With the accumulating researches on its neuroprotection, many related mechanisms were revealed, such as antioxidant, anti-apoptosis, angiogenesis, anti-inflammatory, which suggests a multiple targets role of EPO on brain stroke. However, because of the high risk of thromboembolism in clinical administration of rhEPO and its analogs, the herbs are potential to be a replacer for its less side effects. Many researchers suggested that a larger of herbs were founded having the action of increasing the endogenous EPO in the model of anemia and cerebral ischemia. At the same time, there herbs were also proved that they had the action of against cerebral ischemia while some without considering the role of EPO in the reports. Considering of the action of promoting EPO of these herbs and the neural protection of EPO, this essay mainly summarizes the studies of herbs promoting EPO in the cerebral ischemia and discusses the mechanism of regulating the EPO of these herbs, for the aim of finding the potential drugs against cerebral ischemia.

  20. Effect of minocycline on cerebral ischemia-reperfusion injury★

    PubMed Central

    Zheng, Yuanyin; Xu, Lijuan; Yin, Jinbao; Zhong, Zhichao; Fan, Hongling; Li, Xi; Chang, Quanzhong

    2013-01-01

    Minocylcine, a tetracycline derivate, has been shown to cross the blood-brain barrier and enter the central nervous system. In this study, cerebral ischemia-reperfusion injury models were established using the suture method, and minocycline was immediately injected intraperitoneally after cerebral ischemia-reperfusion (22.5 mg/kg, initially 45 mg/kg) at a 12-hour interval. Results showed that after minocycline treatment, the volume of cerebral infarction was significantly reduced, the number of surviving cell in the hippocampal CA1 region increased, the number of apoptotic cells decreased, the expression of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein was down-regulated, and the escape latency in the water maze test was significantly shortened compared with the ischemia-reperfusion group. Our experimental findings indicate that minocycline can protect against neuronal injury induced by focal ischemia-reperfusion, which may be mediated by the inhibition of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein expression. PMID:25206381

  1. Brain polyphosphoinositide metabolism during focal ischemia in rat cortex

    SciTech Connect

    Lin, T.N.; Liu, T.H.; Xu, J.; Hsu, C.Y.; Sun, G.Y. )

    1991-04-01

    Using a rat model of stroke, we examined the effects of focal cerebral ischemia on the metabolism of polyphosphoinositides by injecting {sup 32}Pi into both the left and right cortices. After equilibration of the label for 2-3 hours, ischemia induced a significant decrease (p less than 0.001) in the concentrations of labeled phosphatidyl 4,5-bisphosphates (66-78%) and phosphatidylinositol 4-phosphate (64-67%) in the right middle cerebral artery cortex of four rats. The phospholipid labeling pattern in the left middle cerebral artery cortex, which sustained only mild ischemia and no permanent tissue damage, was not different from that of two sham-operated controls. However, when {sup 32}Pi was injected 1 hour after the ischemic insult, there was a significant decrease (p less than 0.01) in the incorporation of label into the phospholipids in both cortices of four ischemic rats compared with four sham-operated controls. Furthermore, differences in the phospholipid labeling pattern were observed in the left cortex compared with the sham-operated controls. The change in labeling pattern was attributed to the partial reduction in blood flow following ligation of the common carotid arteries. We provide a sensitive procedure for probing the effects of focal cerebral ischemia on the polyphosphoinositide signaling pathway in the brain, which may play an important role in the pathogenesis of tissue injury.

  2. in vivo ischemia monitoring array for endoscopic surgery.

    PubMed

    Tahirbegi, Islam Bogachan; Mir, Mònica; Schostek, Sebastian; Schurr, Marc; Samitier, Josep

    2014-11-15

    An array with all-solid-state, potentiometric, miniaturized sensors for pH and potassium was developed to be introduced into the stomach or other sectors of the digestive tract by means of flexible endoscopy. These sensors perform continuous and simultaneous measurement of extracellular pH and potassium. This detection seeks to sense ischemia in the gastric mucosa inside the stomach, an event indicative of local microvascular perfusion and tissue oxygenation status. Our array is proposed as a medical tool to identify the occurrence of the ischemia after gastrointestinal or gastroesophageal anastomosis. The stability and feasibility of the miniaturized working and reference electrodes integrated in the array were studied under in vitro conditions, and the behavior of the potassium and pH ion-selective membranes were optimized to work under acidic gastric conditions with high concentrations of HCl. The array was tested in vivo in pigs to measure the ischemia produced by clamping the blood flow into the stomach. Our results indicate that ischemic and reperfusion states can be sensed in vivo and that information on tissue damage can be collected by this sensor array. The device described here provides a miniaturized, inexpensive, and mass producible sensor array for detecting local ischemia caused by unfavorable anastomotic perfusion and will thus contribute to preventing anastomotic leakage and failure caused by tissue necrosis.

  3. Prolonged idiopathic gastric dilatation following revascularization for chronic mesenteric ischemia.

    PubMed

    Gauci, Julia L; Stoven, Samantha; Szarka, Lawrence; Papadakis, Konstantinos A

    2014-01-01

    A 71-year-old female presented with nausea, emesis, early satiety, and abdominal distension following revascularization for chronic mesenteric ischemia. Computed tomography angiogram showed gastric dilatation. Esophagogastroduodenoscopy, small bowel follow through, and paraneoplastic panel were negative. Gastric emptying was delayed. Despite conservative management, she required a percutaneous endoscopic jejunostomy. The development of a prolonged gastroparetic state has not been previously described.

  4. The role of HIFs in ischemia-reperfusion injury

    PubMed Central

    Howell, Neil J; Tennant, Daniel A

    2014-01-01

    The reduction or cessation of the blood supply to an organ results in tissue ischemia. Ischemia can cause significant tissue damage, and is observed as a result of a thrombosis, as part of a disease process, and during surgery. However, the restoration of the blood supply often causes more damage to the tissue than the ischemic episode itself. Research is therefore focused on identifying the cellular pathways involved in the protection of organs from the damage incurred by this process of ischemia reperfusion (I/R). The hypoxia-inducible factors (HIFs) are a family of heterodimeric transcription factors that are stabilized during ischemia. The genes that are expressed downstream of HIF activity enhance oxygen-independent ATP generation, cell survival, and angiogenesis, amongst other phenotypes. They are, therefore, important factors in the protection of tissues from I/R injury. Interestingly, a number of the mechanisms already known to induce organ protection against I/R injury, including preconditioning, postconditioning, and activation of signaling pathways such as adenosine receptor signaling, converge on the HIF system. This review describes the evidence for HIFs playing a role in I/R protection mediated by these factors, highlights areas that require further study, and discuss whether HIFs themselves are good therapeutic targets for protecting tissues from I/R injury. PMID:27774470

  5. Tumor Cold Ischemia - Office of Cancer Clinical Proteomics Research

    Cancer.gov

    In a recently published manuscript in the journal of Molecular and Cellular Proteomics, researchers from the National Cancer Institutes (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigated the effect of cold ischemia on the proteome of fresh frozen tumors.

  6. [Critical incidents].

    PubMed

    Scheidegger, D

    2005-03-01

    In medicine real severe mishaps are rare. On the other hand critical incidents are frequent. Anonymous critical incident reporting systems allow us to learn from these mishaps. This learning process will make our daily clinical work safer Unfortunately, before these systems can be used efficiently our professional culture has to be changed. Everyone in medicine has to admit that errors do occur to see the need for an open discussion. If we really want to learn from errors, we cannot punish the individual, who reported his or her mistake. The interest is primarily in what has happened and why it has happened and not who has committed this mistake. The cause for critical incidents in medicine is in over 80% the human factor Poor communication, work under enormous stress, conflicts and hierarchies are the main cause. This has been known for many years, therefore have already 15 years ago high-tech industries, like e.g. aviation, started to invest in special courses on team training. Medicine is a typical profession were until now only the individual performance decided about the professional career Communication, conflict management, stress management, decision making, risk management, team and team resource management were subjects that have never been taught during our preor postgraduate education. These points are the most important ones for an optimal teamwork. A multimodular course designed together with Swissair (Human Aspect Development medical, HADmedical) helps to cover, as in aviation, the soft factor and behavioural education in medicine and to prepare professionals in health care to work as a real team.

  7. Neuroprotective Antioxidant STAZN Protects Against Myocardial Ischemia/Reperfusion Injury

    PubMed Central

    Ley, James J.; Prado, Ricardo; Wei, Jian Qin; Bishopric, Nanette H.; Becker, David A.; Ginsberg, Myron D.

    2009-01-01

    Background Protecting the myocardium from ischemia-reperfusion injury has significant potential to reduce the complications of myocardial infarction and interventional revascularization procedures. Reperfusion damage is thought to result, in part, from oxidative stress. Here we use a novel method of percutaneous coronary occlusion to show that the potent antioxidant and neuroprotective free-radical scavenger, stilbazulenyl nitrone (STAZN), confers marked cardioprotection when given immediately prior to reperfusion. Methods and Results Physiologically controlled male Sprague-Dawley rats were anesthetized with isoflurane, paralyzed with pancuronium and mechanically ventilated. A guide wire was introduced via the femoral artery and advanced retrogradely via the aorta into the left coronary artery under fluoroscopic guidance. Rats with established coronary ischemia (85 min after occlusion) were given STAZN 3.5 mg/kg or its vehicle 5 minutes before and 2 hours after reperfusion, and were subjected to functional and histopathologic studies at 3 days. Ischemia-associated Q wave amplitude was reduced by 73% in STAZN-treated rats (P=0.01), while infarct-related ejection fraction, fractional shortening and severe regional wall-motion impairments were reduced by 48%, 54% and 37%, respectively, relative to vehicle-treated controls (P=0.05). Total myocardial infarct volume in STAZN-treated rats was correspondingly reduced by 43% (P<0.05), representing a sparing of 14% of the total left ventricular myocardium. Conclusions STAZN, a second-generation azulenyl nitrone with potent neuroprotective efficacy in brain ischemia, is also a rapidly acting and highly effective cardioprotective agent in acute coronary ischemia. Our results suggest the potential for clinical benefit in the setting of acute coronary syndromes. PMID:17936251

  8. Levosimendan Administration in Limb Ischemia: Multicomponent Signaling Serving Kidney Protection

    PubMed Central

    Onody, Peter; Aranyi, Peter; Turoczi, Zsolt; Stangl, Rita; Fulop, Andras; Dudas, Emese; Lotz, Gabor; Szijarto, Attila

    2016-01-01

    Aims and Objectives Acute renal failure is a severe complication of lower extremity major arterial reconstructions, which could even be fatal. Levosimendan is a dual-acting positive inotropic and vasodilatory agent, which is suspected to have protective effects against cardiac ischemia. However, there is no data available on lower limb or remote organ ischemic injuries therefore the aim of the study was to investigate the effect of levosimendan on lower limb ischemia-reperfusion injury and the corollary renal dysfunction. Methods Male Wistar rats underwent 180 min bilateral lower limb ischemia followed by 4 or 24 hours of reperfusion. Intravenous Levosimendan was administered continuously (0.2μg/bwkg/min) throughout the whole course of ischemia and the first 3h of reperfusion. Results were compared with sham-operated and ischemia-reperfusion groups. Hemodynamic monitoring was performed by invasive arterial blood pressure measurement. Kidney and lower limb muscle microcirculation was registered by a laser Doppler flowmeter. After 4h and 24h of reperfusion, serum, urine and histological samples were collected. Results Systemic hemodynamic parameters and microcirculation of kidney and the lower limb significantly improved in the Levosimendan treated group. Muscle viability was significantly preserved 4 and 24 hours after reperfusion. At the same time, renal functional laboratory tests and kidney histology demonstrated significantly less expressive kidney injury in Levosimendan groups. TNF-α levels were significantly less elevated in the Levosimendan group 4 hours after reperfusion. Conclusion The results claim a protective role for Levosimendan administration during major vascular surgeries to prevent renal complications. PMID:27684548

  9. Placental Growth Factor Administration Abolishes Placental Ischemia-Induced Hypertension.

    PubMed

    Spradley, Frank T; Tan, Adelene Y; Joo, Woo S; Daniels, Garrett; Kussie, Paul; Karumanchi, S Ananth; Granger, Joey P

    2016-04-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia because placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and vascular endothelial growth factor are both natural ligands for sFlt-1, vascular endothelial growth factor also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to 4 groups: normal pregnant or RUPP±infusion of recombinant human PlGF (180 μg/kg per day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than normal pregnant rats. Infusion of recombinant human PlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that recombinant human PlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia.

  10. PLACENTAL GROWTH FACTOR ADMINISTRATION ABOLISHES PLACENTAL ISCHEMIA-INDUCED HYPERTENSION

    PubMed Central

    Spradley, Frank T.; Tan, Adelene Y.; Joo, Woo S.; Daniels, Garrett; Kussie, Paul; Karumanchi, S. Ananth; Granger, Joey P.

    2016-01-01

    Preeclampsia is a pregnancy-specific disorder of new-onset hypertension. Unfortunately, the most effective treatment is early delivery of the fetus and placenta. Placental ischemia appears central to the pathogenesis of preeclampsia as placental ischemia/hypoxia induced in animals by reduced uterine perfusion pressure (RUPP) or in humans stimulates release of hypertensive placental factors into the maternal circulation. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1), which antagonizes and reduces bioavailable vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), is elevated in RUPP rats and preeclampsia. Although PlGF and VEGF are both natural ligands for sFlt-1, VEGF also has high affinity to VEGFR2 (Flk-1) causing side effects like edema. PlGF is specific for sFlt-1. We tested the hypothesis that PlGF treatment reduces placental ischemia-induced hypertension by antagonizing sFlt-1 without adverse consequences to the mother or fetus. On gestational day 14, rats were randomized to four groups: normal pregnant (NP) or RUPP ± infusion of rhPlGF (180 μg/kg/day; AG31, a purified, recombinant human form of PlGF) for 5 days via intraperitoneal osmotic minipumps. On day 19, mean arterial blood pressure and plasma sFlt-1 were higher and glomerular filtration rate lower in RUPP than NP rats. Infusion of rhPlGF abolished these changes seen with RUPP along with reducing oxidative stress. These data indicate that the increased sFlt-1 and reduced PlGF resulting from placental ischemia contribute to maternal hypertension. Our novel finding that rhPlGF abolishes placental ischemia-induced hypertension, without major adverse consequences, suggests a strong therapeutic potential for this growth factor in preeclampsia. PMID:26831193

  11. Erythropoietin inhibits HIF-1α expression via upregulation of PHD-2 transcription and translation in an in vitro model of hypoxia-ischemia.

    PubMed

    Souvenir, Rhonda; Flores, Jerry J; Ostrowski, Robert P; Manaenko, Anatol; Duris, Kamil; Tang, Jiping

    2014-02-01

    Hypoxia inducible factor (HIF)-1α is the central transcriptional factor for the regulation of oxygen-associated genes in response to hypoxia. Erythropoietin (EPO), a hematopoietic growth factor, increases oxygen availability during hypoxia/ischemia and is associated with neuroprotection following hypoxia-ischemia in laboratory models of stroke. However, EPO has failed to translate in a clinical setting. Thus, it is critical to elucidate the key players in EPO-induced neuroprotection. Our preliminary studies have shown that EPO, as a downstream gene of HIF, inhibits HIF-1α in a dose-dependent manner in an in vitro model of hypoxia-ischemia. This study is designed to elucidate the primary mediator of EPO-induced HIF-1α inhibition and subsequent cell survival/neuroprotection. Oxygen and glucose deprivation (OGD) of nerve growth factor-differentiated rat pheochromocytoma (PC-12) cells were used to model hypoxia-ischemia in an in vitro environment. The profile of HIF-1α, HIF-2α and prolyl hydroxylase domain 2 (PHD-2) expression; HIF-1α and prolyl hydroxylase (PHD-2) mRNA levels; matrix metalloproteinase (MMP)-9; and cell death was evaluated in the presence and absence of either EPO or PHD-2 inhibitor during OGD. Our findings showed that EPO treatment resulted in an increase in PHD-2 transcription and translation, inhibition of HIF-1α expression, reactive oxygen species formation, and MMP-9 activity, resulting in increased cell survival after OGD. We also observed that EPO-induced cell survival/neuroprotection was reversed by siRNA silencing of PHD-2. This led to the conclusion that PHD-2 is a key mediator of EPO-induced HIF-1α inhibition and subsequent neuroprotection in an in vitro model of hypoxia-ischemia.

  12. Critical evaluation of endovascular surgery for limb salvage.

    PubMed

    Lucas, Layla C; Mills, Joseph L

    2011-01-01

    Rest pain, tissue loss, and gangrene are manifestations of critical limb ischemia caused by peripheral arterial disease and define a patient subgroup at highest risk for major limb amputation. Patients with nonhealing lower extremity wounds should be screened for the risk factors for peripheral arterial disease and offered noninvasive vascular testing. The diagnosis of critical limb ischemia mandates prompt institution of medical and surgical management to achieve the best chance of limb salvage. Surgical intervention has evolved from primary amputation to open bypass to the present era of endovascular therapy. The goals of surgical bypass and endovascular therapy are to improve perfusion sufficiently to permit healing. Despite poorer patency rates and the more frequent need for reintervention, endovascular therapy has been shown in multiple retrospective studies to achieve limb salvage similar to open bypass. Only one large, prospective, randomized controlled trial exists comparing open bypass with endovascular therapy: The Bypass versus Angioplasty in Severe Limb Ischemia of the Leg (BASIL) trial. Close clinical surveillance and serial monitoring of limb perfusion by means of noninvasive arterial studies are needed to determine the need for further vascular intervention. Limb salvage patients suffer from multiple comorbidities and benefit from a multidisciplinary, team approach to care.

  13. Treatment of mice with cromolyn sodium after reperfusion, but not prior to ischemia, attenuates small intestinal ischemia-reperfusion injury.

    PubMed

    Gan, Xiaoliang; Liu, Dezhao; Ge, Mian; Luo, Chenfang; Gao, Wanling; Hei, Ziqing

    2013-09-01

    Stabilizing mast cells (MCs) can either inhibit or augment inflammation; however, how improved therapeutic benefits against small intestinal ischemia-reperfusion injury (IIRI) can be achieved by stabilizing MCs remains to be elucidated. The present study was designed to evaluate different treatments with cromolyn sodium (CS, an MC stabilizer), which was administrated either prior to ischemia or after reperfusion. Kunming mice were randomized into a sham-operated group (SH), a sole IIR group (M), in which mice were subjected to 30 min superior mesenteric artery occlusion followed by 3 day or 3 h reperfusion, or IIR, treated with CS 15 min prior to ischemia or 15 min after reperfusion in the PreCr and PostCr groups. The survival rate and Chiu's scores were evaluated. The levels of ET-1, histamine, TNF-α and IL-6, and expression of MC protease 7 (MCP7), MC counts and myeloperoxidase (MPO) activity were quantified. IIR resulted in severe injury as demonstrated by significant increases in mortality and injury score. IIR also led to substantial elevations in the levels of ET-1, histamine, TNF-α and IL-6, expression of MCP7, MC counts and MPO activities (P<0.05, M vs. SH groups). All biochemical changes were markedly reduced in the PostCr group (P<0.05, PostCr vs. M groups), whereas pretreatment of IIR mice with CS prior to ischemia exhibited no changes of ET-1 levels, injury score and inflammation (P>0.05, PreCr vs. M groups). In conclusion, administration of CS after reperfusion, but not prior to ischemia, attenuates IIRI by downregulating ET-1 and suppressing sustained MC activation.

  14. TRPM2 channel deficiency prevents delayed cytosolic Zn2+ accumulation and CA1 pyramidal neuronal death after transient global ischemia

    PubMed Central

    Ye, M; Yang, W; Ainscough, J F; Hu, X-P; Li, X; Sedo, A; Zhang, X-H; Zhang, X; Chen, Z; Li, X-M; Beech, D J; Sivaprasadarao, A; Luo, J-H; Jiang, L-H

    2014-01-01

    Transient ischemia is a leading cause of cognitive dysfunction. Postischemic ROS generation and an increase in the cytosolic Zn2+ level ([Zn2+]c) are critical in delayed CA1 pyramidal neuronal death, but the underlying mechanisms are not fully understood. Here we investigated the role of ROS-sensitive TRPM2 (transient receptor potential melastatin-related 2) channel. Using in vivo and in vitro models of ischemia–reperfusion, we showed that genetic knockout of TRPM2 strongly prohibited the delayed increase in the [Zn2+]c, ROS generation, CA1 pyramidal neuronal death and postischemic memory impairment. Time-lapse imaging revealed that TRPM2 deficiency had no effect on the ischemia-induced increase in the [Zn2+]c but abolished the cytosolic Zn2+ accumulation during reperfusion as well as ROS-elicited increases in the [Zn2+]c. These results provide the first evidence to show a critical role for TRPM2 channel activation during reperfusion in the delayed increase in the [Zn2+]c and CA1 pyramidal neuronal death and identify TRPM2 as a key molecule signaling ROS generation to postischemic brain injury. PMID:25429618

  15. Overactivation of the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element pathway in hepatocytes decreases hepatic ischemia/reperfusion injury in mice.

    PubMed

    Lee, Lung-Yi; Harberg, Calvin; Matkowskyj, Kristina A; Cook, Shelly; Roenneburg, Drew; Werner, Sabine; Johnson, Jeffrey; Foley, David P

    2016-01-01

    Hepatic ischemia/reperfusion injury (IRI) is a critical component of hepatic surgery. Oxidative stress has long been implicated as a key player in IRI. In this study, we examine the cell-specific role of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element pathway in warm hepatic IRI. Nrf2 knockout (KO) and wild-type (WT) animals and novel transgenic mice expressing a constitutively active nuclear factor (erythroid-derived 2)-like 2 (caNrf2) mutant in hepatocytes (AlbCre+/caNrf2+) and their littermate controls underwent partial hepatic ischemia or sham surgery. The animals were killed 6 hours after reperfusion, and their serum and tissue were collected for analysis. As compared to WT animals after ischemia/reperfusion (IR), Nrf2 KO mice had increased hepatocellular injury with increased serum alanine aminotransferase and aspartate aminotransferase, Suzuki score, apoptosis, an increased inflammatory infiltrate, and enhanced inflammatory cytokine expression. On the other hand, AlbCre+/caNrf2+ that underwent IR had significantly reduced serum transaminases, less necrosis on histology, and a less pronounced inflammatory infiltrate and inflammatory cytokine expression as compared to the littermate controls. However, there were no differences in apoptosis. Taken together, Nrf2 plays a critical role in our murine model of warm hepatic IRI, with Nrf2 deficiency exacerbating hepatic IRI and hepatocyte-specific Nrf2 overactivation providing protection against warm hepatic IRI.

  16. Clinical Outcome Following Infra-Inguinal Percutaneous Transluminal Angioplasy for Critical Limb Ischemia

    SciTech Connect

    Matsagas, Miltiadis I.; Rivera, Marco A.; Tran, Tan; Mitchell, Adam; Robless, Peter; Davies, Alun H.; Geroulakos, George

    2003-06-15

    Objective: The aim of this study was to assess the efficacy and durability of infra-inguinal PTA in patients with CLI, in terms of clinical outcome. Design:Retrospective study of 50 consecutive patients with CLI that were exclusively treated by infra-inguinal PTA. Methods: The indications for intervention were rest pain in seven (14%) patients,non-healing ulcers in 27 (54%), and gangrenous lesions in 16 (32%).Thirty-three (66%) of these patients presented with a single arterial lesion, and the remaining 17 (34%) with multilevel arterial lesions.Kaplan-Meier analysis was used to assess survival, patency,limb-salvage rates, and amputation-free survival. Results: A total of 67 endovascular procedures were performed and 59 (88.1%) of them were considered to be technically successful. The median follow-up period was 12 months (interquartilerange: 17 months). The 30-day mortality was 4%, while the cumulative survival rates at 12, 24, and 36 months were 73%, 67%, and 59%,respectively. The cumulative primary patency rates at 12 and 24 months were 63% and 52%, respectively, and remained unchanged thereafter.The estimated secondary patency rate was 72% at 36 months. There was only one below-knee amputation in the patients that were treated exclusively with infra-inguinal PTA. The cumulative amputation-free survival at the same period was estimated at 60%. Conclusions: Infra-inguinal PTA had a good early and late outcome in this series of patients with a limited life expectancy.These results are comparable to historical results of surgical revascularization in the treatment of CLI. There is need for a randomized study to determine the primary optimal interventional approach for patients with CLI.

  17. Development of administrative data algorithms to identify patients with critical limb ischemia.

    PubMed

    Bekwelem, Wobo; Bengtson, Lindsay G S; Oldenburg, Niki C; Winden, Tamara J; Keo, Hong H; Hirsch, Alan T; Duval, Sue

    2014-12-01

    Administrative data have been used to identify patients with various diseases, yet no prior study has determined the utility of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)-based codes to identify CLI patients. CLI cases (n=126), adjudicated by a vascular specialist, were carefully defined and enrolled in a hospital registry. Controls were frequency matched to cases on age, sex and admission date in a 2:1 ratio. ICD-9-CM codes for all patients were extracted. Algorithms were developed using frequency distributions of these codes, risk factors and procedures prevalent in CLI. The sensitivity for each algorithm was calculated and applied within the hospital system to identify CLI patients not included in the registry. Sensitivity ranged from 0.29 to 0.92. An algorithm based on diagnosis and procedure codes exhibited the best overall performance (sensitivity of 0.92). Each algorithm had differing CLI identification characteristics based on patient location. Administrative data can be used to identify CLI patients within a health system. The algorithms, developed from these data, can serve as a tool to facilitate clinical care, research, quality improvement, and population surveillance.

  18. Critical limb ischemia in association with Charcot neuroarthropathy: complex endovascular therapy for limb salvage.

    PubMed

    Palena, Luis Mariano; Brocco, Enrico; Manzi, Marco

    2014-02-01

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

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

    SciTech Connect

    Palena, Luis Mariano; Brocco, Enrico; Manzi, Marco

    2013-05-09

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

  20. Age-related differences of neutrophil activation in a skeletal muscle ischemia-reperfusion model.

    PubMed

    Mowlavi, Arian; Reynolds, Christopher; Neumeister, Michael W; Wilhelmi, Bradon J; Song, Yao-Hua; Naffziger, Ryan; Glatz, Frank R; Russell, Robert C

    2003-04-01

    Free tissue transfers and replantation of amputated limbs are better tolerated by young adolescents than mature adults. The authors hypothesized that this observation may be, in part, because of an attenuated ischemia-reperfusion (IR) injury in younger patients. Because neutrophils have been identified as a critical cell line responsible for IR injury, the authors investigated the effects of animal age on the degree of neutrophil activation in a rat model. Activation was evaluated by monitoring expression of integrin surface markers (mean fluorescence intensity [MFI] of CD11b) and oxidative burst potential (MFI of dihydrorhodamine [DHR] oxidation) by flow cytometry in neutrophils analyzed after 4 hours of ischemia and 1, 4, and 16 hours of reperfusion in a gracilis muscle flap model in mature adult and young adolescent rats. Neutrophil activation was also evaluated in control sham-operated animals, which underwent elevation of gracilis muscle flaps without exposure to an ischemic insult. Muscle edema, determined by wet-to-dry muscle weight ratio, and muscle viability, determined by nitro blue tetrazolium (NBT) staining, were completed for gracilis muscles exposed to ischemia after 24 hours of reperfusion for each of the groups. Integrin expression, assessed by MFI of CD11b, was increased significantly in ischemic muscles of mature adult rats at 4 hours of reperfusion (71.10+/-3.53 MFI vs. 54.88+/-12.73 MFI, p=0.025). Neutrophil oxidative potential, assessed by MFI of DHR oxidation, was increased significantly in ischemic muscles of mature adult rats compared with young adolescent rats at 1 hour of reperfusion (78.10+/-9.53 MFI vs. 51.78+/-16.91 MFI, p=0.035) and 4 hours of reperfusion (83.69+/-15.29 MFI vs. 46.55+/-8.09 MFI, p=0.005). Increased edema formation was observed in the ischemic muscles of mature adult rats when compared with young adolescent rats (1.25+/-0.04 vs. 1.12+/-0.05, p=0.031) after 24 hours of reperfusion. A trend toward decreased muscle

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

    SciTech Connect

    Marcus, A.J. Lotzof, K.; Kamath, B.S.K.; Shanthakumar, R.E.; Munir, N.; Loh, A.; Bird, R.; Howard, A.

    2006-04-15

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

  2. Irisin Plays a Pivotal Role to Protect the Heart Against Ischemia and Reperfusion Injury.

    PubMed

    Wang, Hao; Zhao, Yu Tina; Zhang, Shouyan; Dubielecka, Patrycja M; Du, Jianfeng; Yano, Naohiro; Chin, Y Eugene; Zhuang, Shougang; Qin, Gangjian; Zhao, Ting C

    2017-02-09

    Irisin, a newly identified hormone, is critical to modulating body metabolism, thermogenesis and reducing oxidative stresses. However, whether irisin protects the heart against myocardial ischemia and reperfusion (I/R) injury remains unknown. In this study, we determine the effect of irisin on myocardial I/R injury in the Langendorff perfused heart and cultured myocytes. Adult C57/BL6 mice were treated with irisin (100mg/kg) or vehicle for 30 minutes to elicit preconditioning. The isolated hearts were subjected to 30 min ischemia followed by 30 min reperfusion. Left ventricular function was measured and infarction size were determined using by tetrazolium staining. Western blot was employed to determine myocardial SOD-1, active-caspase 3, annexin V, p38 and phospho-p38. H9c2 cardiomyoblasts were exposed to hypoxia and reoxygenation for assessment of the effects of irisin on mitochondrial respiration and mitochondrial permeability transition pore (mPTP). Irisin treatment produced remarkable improvements in ventricular functional recovery, as evident by the increase in RPP and attenuation in LVEDP. As compared to the vehicle treatment, irisin resulted in a marked reduction of myocardial infarct size. Notably, irisin treatment increased SOD-1 and p38 phosphorylation, but suppressed levels of active-caspase 3, cleaved PARP, and annexin V. In cardiomyoblasts exposed to hypoxia/reoxygenation, irisin treatment significantly attenuated hypoxia/reoxygenation (H/R), as indicated by the reduction of lactate dehydrogenase (LDH) leakage and apoptotic cardiomyocytes. Furthermore, irisin treatments suppressed the opening of mPTP, mitochondrial swelling, and protected mitochondria function. Our results indicate that irisin serves as a novel approach to eliciting cardioprotection, which is associated with the improvement of mitochondrial function. This article is protected by copyright. All rights reserved.

  3. Both PD-1 ligands protect the kidney from ischemia reperfusion injury

    PubMed Central

    Jaworska, Katarzyna; Ratajczak, Joanna; Huang, Liping; Whalen, Kristen; Yang, Mana; Stevens, Brian K.; Kinsey, Gilbert R.

    2014-01-01

    Acute kidney injury (AKI) is a common problem in hospitalized patients which enhances morbidity and mortality and promotes the development of chronic and end stage renal disease. Ischemia reperfusion injury (IRI) is one of the major causes of AKI and is characterized by uncontrolled renal inflammation and tubular epithelial cell death. Our recent studies demonstrated that regulatory T cells (Tregs) protect the kidney from IR-induced inflammation and injury. Blockade of programmed cell death 1 (PD-1) on the surface of Tregs, prior to adoptive transfer, negates their ability to protect against ischemic kidney injury. The current study was designed to investigate the role of the known PD-1 ligands, PD-L1 and PD-L2 in kidney IRI. Administration of PD-L1 or PD-L2 blocking antibodies prior to mild or moderate kidney IRI significantly exacerbated the loss of renal function, renal inflammation and acute tubular necrosis (ATN) compared to mice receiving isotype control antibodies. Interestingly, blockade of both PD-1 ligands resulted in worse injury, dysfunction and inflammation than blocking either ligand alone. Genetic deficiency of either PD-1 ligand also exacerbated kidney dysfunction and ATN after sub-threshold ischemia. Bone marrow chimeric studies revealed that PD-L1 expressed on non-bone marrow derived cells is critical for this resistance to IRI. Finally, blockade of either PD-1 ligand negated the protective ability of adoptively-transferred Tregs in IRI. These findings suggest that PD-L1 and PD-L2 are non-redundant aspects of the natural protective response to ischemic injury and may be novel therapeutic targets for AKI. PMID:25404361

  4. Propofol inhibits inflammation and lipid peroxidation following cerebral ischemia/reperfusion in rabbits☆

    PubMed Central

    Wei, Xiaodong; Wan, Xing; Zhao, Bo; Hou, Jiabao; Liu, Min; Cheng, Bangchang

    2012-01-01

    The present study established a rabbit model of global cerebral ischemia using the ‘six-vessel’ method, which was reperfused after 30 minutes of ischemia. Rabbits received intravenous injection of propofol at 5 mg/kg prior to ischemia and 20 mg/kg per hour after ischemia until samples were prepared. Results revealed that propofol inhibited serum interleukin-8, endothelin-1 and malondialdehyde increases and promoted plasma superoxide dismutase activity after cerebral ischemia/reperfusion. In addition, cerebral cortex edema was attenuated with little neuronal nuclear degeneration and pyknosis with propofol treatment. The cross-sectional area of neuronal nuclei was, however, increased following propofol treatment. These findings suggested that propofol could improve anti-oxidant activity and inhibit synthesis of inflammatory factors to exert a protective effect on cerebral ischemia/reperfusion injury. PMID:25737711

  5. Raynaud’s phenomenon and digital ischemia: a practical approach to risk stratification, diagnosis and management

    PubMed Central

    McMahan, Zsuzsanna H.; Wigley, Fredrick M.

    2015-01-01

    Digital ischemia is a painful and often disfiguring event. Such an ischemic event often leads to tissue loss and can significantly affect the patient’s quality of life. Digital ischemia can be secondary to a vasculopathy, vasculitis, embolic disease, trauma, or extrinsic vascular compression. It is an especially serious complication in patients with scleroderma. Risk stratification of patients with scleroderma at risk for digital ischemia is now possible with clinical assessment and autoantibody profiles. Because there are a variety of conditions that lead to digital ischemia, it is important to understand the pathophysiology underlying each ischemic presentation in order to target therapy appropriately. Significant progress has been made in the last two decades in defining the pathophysiological processes leading to digital ischemia in rheumatic diseases. In this article we review the risk stratification, diagnosis, and management of patients with digital ischemia and provide a practical approach to therapy, particularly in scleroderma. PMID:26523153

  6. Acute coronary ischemia during alcohol withdrawal: a case report

    PubMed Central

    2011-01-01

    Introduction The potential of alcohol withdrawal to cause acute coronary events is an area that needs the urgent attention of clinicians and researchers. Case presentation We report the case of a 52-year-old heavy-alcohol-using Sri Lankan man who developed electocardiogram changes suggestive of an acute coronary event during alcohol withdrawal. Despite the patient being asymptomatic, subsequent echocardiogram showed evidence of ischemic myocardial dysfunction. We review the literature on precipitation of myocardial ischemia during alcohol withdrawal and propose possible mechanisms. Conclusions Alcohol withdrawal is a commonly observed phenomenon in hospitals. However, the number of cases reported in the literature of acute coronary events occurring during withdrawal is few. Many cases of acute ischemia or sudden cardiac deaths may be attributed to other well known complications of delirium tremens. This is an area needing the urgent attention of clinicians and epidemiologists. PMID:21838872

  7. [Transient brain ischemia: NMDA receptor modulation and delayed neuronal death].

    PubMed

    Benquet, Pascal; Gee, Christine E; Gerber, Urs

    2008-02-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiological, cellular and molecular mechanisms inducing post-ischemic plasticity of NMDA receptors, focusing on the sensitive CA1 pyramidal neurons in the hippocampus as compared to the relatively resistant neighboring CA3 neurons. Both a change in the equilibrium between protein tyrosine kinases/phosphatases and an increased density of surface NMDA receptors in response to ischemia may explain the selective vulnerability of specific cell types. Implications for the treatment of stroke and reasons for the failures of human clinical trials utilizing NMDA receptor antagonists are also discussed.

  8. One of the most urgent vascular circumstances: Acute limb ischemia

    PubMed Central

    Sahin, Muslum; Kirma, Cevat

    2013-01-01

    Acute limb ischemia is a sudden decrease in limb perfusion that threatens limb viability and requires urgent evaluation and management. Most of the causes of acute limb ischemia are thrombosis of a limb artery or bypass graft, embolism from the heart or a disease artery, dissection, and trauma. Assessment determines whether the limb is viable or irreversibly damaged. Prompt diagnosis and revascularization by means of catheter-based thrombolysis or thrombectomy and by surgery reduce the risk of limb loss and mortality. Amputation is performed in patients with irreversible damage. Despite urgent revascularization, amputation rate is 10%–15% in patients during hospitalization, mostly above the knee, and mortality within 1 year is 10%–15% due to the coexisting conditions. PMID:26770694

  9. Regional Myocardial Blood Flow and Ultrastructure Following Acute Temporary Ischemia.

    DTIC Science & Technology

    1982-01-01

    kidneys of dogs and cats , and suggest some element present in whole blood, but not present in filtered blood may serve to further damage ischemic...minutes of myocardial ischemia in the dog as Krug et al. (66) has reported in the cat . Finally, in this experiment the relationship of inhibited reflow...transient inhibition of flow. One has to wonder if their 6 cats with smaller areas of risk are more like the dogs in this study and may also have had

  10. Fatal subarachnoid hemorrhage following ischemia in vertebrobasilar dolichoectasia

    PubMed Central

    Sokolov, Arseny A.; Husain, Shakir; Sztajzel, Roman; Croquelois, Alexandre; Lobrinus, Johannes A.; Thaler, David; Städler, Claudio; Hungerbühler, Hansjörg; Caso, Valeria; Rinkel, Gabriel J.; Michel, Patrik

    2016-01-01

    Abstract Vertebrobasilar dolichoectasia (VBD) is a chronic disorder with various cerebrovascular and compressive manifestations, involving subarachnoid hemorrhage (SAH). Occurrence of SAH shortly after worsening of clinical VBD symptoms has occasionally been reported. The goal of the study was to examine this association, in particular its pathophysiology, clinical precursor signs, time course, and outcome. To this end, in a retrospective multicenter study, we analyzed 20 patients with VBD and SAH in regard to preceding clinical symptoms, presence of vertebrobasilar thrombosis and ischemia, outcome and neuropathological correlates. Median age of the 7 female and 13 male patients was 70 years (interquartile range [IQR] 18.3 years). Fourteen patients (70%) presented with new or acutely worsening posterior fossa signs at a median of 3 days prior to SAH (IQR 2, range 0.5–14). A thrombus within the VBD was detected in 12 patients (60%). Thrombus formation was associated with clinical deterioration (χ2 = 4.38, P = 0.04) and ponto-cerebellar ischemia (χ2 = 8.09, P = 0.005). During follow-up after SAH, 13 patients (65%) died, after a median survival time of 24 hours (IQR 66.2, range 2–264 hours), with a significant association between proven ponto-cerebellar ischemia and case fatality (χ2 = 6.24, P = 0.01). The data establish an association between clinical deterioration in patients with VBD, vertebrobasilar ischemia, and subsequent SAH. Antithrombotic treatment after deterioration appears controversial and SAH outcome is frequently fatal. Our data also indicate a short window of 3 days that may allow for evaluating interventional treatment, preferably within randomized trials. PMID:27399083

  11. Ischemia Induced Neutrophil Activation and Diapedesis is Lipoxygenase Dependent.

    DTIC Science & Technology

    2007-11-02

    activity in mediating PMN activation and diapedesis . Anesthetized rabbits (n = 8) underwent 3 h of bilateral hindlimb ischemia. At 10 min of reperfusion...enhanced response of 337% to PMA stimulation. To study diapedesis , plasma collected at 10 min of reperfusion was introduced into plastic chambers taped...abolished PMN activation (51 +/- 12 fM DCF/cell) and ischemic plasma induced diapedesis into the plastic chamber (38 +/- 18 PMN/mm(exp 3)).

  12. Platelets Orchestrate Remote Tissue Damage After Mesenteric Ischemia-Reperfusion

    DTIC Science & Technology

    2012-02-02

    the inflam- matory response in immune complex disease and ischemia/reperfusion injury. J Immunol 163: 985–994, 1999. 37. Herd CM, Page CP. Pulmonary...Components from both innate and adaptive immunity , including natural immunoglobulin and complement compo- nents, as well as different leukocyte...modifiers of innate and adaptive immune responses to transplants. Curr Opin Organ Transplant 16: 41–46, 2010. 4. Bishop MJ, Giclas PC, Guidotti SM, Su ML

  13. The Neuroprotective Effect of Kefir on Spinal Cord Ischemia/Reperfusion Injury in Rats

    PubMed Central

    Akman, Tarik; Yener, Ali Umit; Sehitoglu, Muserref Hilal; Yuksel, Yasemin; Cosar, Murat

    2015-01-01

    Objective The main causes of spinal cord ischemia are a variety of vascular pathologies causing acute arterial occlusions. We investigated neuroprotective effects of kefir on spinal cord ischemia injury in rats. Methods Rats were divided into three groups : 1) sham operated control rats; 2) spinal cord ischemia group fed on a standard diet without kefir pretreatment; and 3) spinal cord ischemia group fed on a standard diet plus kefir. Spinal cord ischemia was performed by the infrarenal aorta cross-clamping model. The spinal cord was removed after the procedure. The biochemical and histopathological changes were observed within the samples. Functional assessment was performed for neurological deficit scores. Results The kefir group was compared with the ischemia group, a significant decrease in malondialdehyde levels was observed (p<0.05). Catalase and superoxide dismutase levels of the kefir group were significantly higher than ischemia group (p<0.05). In histopathological samples, the kefir group is compared with ischemia group, there was a significant decrease in numbers of dead and degenerated neurons (p<0.05). In immunohistochemical staining, hipoxia-inducible factor-1α and caspase 3 immunopositive neurons were significantly decreased in kefir group compared with ischemia group (p<0.05). The neurological deficit scores of kefir group were significantly higher than ischemia group at 24 h (p<0.05). Conclusion Our study revealed that kefir pretreatment in spinal cord ischemia/reperfusion reduced oxidative stress and neuronal degeneration as a neuroprotective agent. Ultrastructural studies are required in order for kefir to be developed as a promising therapeutic agent to be utilized for human spinal cord ischemia in the future. PMID:26113960

  14. Vagal enhancement linking abnormal blood pressure response and subendocardial ischemia in hypertrophic cardiomyopathy.

    PubMed

    Kawasaki, Tatsuya; Sugihara, Hiroki

    2014-01-01

    An abnormal blood pressure response to exercise has been reported to be associated with left ventricular subendocardial ischemia in patients with hypertrophic cardiomyopathy (HCM), but the underlying mechanism remains unclear. We report a case of HCM with an abnormal blood pressure response and subendocardial ischemia, in which the analysis of heart rate variability revealed exercise-induced vagal enhancement. The present case highlights the possible mechanism linking abnormal blood pressure response and left ventricular subendocardial ischemia in patients with HCM.

  15. 13-Methyltetradecanoic acid mitigates cerebral ischemia/reperfusion injury

    PubMed Central

    Yu, Juan; Yang, Li-nan; Wu, Yan-yun; Li, Bao-hua; Weng, Sheng-mei; Hu, Chun-lan; Han, Yong-ling

    2016-01-01

    13-Methyltetradecanoic acid can stabilize cell membrane and have anti-inflammatory, antioxidant and anti-apoptotic effects. Previous studies mainly focused on peripheral nerve injury, but seldom on the central nervous system. We investigated whether these properties of 13-methyltetradecanoic acid have a neuroprotective effect on focal cerebral ischemia/reperfusion injury, and detected the expression of basic fibroblast growth factor and vascular endothelial growth factor. This study established rat models of middle cerebral artery occlusion/reperfusion injury by ischemia for 2 hours and reperfusion for 24 hours. At the beginning of reperfusion, 13-methyltetradecanoic acid 10, 40 or 80 mg/kg was injected into the tail vein. Results found that various doses of 13-methyltetradecanoic acid effectively reduced infarct volume, mitigate cerebral edema, and increased the mRNA and protein expression of basic fibroblast growth factor and vascular endothelial growth factor at 24 hours of reperfusion. The effect was most significant in the 13-methyltetradecanoic acid 40 and 80 mg/kg groups. The findings suggest that 13-methyltetradecanoic acid can relieve focal ischemia/reperfusion injury immediately after reperfusion, stimulate the upregulation of basic fibroblast growth factor and vascular endothelial growth factor to exert neuroprotective effects. PMID:27857745

  16. Renal oxygenation in acute renal ischemia-reperfusion injury.

    PubMed

    Abdelkader, Amany; Ho, Julie; Ow, Connie P C; Eppel, Gabriela A; Rajapakse, Niwanthi W; Schlaich, Markus P; Evans, Roger G

    2014-05-01

    Tissue hypoxia has been demonstrated, in both the renal cortex and medulla, during the acute phase of reperfusion after ischemia induced by occlusion of the aorta upstream from the kidney. However, there are also recent clinical observations indicating relatively well preserved oxygenation in the nonfunctional transplanted kidney. To test whether severe acute kidney injury can occur in the absence of widespread renal tissue hypoxia, we measured cortical and inner medullary tissue Po2 as well as total renal O2 delivery (Do2) and O2 consumption (Vo2) during the first 2 h of reperfusion after 60 min of occlusion of the renal artery in anesthetized rats. To perform this experiment, we used a new method for measuring kidney Do2 and Vo2 that relies on implantation of fluorescence optodes in the femoral artery and renal vein. We were unable to detect reductions in renal cortical or inner medullary tissue Po2 during reperfusion after ischemia localized to the kidney. This is likely explained by the observation that Vo2 (-57%) was reduced by at least as much as Do2 (-45%), due to a large reduction in glomerular filtration (-94%). However, localized tissue hypoxia, as evidence by pimonidazole adduct immunohistochemistry, was detected in kidneys subjected to ischemia and reperfusion, particularly in, but not exclusive to, the outer medulla. Thus, cellular hypoxia, particularly in the outer medulla, may still be present during reperfusion even when reductions in tissue Po2 are not detected in the cortex or inner medulla.

  17. Effect of carnosine on rats under experimental brain ischemia.

    PubMed

    Gallant, S; Kukley, M; Stvolinsky, S; Bulygina, E; Boldyrev, A

    2000-06-01

    The effect of dietary carnosine on the behavioral and biochemical characteristics of rats under experimental ischemia was studied. Carnosine was shown to improve the animals orientation and learning in "Open Field" and "T-Maze" tests, and this effect was accompanied with an increase in glutamate binding to N-methyl-D-aspartate (NMDA) receptors in brain synaptosomes. Long-term brain ischemia induced by both sides' occlusion of common carotid arteries resulted in 55% mortality of experimental rats, and those who survived were characterized by partial suppression of orientation in T-maze. In the group of rats treated with carnosine, mortality after ischemic attack was decreased (from 55% to 17%) and most of the learning parameters were kept at the pre-ischemic level. Monoamine oxidase B (MAO B) activity in brain of the carnosine treated rats was not changed by ischemia significantly (compared to that of ischemic untreated rats) but NMDA binding to brain synaptosomal membranes being increased by ischemic attack was significantly suppressed and reached the level characteristic of normal brain. The suggestion was made that carnosine possesses a dual effect on NMDA receptors resulting in increase in their amount after long-term treatment but decrease the capacity to bind NMDA after ischemic attack.

  18. Sirtinol abrogates late phase of cardiac ischemia preconditioning in rats.

    PubMed

    Safari, Fereshteh; Shekarforoosh, Shahnaz; Hashemi, Tahmineh; Namvar Aghdash, Simin; Fekri, Asefeh; Safari, Fatemeh

    2016-09-27

    The aim of this study was to investigate the effect of sirtinol, as an inhibitor of sirtuin NAD-dependent histone deacetylases, on myocardial ischemia reperfusion injury following early and late ischemia preconditioning (IPC). Rats underwent sustained ischemia and reperfusion (IR) alone or proceeded by early or late IPC. Sirtinol (S) was administered before IPC. Arrhythmias were evaluated based on the Lambeth model. Infarct size (IS) was measured using triphenyltetrazolium chloride staining. The transcription level of antioxidant-coding genes was assessed by real-time PCR. In early and late IPC groups, IS and the number of arrhythmia were significantly decreased (P < 0.05 and P < 0.01 vs IR, respectively). In S + early IPC, incidences of arrhythmia and IS were not different compared with the early IPC group. However, in S + late IPC the IS was different from the late IPC group (P < 0.05). In late IPC but not early IPC, transcription levels of catalase (P < 0.01) and Mn-SOD (P < 0.05) increased, although this upregulation was not significant in the S + late IPC group. Our results are consistent with the notion that different mechanisms are responsible for early and late IPC. In addition, sirtuin NAD-dependent histone deacetylases may be implicated in late IPC-induced cardioprotection.

  19. Diffractomery analysis of human and rat erythrocytes deformability under ischemia

    NASA Astrophysics Data System (ADS)

    Lugovtsov, Andrei E.; Priezzhev, Alexander V.; Nikitin, Sergei Y.; Koshelev, Vladimir B.

    2007-07-01

    In this work, the analysis of human and rat red blood cells (RBC) deformability, internal viscosity and yield stress of RBC in norm and ischemia was performed by means of laser diffractometry - a modern technique allowing for measuring the flexibility of RBC, which determines the blood flow parameters in vessels. Ischemic diseases of people and animals are accompanied with deterioration of microrheologic properties of their blood, in particular, with impairing the RBC deformability. Human RBCs were obtained from the blood of healthy individuals and from patients suffering from ischemic diseases. The RBC deformability indices from both groups of individuals were measured. Rat RBCs were obtained from a control group of animals and from a group with experimentally induced ischemia (EII). This animal model is frequently used for studying the response of an organism to ischemia. The effect of semax, a medication that is frequently used for therapeutic treatments of human brain diseases in clinical practice, on RBC deformability was studied with its application in vitro and in vivo. It is shown that in human ischemic patients, the deformability index of RBC was lower than that from healthy individuals. Both in vivo and in vitro applied semax positively influences the impaired deformability properties of RBCs of ischemic rats.

  20. Endovascular Treatment of Chronic Mesenteric Ischemia: Report of Five Cases

    SciTech Connect

    Nyman, Ulf; Ivancev, Krasnodar; Lindh, Mats; Uher, Petr

    1998-07-15

    Purpose: To evaluate the midterm results of percutaneous transluminal angioplasty (PTA) and stent placement in stenotic and occluded mesenteric arteries in five consecutive patients with chronic mesenteric ischemia. Methods: Five patients with 70%-100% obliterations of all mesenteric vessels resulting in chronic mesenteric ischemia (n= 4) and as a prophylactic measure prior to abdominal aortic aneurysm repair (n= 1) underwent PTA of celiac and/or superior mesenteric artery (SMA) stenoses (n= 2), primary stenting of ostial celiac occlusions (n= 2), and secondary stenting of a SMA occlusion (n= 1; recoil after initial PTA). All patients underwent duplex ultrasonography (US) (n= 3) and/or angiography (n= 5) during a median follow-up of 21 months (range 8-42 months). Results: Clinical success was obtained in all five patients. Asymptomatic significant late restenoses (n3) were successfully treated with repeat PTA (n= 2) and stenting of an SMA occlusion (n= 1; celiac stent restenosis). Recurrent pain in one patient was interpreted as secondary to postsurgical abdominal adhesions. Two puncture-site complications occurred requiring local surgical treatment. Conclusions: Endovascular techniques may be attempted prior to surgery in cases of stenotic or short occlusive lesions in patients with chronic mesenteric ischemia. Surgery may still be preferred in patients with long occlusions and a low operative risk.

  1. Progesterone Treatment in Two Rat Models of Ocular Ischemia

    PubMed Central

    Allen, Rachael S.; Olsen, Timothy W.; Sayeed, Iqbal; Cale, Heather A.; Morrison, Katherine C.; Oumarbaeva, Yuliya; Lucaciu, Irina; Boatright, Jeffrey H.; Pardue, Machelle T.; Stein, Donald G.

    2015-01-01

    Purpose. To determine whether the neurosteroid progesterone, shown to have protective effects in animal models of traumatic brain injury, stroke, and spinal cord injury, is also protective in ocular ischemia animal models. Methods. Progesterone treatment was tested in two ocular ischemia models in rats: a rodent anterior ischemic optic neuropathy (rAION) model, which induces permanent monocular optic nerve stroke, and the middle cerebral artery occlusion (MCAO) model, which causes transient ischemia in both the retina and brain due to an intraluminal filament that blocks the ophthalmic and middle cerebral arteries. Visual function and retinal histology were assessed to determine whether progesterone attenuated retinal injury in these models. Additionally, behavioral testing and 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining in brains were used to compare progesterone's neuroprotective effects in both retina and brain using the MCAO model. Results. Progesterone treatment showed no effect on visual evoked potential (VEP) reduction and retinal ganglion cell loss in the permanent rAION model. In the transient MCAO model, progesterone treatment reduced (1) electroretinogram (ERG) deficits, (2) MCAO-induced upregulation of glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), and (3) retinal ganglion cell loss. As expected, progesterone treatment also had significant protective effects in behavioral tests and a reduction in infarct size in the brain. Conclusions. Progesterone treatment showed protective effects in the retina following MCAO but not rAION injury, which may result from mechanistic differences with injury type and the therapeutic action of progesterone. PMID:26024074

  2. Transluminal coronary angioplasty in the treatment of silent ischemia

    SciTech Connect

    Bergin, P.; Myler, R.K.; Shaw, R.E.; Stertzer, S.H.; Clark, D.A.; Ryan, C.; Murphy, M.C.

    1988-01-01

    Fifty-four asymptomatic patients with positive thallium exercise tests underwent coronary angiography followed by coronary angioplasty (PTCA), as the primary therapy for silent ischemia. The procedure was technically successful in 89% of these patients. Emergency bypass graft surgery was necessary in 2 (3.6%) and q-wave myocardial infarction occurred in 1 (1.8%) of these. All fifty-four patients have been followed for a mean of 35 months since angioplasty. Of the 48 patients with initially successful PTCA, 12 had either clinical restenosis (9/14 or 19%) or a new lesion (3/48 or 6%) during follow-up, which required a repeat PTCA. At the longest follow-up, 46 (85%) had been successfully treated with on or more PTCA procedures. Two patients (3.6%) had sustained late q-wave myocardial infarction and two additional patients reported angina pectoris. There were no deaths. Angioplasty as a primary therapy for silent ischemia appears efficacious, with success and restenosis rates comparable to those in the symptomatic population. Event-free survival is improved, compared with natural history data for patients with silent ischemia from other studies. Prudent risk/benefit analysis may help to define subgroups most likely to benefit from this intervention.

  3. Global Consequences of Liver Ischemia/Reperfusion Injury

    PubMed Central

    Kalimeris, Konstantinos; Tasoulis, Marios-Konstantinos; Lykoudis, Panagis M.; Smyrniotis, Vassilios; Arkadopoulos, Nikolaos

    2014-01-01

    Liver ischemia/reperfusion injury has been extensively studied during the last decades and has been implicated in the pathophysiology of many clinical entities following hepatic surgery and transplantation. Apart from its pivotal role in the pathogenesis of the organ's post reperfusion injury, it has also been proposed as an underlying mechanism responsible for the dysfunction and injury of other organs as well. It seems that liver ischemia and reperfusion represent an event with “global” consequences that influence the function of many remote organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organs injury may lead to the multiple organ dysfunction syndrome, frequently encountered in these patients. Remote organ injury seems to be in part the result of the oxidative burst and the inflammatory response following reperfusion. The present paper aims to review the existing literature regarding the proposed mechanisms of remote organ injury after liver ischemia and reperfusion. PMID:24799983

  4. Ion-sensitive field effect transistors for pH and potassium ion concentration sensing: towards detection of myocardial ischemia

    NASA Astrophysics Data System (ADS)

    Rai, Pratyush; Jung, Soyoun; Ji, Taeksoo; Varadan, Vijay K.

    2008-03-01

    Ion Sensitive Field Effect Transistors (ISFETs) for sensing change in ionic concentration in biological systems can be used for detecting critical conditions like Myocardial Ischemia. Having the ability to yield steady signal characteristics can be used to observe the ionic concentration gradients which mark the onset of ischemia. Two ionic concentrations, pH and [K +], have been considered as the indicator for Myocardial Ischemia in this study. The ISFETs in this study have an organic semi-conductor film as the electronically active component. Poly-3 hexylthiophene was chosen for its compatibility to the solution processing, which is a simple and economical method of thin film fabrication. The gate electrode, which regulates the current in the active layer, has been employed as the sensor element. The devices under study here were fabricated on a flexible substrate PEN. The pH sensor was designed with the Tantalum Oxide gate dielectric as the ion selective component. The charge accumulated on the surface of the metal oxide acts as the source of the effecter electric field. The device was tested for pH values between 6.5 and 7.5, which comprises the variation observed during ischemic attack. The potassium ion sensor has got a floating gate electrode which is functionalized to be selective to potassium ion. The device was tested for potassium ion concentration between 5 and 25 mM, which constitutes the variation in extra cellular potassium ion concentration during ischemic attack. The device incorporated a monolayer of Valinomycin, a potassium specific ionophore, on top of the gate electrode.

  5. Dual AAV therapy ameliorates exercise-induced muscle injury and functional ischemia in murine models of Duchenne muscular dystrophy.

    PubMed

    Zhang, Yadong; Yue, Yongping; Li, Liang; Hakim, Chady H; Zhang, Keqing; Thomas, Gail D; Duan, Dongsheng

    2013-09-15

    Neuronal nitric oxide synthase (nNOS) membrane delocalization contributes to the pathogenesis of Duchenne muscular dystrophy (DMD) by promoting functional muscle ischemia and exacerbating muscle injury during exercise. We have previously shown that supra-physiological expression of nNOS-binding mini-dystrophin restores normal blood flow regulation and prevents functional ischemia in transgenic mdx mice, a DMD model. A critical next issue is whether systemic dual adeno-associated virus (AAV) gene therapy can restore nNOS-binding mini-dystrophin expression and mitigate muscle activity-related functional ischemia and injury. Here, we performed systemic gene transfer in mdx and mdx4cv mice using a pair of dual AAV vectors that expressed a 6 kb nNOS-binding mini-dystrophin gene. Vectors were packaged in tyrosine mutant AAV-9 and co-injected (5 × 10(12) viral genome particles/vector/mouse) via the tail vein to 1-month-old dystrophin-null mice. Four months later, we observed 30-50% mini-dystrophin positive myofibers in limb muscles. Treatment ameliorated histopathology, increased muscle force and protected against eccentric contraction-induced injury. Importantly, dual AAV therapy successfully prevented chronic exercise-induced muscle force drop. Doppler hemodynamic assay further showed that therapy attenuated adrenergic vasoconstriction in contracting muscle. Our results suggest that partial transduction can still ameliorate nNOS delocalization-associated functional deficiency. Further evaluation of nNOS binding mini-dystrophin dual AAV vectors is warranted in dystrophic dogs and eventually in human patients.

  6. Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury.

    PubMed

    Packard, Amy E B; Hedges, Jason C; Bahjat, Frances R; Stevens, Susan L; Conlin, Michael J; Salazar, Andres M; Stenzel-Poore, Mary P

    2012-02-01

    Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

  7. Update on ischemia-reperfusion injury for the plastic surgeon: 2011.

    PubMed

    Wang, Wei Z; Baynosa, Richard C; Zamboni, William A

    2011-12-01

    Ischemia-reperfusion injury occurs when tissue is reperfused following a prolonged period of ischemia. It is a subject of interest to plastic surgeons involved in replantation, free tissue transfer, and composite tissue allotransplantation, as it can have a significant impact on the overall success of these procedures. The purpose of this article is to review the recent progress in the investigation of ischemia-reperfusion injury in skeletal muscle and skin and to highlight the potential clinical implications of therapeutic interventions aimed at reducing ischemia-reperfusion injury.

  8. Carnosine pretreatment protects against hypoxia-ischemia brain damage in the neonatal rat model.

    PubMed

    Zhang, Xiangmin; Song, Lili; Cheng, Xiuyong; Yang, Yi; Luan, Bin; Jia, Liting; Xu, Falin; Zhang, Zhan

    2011-09-30

    Perinatal hypoxia-ischemia brain injury is a major cause of mortality and morbidity in neonates and lacks an effective treatment thus far. Carnosine has been demonstrated to play a neuroprotective role in the adult brain injuries. However, there is no information available concerning its neuroprotective role in the immature brains after hypoxia-ischemia insults. Therefore, we investigated whether carnosine could also confer neuroprotective effects in a neonatal rat hypoxia-ischemia model. Hypoxia-ischemia was induced in rats on postnatal day 7 (P7). Carnosine (250 mg/kg) was administered intraperitoneally, 30 min prior to hypoxia-ischemia induction. Morphological brain injury and biochemical markers of apoptosis and oxidative stress were evaluated 24 h after hypoxia-ischemia induction. Cognitive performance was evaluated by the Morris Water Maze test on P28-P33. We found that pretreatment with carnosine significantly reduced the infarct volume and the number of terminal-deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells in the hypoxia-ischemia brain. Carnosine also inhibited mRNA expression of apoptosis-inducing factor(AIF) and caspase-3, which was accompanied by an increase in superoxide dismutase(SOD)activity and a decrease in the malondialdehyde(MDA)level in carnosine-treated rats. Furthermore, carnosine also improved the spatial learning and memory abilities of rats declined due to hypoxia-ischemia. These results demonstrate that carnosine can protect rats against hypoxia-ischemia-induced brain damage by antioxidation.

  9. Effect of dexmedetomidine on lung ischemia-reperfusion injury

    PubMed Central

    JIANG, LILI; LI, LI; SHEN, JINMEI; QI, ZEYOU; GUO, LIANG

    2014-01-01

    Dexmedetomidine, a specific selective α2-adrenergic agonist, does not only have the characteristics of being a sedative and analgesic, but also exhibits a protective role in brain ischemia-reperfusion injury and inhibits the inflammation in animals with sepsis. The objective of the present study was to investigate whether dexmedetomidine is capable of attenuating rat pulmonary damage induced by ischemia-reperfusion injury, which is a type of acute sterile lung injury. Sprague-Dawley rats were randomly assigned into six groups: The sham-operated (sham) group, the lung ischemia-reperfusion (I/R) group, intravenous injection of dexmedetomidine 2.5 μg/kg/h (Dex2.5) or 5 μg/kg/h (Dex5) for 1 h prior to ischemia, combination of α2-adrenergic antagonist yohimbine prior to dexmedetomidine pre-treatment (Dex+Yoh) and pre-administration of yohimbine alone (Yoh) prior to ischemia. Lung injury was assessed by the histopathological changes, arterial blood gas, wet/dry (w/d) weight ratio and myeloperoxidase (MPO) activity of the lung. The concentration of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) in bronchoalveolar lavage fluid (BALF) was measured by an enzyme-linked immunosorbent assay. The expression of toll-like receptor-4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA in the lung were determined by quantitative PCR, and phosphorylated levels of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2 were determined by western blotting. Pre-treatment with dexmedetomidine significantly reduced the lung injury, w/d weight ratio and MPO activity, and decreased the concentration of TNF-α, IL-6 and MCP-1 in BALF compared with the I/R group. The expression of TLR4 and MyD88 mRNA and the levels of phosphorylated JNK and ERK1/2 in the lung tissue were markedly downregulated by intravenous injection of dexmedetomidne for 1 h prior to lung I/R. The protective effects of dexmedetomidine

  10. Major Ozonated Autohemotherapy Preconditioning Ameliorates Kidney Ischemia-Reperfusion Injury.

    PubMed

    Sancak, Eyup Burak; Turkön, Hakan; Çukur, Selma; Erimsah, Sevilay; Akbas, Alpaslan; Gulpinar, Murat Tolga; Toman, Huseyin; Sahin, Hasan; Uzun, Metehan

    2016-02-01

    Medical ozone has therapeutic properties as an antimicrobial, anti-inflammatory, modulator of antioxidant defense system. Major ozonated autohemotherapy (MOA) is a new therapeutic approach that is widely used in the treatment of many diseases. The objective of the present study was to determine whether preischemic application of MOA would attenuate renal ischemia-reperfusion injury (IRI) in rabbits. Twenty-four male New Zealand white rabbits were divided into four groups, each including six animals: (1) Sham-operated group, (2) Ozone group (the MOA group without IRI), (3) IR group (60 min ischemia followed by 24 h reperfusion), and (4) IR + MOA group (MOA group). The effects of MOA were examined by use of hematologic and biochemical parameters consisting of neutrophil to lymphocyte ratio (NLR), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ischemia-modified albumin (IMA), total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI). In addition, the histopathological changes including the tubular brush border loss (TBBL), tubular cast (TC), tubular necrosis (TN), intertubular hemorrhage and congestion (IHC), dilatation of bowman space (DBS), and interstitial inflammatory cells infiltration (IECI) were evaluated. In the IR group, compared to the Sham group, biochemical parameters indicating oxidative stress, NLR, IL-6, TNF-α, IMA, TOS, and OSI have increased. MOA reduced inflammation and oxidative stress parameters. Although TAS values have decreased in the IR group and increased in the MOA-pretreated group, no significant changes in TAS values were detected between the IR and MOA groups. The total score was obtained by summing all the scores from morphological kidney damage markers. The total score has increased with IR damage when compared with the Sham group (13.83 ± 4.30 vs 1.51 ± 1.71; p = 0.002). But, the total score has decreased significantly after application of MOA (5.01 ± 1.49; p = 0.002; compared

  11. [Free radicals and hepatic ischemia-reperfusion].

    PubMed

    Szijártó, Attila

    2015-11-22

    The critical importance of the ischemic-reperfusive injury is well documented with regards to numerous organs and clinical conditions. Oxygen free radicals play a central role in the mediation of the injury, which dominantly influences the prevalence of postoperative complications, (long term) organ damage, and the potential manifestation of systemic reactions. The both anatomically and pathophysiologically unique ischemic-reperfusive injury of the liver, which is expressively vulnerable to free radicals, is of utmost importance in liver surgery. Several techniques (adaptive maneuvers, chemical agents) are known to ameliorate the reperfusive injury. Based on the prior research of the workgroup of the author, the aim of the current article is to overview the set of measures capable of attenuating ischemic-reperfusive injury (ischemic preconditioning, -perconditioning, administration of adenosine, -inosine, -levosimendan, and -poly-ADP-ribose-polymerase inhibitor), with special attention to the ischemic-reperfusive injury of the liver, as well as the special pathophysiological role of free radicals in mediating hepatic damage.

  12. GM-CSF treated F4/80+ BMCs improve murine hind limb ischemia similar to M-CSF differentiated macrophages.

    PubMed

    Kuwahara, Go; Nishinakamura, Hitomi; Kojima, Daibo; Tashiro, Tadashi; Kodama, Shohta

    2014-01-01

    Novel cell therapy is required to treat critical limb ischemia (CLI) as many current approaches require repeated aspiration of bone marrow cells (BMCs). The use of cultured BMCs can reduce the total number of injections required and were shown to induce therapeutic angiogenesis in a murine model of hind limb ischemia. Blood flow recovery was significantly improved in mice treated with granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent BMCs that secreted inflammatory cytokines. Angiogenesis, lymphangiogenesis, and blood flow recovery ratio were significantly higher in the GM-CSF-cultured F4/80+ macrophage (GM-Mø)-treated group compared with controls. Furthermore, Foxp3+ cell numbers and tissue IL-10 concentrations were significantly increased compared with controls. There was no significant difference in blood flow recovery between GM-Mø and M-CSF-cultured F4/80+ macrophages (M-Mø). Thus, GM-Mø were associated with improved blood flow in hind limb ischemia similar to M-Mø. The selective methods of culturing and treating GM-Mø cells similar to M-Mø cells could be used clinically to help resolve the large number of cells required for BMC treatment of CLI. This study demonstrates a novel cell therapy for CLI that can be used in conjunction with conventional therapy including percutaneous intervention and surgical bypass.

  13. A Type-II Positive Allosteric Modulator of α7 nAChRs Reduces Brain Injury and Improves Neurological Function after Focal Cerebral Ischemia in Rats

    PubMed Central

    Sun, Fen; Jin, Kunlin; Uteshev, Victor V.

    2013-01-01

    In the absence of clinically-efficacious therapies for ischemic stroke there is a critical need for development of new therapeutic concepts and approaches for prevention of brain injury secondary to cerebral ischemia. This study tests the hypothesis that administration of PNU-120596, a type-II positive allosteric modulator (PAM-II) of α7 nicotinic acetylcholine receptors (nAChRs), as long as 6 hours after the onset of focal cerebral ischemia significantly reduces brain injury and neurological deficits in an animal model of ischemic stroke. Focal cerebral ischemia was induced by a transient (90 min) middle cerebral artery occlusion (MCAO). Animals were then subdivided into two groups and injected intravenously (i.v.) 6 hours post-MCAO with either 1 mg/kg PNU-120596 (treated group) or vehicle only (untreated group). Measurements of cerebral infarct volumes and neurological behavioral tests were performed 24 hrs post-MCAO. PNU-120596 significantly reduced cerebral infarct volume and improved neurological function as evidenced by the results of Bederson, rolling cylinder and ladder rung walking tests. These results forecast a high therapeutic potential for PAMs-II as effective recruiters and activators of endogenous α7 nAChR-dependent cholinergic pathways to reduce brain injury and improve neurological function after cerebral ischemic stroke. PMID:23951360

  14. MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine.

    PubMed

    Sala, V; Bergerone, S; Gatti, S; Gallo, S; Ponzetto, A; Ponzetto, C; Crepaldi, T

    2014-04-01

    MicroRNAs (miRNAs) are natural, single-stranded, small RNA molecules which subtly control gene expression. Several studies indicate that specific miRNAs can regulate heart function both in development and disease. Despite prevention programs and new therapeutic agents, cardiovascular disease remains the main cause of death in developed countries. The elevated number of heart failure episodes is mostly due to myocardial infarction (MI). An increasing number of studies have been carried out reporting changes in miRNAs gene expression and exploring their role in MI and heart failure. In this review, we furnish a critical analysis of where the frontier of knowledge has arrived in the fields of basic and translational research on miRNAs in cardiac ischemia. We first summarize the basal information on miRNA biology and regulation, especially concentrating on the feedback loops which control cardiac-enriched miRNAs. A focus on the role of miRNAs in the pathogenesis of myocardial ischemia and in the attenuation of injury is presented. Particular attention is given to cardiomyocyte death (apoptosis and necrosis), fibrosis, neovascularization, and heart failure. Then, we address the potential of miR-diagnosis (miRNAs as disease biomarkers) and miR-drugs (miRNAs as therapeutic targets) for cardiac ischemia and heart failure. Finally, we evaluate the use of miRNAs in the emerging field of regenerative medicine.

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

    PubMed

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

    2014-01-01

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

  16. Enteral nutrition in the hemodynamically unstable critically ill patient.

    PubMed

    Flordelís Lasierra, J L; Pérez-Vela, J L; Montejo González, J C

    2015-01-01

    The benefit of enteral nutrition in critically ill patients has been demonstrated by several studies, especially when it is started early, in the first 24-48h of stay in the Intensive Care Unit, and this practice is currently advised by the main clinical guidelines. The start of enteral nutrition is controversial in patients with hemodynamic failure, since it may trigger intestinal ischemia. However, there are data from experimental studies in animals, as well as from observational studies in humans that allow for hypotheses regarding its beneficial effect and safety. Interventional clinical trials are needed to confirm these findings.

  17. An immunohistochemical study of parvalbumin containing interneurons in the gerbil hippocampus after cerebral ischemia.

    PubMed

    Araki, T; Kato, H; Liu, X H; Kogure, K; Kato, K; Itoyama, Y

    1994-09-01

    We investigated postischemic changes of non-pyramidal neurons in the gerbil hippocampus 1 h - 7 days after 10 min of cerebral ischemia, with parvalbumin and microtubule-associated protein 2 (MAP2)-immunohistochemistry. Parvalbumin-immunoreactive interneurons in the hippocampus were unaffected up to 24 h after ischemia. A slight reduction of the immunoreactivity in neuronal processes was seen in the hippocampal CA1 sector 48 h after ischemia. Seven days after ischemia, a marked loss of parvalbumin-immunoreactive interneurons was observed in the hippocampal CA1 and CA3 sectors. Furthermore, reduced staining in the dentate granular and molecular layers was observed. MAP2-immunoreactive pyramidal neurons in the hippocampus were unchanged up to 48 h after ischemia. Seven days after ischemia, a severe loss of MAP2 immunoreactivity was found in the hippocampal CA1 and CA3 neurons and dentate hilar neurons. However, scattered CA1 neurons, most likely interneurons, preserved MAP2 immunoreactivity. The results demonstrate that transient cerebral ischemia can cause a loss of parvalbumin-immunoreactive interneurons in the hippocampus. Furthermore, some interneurons seem to lose parvalbumin synthesis. Although dentate granule cells are resistant to ischemia, considerable reductions of afferent input was suggested by parvalbumin staining.

  18. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice

    SciTech Connect

    Cao Canxiang; Yang Qingwu . E-mail: yangqwmlys@hotmail.com; Lv Fenglin; Cui Jie; Fu Huabin; Wang Jingzhou

    2007-02-09

    Inflammatory reaction plays an important role in cerebral ischemia-reperfusion injury, however, its mechanism is still unclear. Our study aims to explore the function of Toll-like receptor 4 (TLR4) in the process of cerebral ischemia-reperfusion. We made middle cerebral artery ischemia-reperfusion model in mice with line embolism method. Compared with C3H/OuJ mice, scores of cerebral water content, cerebral infarct size and neurologic impairment in C3H/Hej mice were obviously lower after 6 h ischemia and 24 h reperfusion. Light microscopic and electron microscopic results showed that cerebral ischemia-reperfusion injury in C3H/Hej mice was less serious than that in C3H/OuJ mice. TNF-{alpha} and IL-6 contents in C3H/HeJ mice were obviously lower than that in C3H/OuJ mice with ELISA. The results showed that TLR4 participates in the process of cerebral ischemia-reperfusion injury probably through decrease of inflammatory cytokines. TLR4 may become a new target for prevention of cerebral ischemia-reperfusion injury. Our study suggests that TLR4 is one of the mechanisms of cerebral ischemia-reperfusion injury besides its important role in innate immunity.

  19. Animal models of ischemia-reperfusion-induced intestinal injury: progress and promise for translational research.

    PubMed

    Gonzalez, Liara M; Moeser, Adam J; Blikslager, Anthony T

    2015-01-15

    Research in the field of ischemia-reperfusion injury continues to be plagued by the inability to translate research findings to clinically useful therapies. This may in part relate to the complexity of disease processes that result in intestinal ischemia but may also result from inappropriate research model selection. Research animal models have been integral to the study of ischemia-reperfusion-induced intestinal injury. However, the clinical conditions that compromise intestinal blood flow in clinical patients ranges widely from primary intestinal disease to processes secondary to distant organ failure and generalized systemic disease. Thus models that closely resemble human pathology in clinical conditions as disparate as volvulus, shock, and necrotizing enterocolitis are likely to give the greatest opportunity to understand mechanisms of ischemia that may ultimately translate to patient care. Furthermore, conditions that result in varying levels of ischemia may be further complicated by the reperfusion of blood to tissues that, in some cases, further exacerbates injury. This review assesses animal models of ischemia-reperfusion injury as well as the knowledge that has been derived from each to aid selection of appropriate research models. In addition, a discussion of the future of intestinal ischemia-reperfusion research is provided to place some context on the areas likely to provide the greatest benefit from continued research of ischemia-reperfusion injury.

  20. DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats.

    PubMed

    Li, Zhen; Cui, Shengzhong; Zhang, Zhuo; Zhou, Rong; Ge, Yingbin; Sokabe, Masahiro; Chen, Ling

    2009-02-01

    Dehydroepiandrosterone (DHEA) has been implicated not only to prevent N-methyl-D-aspartate (NMDA)-induced neurotoxicity but also to enhance Ca(2+) influx through NMDA receptor (NMDAr). However, these DHEA effects, which would produce inconsistent outcomes about neuronal damages, are not well studied in ischemia-induced cerebral damages. Herein, we report that a single administration of DHEA (20 mg/kg) during 3 to 48 h after transient global cerebral ischemia in rats exerted neuroprotective effects such as reduction of ischemia-induced neuronal death in the hippocampal CA1 and improvement of ischemia-induced deficits in spatial learning. By contrast, at 1 h before or after ischemia, the administration of DHEA exacerbated the ischemia-induced neuronal death and learning impairment. This DHEA neurotoxicity appeared to be caused by DHEA itself, but not through its metabolite testosterone, and was inhibited by a pretreatment with the NMDAr blocker MK801 or the sigma-1 (sigma(1)) receptor antagonist NE100. However, the DHEA neuroprotection was blocked by NE100. These results show that DHEA not only provides robust ischemic neuroprotection with a long therapeutic opportunity but also exerts neurotoxicity when administered during ischemia and early reperfusion, which points to the importance of administration timing of DHEA in the clinical treatment of brain damages by the transient brain ischemia including stroke.

  1. Oxidant stress during simulated ischemia primes cardiomyocytes for cell death during reperfusion.

    PubMed

    Robin, Emmanuel; Guzy, Robert D; Loor, Gabriel; Iwase, Hirotaro; Waypa, Gregory B; Marks, Jeremy D; Hoek, Terry L Vanden; Schumacker, Paul T

    2007-06-29

    Ischemia-reperfusion injury induces oxidant stress, and the burst of reactive oxygen species (ROS) production after reperfusion of ischemic myocardium is sufficient to induce cell death. Mitochondrial oxidant production may begin during ischemia prior to reperfusion because reducing equivalents accumulate and promote superoxide production. We utilized a ratiometric redox-sensitive protein sensor (heat shock protein 33 fluorescence resonance energy transfer (HSP-FRET)) to assess oxidant stress in cardiomyocytes during simulated ischemia. HSP-FRET consists of the cyan and yellow fluorescent protein fluorophores linked by the cysteine-containing regulatory domain from bacterial HSP-33. During ischemia, ROS-mediated oxidation of HSP-FRET was observed, along with a decrease in cellular reduced glutathione levels. These findings were corroborated by measurements using redox-sensitive green fluorescent protein, another protein thiol ratiometric sensor, which became 93% oxidized by the end of simulated ischemia. However, cell death did not occur during ischemia, indicating that this oxidant stress is not sufficient to induce death before reperfusion. However, interventions that attenuate ischemic oxidant stress, including antioxidants or scavengers of residual O(2) that attenuate/prevent ROS generation during ischemia, abrogated cell death during simulated reperfusion. These findings reveal that, in isolated cardiomyocytes, sublethal H(2)O(2) generation during simulated ischemia regulates cell death during simulated reperfusion, which is mediated by the reperfusion oxidant burst.

  2. Dietary and plant polyphenols exert neuroprotective effects and improve cognitive function in cerebral ischemia

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cerebral ischemia is caused by an interruption of blood flow to the brain which generally leads to irreversible brain damage. Ischemic injury is associated with vascular leakage, inflammation, tissue injury, and cell death. Cellular changes associated with ischemia include impairment of metabolism, ...

  3. Constrictive pericarditis causing a positive TI-201 SPECT stress test for myocardial ischemia

    SciTech Connect

    Matthews, R.J.; Lightfoote, J.; Grusd, R.S. )

    1990-08-01

    A case of constritive pericarditis was demonstrated by a positive thallium SPECT stress test for myocardial ischemia. After pericardiectomy, the repeat thallium stress test was normal. The disappearance of the criteria for a positive test suggests that constrictive pericarditis can cause myocardial ischemia, which can be demonstrated by thallium SPECT stress testing.

  4. Ischemia/reperfusion injury in the rat colon.

    PubMed

    Murthy, S; Hui-Qi, Q; Sakai, T; Depace, D E; Fondacaro, J D

    1997-04-01

    This study investigated metabolic and biochemical consequences of colonic ischemia/reperfusion (I/R) in the rat and evaluated whether antioxidants prevent I/R-induced functional damage in the rat colon. The surgical preparation involved a 10 cm segment of the colon and occlusion of the superior mesenteric artery (SMA) to induce I/R. Arterial blood from the aorta and venous blood from the superior mesenteric vein (SMV) was collected to measure blood gases, lactic acid (LA) and arachidonic acid (AA) metabolites. Tissue xanthine oxidase (XO) and thiobarbituric acid (TBA) derivatives were measured before and after reperfusion. In addition, vascular and mucosal permeability, and the effect of MDL 73404 (a water soluble vitamin E analog) and 5-aminosalicylic acid on LA, AA, XO and TBA was measured. After ischemia, the colon displayed a metabolic shift from aerobic to anaerobic course by increasing lactic acid production in the colon (183% increase in SMV lactate level compared 87% in the SMA; p < 0.03). After 10 minutes of reperfusion, circulating 6-keto-prostaglandin F1 alpha increased by 3.85 fold (p < 0.001) and thromboxane B2 increased by 2 to 3 fold. An Ischemia time longer than 60 minutes was required to cause changes in tissue XO levels. Tissue TBA levels showed a good dose response corresponding with I/R time. I/R (60 minutes) caused a three and 16 fold increase (p < 0.01) in vascular and mucosal permeability, respectively. MDL 73404 and 5-aminosalicylic acid significantly inhibited the vascular permeability and decreased LA, AA, XO and TBA. These observations provide the first direct experimental evidence for I/R-induced damage in the colon and some of its effects can be reversed by conventional and novel antioxidants.

  5. Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury.

    PubMed

    Kishi, Seiji; Campanholle, Gabriela; Gohil, Vishal M; Perocchi, Fabiana; Brooks, Craig R; Morizane, Ryuji; Sabbisetti, Venkata; Ichimura, Takaharu; Mootha, Vamsi K; Bonventre, Joseph V

    2015-09-01

    Global or local ischemia contributes to the pathogenesis of acute kidney injury (AKI). Currently there are no specific therapies to prevent AKI. Potentiation of glycolytic metabolism and attenuation of mitochondrial respiration may decrease cell injury and reduce reactive oxygen species generation from the mitochondria. Meclizine, an over-the-counter anti-nausea and -dizziness drug, was identified in a 'nutrient-sensitized' chemical screen. Pretreatment with 100 mg/kg of meclizine, 17 h prior to ischemia protected mice from IRI. Serum creatinine levels at 24 h after IRI were 0.13 ± 0.06 mg/dl (sham, n = 3), 1.59 ± 0.10 mg/dl (vehicle, n = 8) and 0.89 ± 0.11 mg/dl (meclizine, n = 8). Kidney injury was significantly decreased in meclizine treated mice compared with vehicle group (p < 0.001). Protection was also seen when meclizine was administered 24 h prior to ischemia. Meclizine reduced inflammation, mitochondrial oxygen consumption, oxidative stress, mitochondrial fragmentation, and tubular injury. Meclizine preconditioned kidney tubular epithelial cells, exposed to blockade of glycolytic and oxidative metabolism with 2-deoxyglucose and NaCN, had reduced LDH and cytochrome c release. Meclizine upregulated glycolysis in glucose-containing media and reduced cellular ATP levels in galactose-containing media. Meclizine inhibited the Kennedy pathway and caused rapid accumulation of phosphoethanolamine. Phosphoethanolamine recapitulated meclizine-induced protection both in vitro and in vivo.

  6. Autophagy activation attenuates renal ischemia-reperfusion injury in rats

    PubMed Central

    Zhang, Ya-Li; Cui, Li-Yan; Yang, Shuo

    2015-01-01

    Ischemia-reperfusion (I/R) injury is a leading cause of acute kidney injury (AKI), which is a common clinical complication but lacks effective therapies. This study investigated the role of autophagy in renal I/R injury and explored potential mechanisms in an established rat renal I/R injury model. Forty male Wistar rats were randomly divided into four groups: Sham, I/R, I/R pretreated with 3-methyladenine (3-MA, autophagy inhibitor), or I/R pretreated with rapamycin (autophagy activator). All rats were subjected to clamping of the left renal pedicle for 45 min after right nephrectomy, followed by 24 h of reperfusion. The Sham group underwent the surgical procedure without ischemia. 3-MA and rapamycin were injected 15 min before ischemia. Renal function was indicated by blood urea nitrogen and serum creatinine. Tissue samples from the kidneys were scored histopathologically. Autophagy was indicated by light chain 3 (LC3), Beclin-1, and p62 levels and the number of autophagic vacuoles. Apoptosis was evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method and expression of caspase-3. Autophagy was activated after renal I/R injury. Inhibition of autophagy by 3-MA before I/R aggravated renal injury, with worsened renal function, higher renal tissue injury scores, and more tubular apoptosis. In contrast, rapamycin pretreatment ameliorated renal injury, with improved renal function, lower renal tissue injury scores, and inhibited apoptosis based on fewer TUNEL-positive cells and lower caspase-3 expression. Our results demonstrate that autophagy could be activated during I/R injury and play a protective role in renal I/R injury. The mechanisms were involved in the regulation of several autophagy and apoptosis-related genes. Furthermore, autophagy activator may be a promising therapy for I/R injury and AKI in the future. PMID:25898836

  7. Effect of hydrogen sulfide on inflammatory cytokines in acute myocardial ischemia injury in rats

    PubMed Central

    LIU, FANG; LIU, GUANG-JIE; LIU, NA; ZHANG, GANG; ZHANG, JIAN-XIN; LI, LAN-FANG

    2015-01-01

    Hydrogen sulfide (H2S) is believed to be involved in numerous physiological and pathophysiological processes, and now it is recognized as the third endogenous signaling gasotransmitter, following nitric oxide and carbon monoxide; however, the effects of H2S on inflammatory factors in acute myocardial ischemia injury in rats have not been clarified. In the present study, sodium hydrosulfide (NaHS) was used as the H2S donor. Thirty-six male Sprague Dawley rats were randomly divided into five groups: Sham, ischemia, ischemia + low-dose (0.78 mg/kg) NaHS, ischemia + medium-dose (1.56 mg/kg) NaHS, ischemia + high-dose (3.12 mg/kg) NaHS and ischemia + propargylglycine (PPG) (30 mg/kg). The rats in each group were sacrificed 6 h after the surgery for sample collection. Compared with the ischemia group, the cardiac damage in the rats in the ischemia + NaHS groups was significantly reduced, particularly in the high-dose group; in the ischemia + PPG group, the myocardial injury was aggravated compared with that in the ischemia group. Compared with the ischemia group, the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the serum of rats in the ischemia + medium- and high-dose NaHS groups were significantly reduced, and the expression of intercellular adhesion molecule-1 (ICAM-1) mRNA and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) protein in the myocardial tissues of rats was significantly reduced. In the ischemia + PPG group, the TNF-α, IL-1β and IL-6 levels in the serum were significantly increased, the expression of ICAM-1 mRNA was increased, although without a significant difference, and the expression of NF-κB was increased. The findings of the present study provide novel evidence for the dual effects of H2S on acute myocardial ischemia injury via the modulation of inflammatory factors. PMID:25667680

  8. Interleukin-6 receptor expression and localization after transient global ischemia in gerbil hippocampus.

    PubMed

    Vollenweider, Florence; Herrmann, Martina; Otten, Uwe; Nitsch, Cordula

    2003-04-24

    Ischemia results in increased interleukin-6 (IL-6) expression in the brain. To prove a connection between IL-6 upregulation and IL-6 receptor (IL-6R) expression following ischemia, we analyzed cell-type specific expression changes of IL-6R using transient global ischemia in the gerbil as a model. In sham operated animals, IL-6R mRNA and protein were mainly detected in hippocampal pyramidal cells and interneurons. After ischemia, IL-6R was expressed in neurons but there was no increase during the peak IL-6 expression. Neuronal IL-6R mRNA and protein decreased in parallel with pyramidal cell death, starting 2 days after ischemia. Double-labeling experiments revealed that in postischemic hippocampus IL-6R was not present in GFAP-reactive astrocytes but that the surviving parvalbumin containing interneurons expressed IL-6R mRNA.

  9. Delayed administration IL-1β neutralizing antibody improves cognitive function after transient global ischemia in rats.

    PubMed

    Zhao, Bei; Zou, Chang-Jiang; Zhou, Ping

    2016-04-15

    In order to study the protective effects on motor and cognitive function by inhibiting IL-1β as delayed as 24h after global ischemia, we designed behavioral testing protocol and histology detection after 10 min transient global ischemia followed by IL-1β or its antibody intracerebroventricular injection. We found benefit of IL-1β antibody treatment 24h after ischemia in cognitive function recovery. But no obvious amelioration in motor function was found. Further we detected cell morphology and survival by histology staining and proved IL-1β antibody could reduce ischemia induced cell morphological changes and cell loss in hippocampus, which related with cognitive function. Present results indicate intervening IL-1β pathway could be helpful in cognitive function recovery even as late as 24h after ischemia happens.

  10. Identification of intestinal wall abnormalities and ischemia by modeling spatial uncertainty in computed tomography imaging findings.

    PubMed

    Tsunoyama, Taichiro; Pham, Tuan D; Fujita, Takashi; Sakamoto, Tetsuya

    2014-10-01

    Intestinal abnormalities and ischemia are medical conditions in which inflammation and injury of the intestine are caused by inadequate blood supply. Acute ischemia of the small bowel can be life-threatening. Computed tomography (CT) is currently a gold standard for the diagnosis of acute intestinal ischemia in the emergency department. However, the assessment of the diagnostic performance of CT findings in the detection of intestinal abnormalities and ischemia has been a difficult task for both radiologists and surgeons. Little effort has been found in developing computerized systems for the automated identification of these types of complex gastrointestinal disorders. In this paper, a geostatistical mapping of spatial uncertainty in CT scans is introduced for medical image feature extraction, which can be effectively applied for diagnostic detection of intestinal abnormalities and ischemia from control patterns. Experimental results obtained from the analysis of clinical data suggest the usefulness of the proposed uncertainty mapping model.

  11. Acute arterial ischemia in a patient with polyarthritis.

    PubMed

    Soro Marín, Sandra; Júdez Navarro, Enrique; Alamillo Sanz, Antonio Salvador; Sánchez Nievas, Ginés

    Cryoglobulins are immunoglobulins that precipitate at cold temperatures. Their presence can be related to a type of vasculitis referred to as cryoglobulinemia. This condition, especially mixed cryoglobulinemia, has been associated with viral infections like hepatitis C virus in 60%-90% of cases, but it has also been reported in relation to connective tissue diseases, usually resulting in a more severe course. We describe the case of a patient with seronegative polyarthritis who developed acute arterial ischemia in association with cryoglobulinemia, with a good response to rituximab therapy.

  12. Testicular ischemia following mesh hernia repair and acute prostatitis

    PubMed Central

    Pietro, Pepe; Francesco, Aragona

    2007-01-01

    We present a case of a man admitted to our Hospital for right acute scrotum that six months before had undergone a right hernioplasty with mesh implantation. Clinical history and testicular color Doppler sonography (CDS) patterns suggested an orchiepididymitis following acute prostatitis. After 48h the clinical picture worsened and testicular CDS showed a decreased telediastolic velocity that suggested testicular ischemia. The patient underwent surgical exploration: spermatic cord appeared stretched by an inflammatory tissue in absence of torsion and releasing of spermatic cord was performed. In patients with genitourinary infection who previously underwent inguinal mesh implantation, testicular CDS follow-up is mandatory. PMID:19718342

  13. Chronic mesenteric ischemia: Time to remember open revascularization

    PubMed Central

    Keese, Michael; Schmitz-Rixen, Thomas; Schmandra, Thomas

    2013-01-01

    Chronic mesenteric ischemia is caused by stenosis or occlusion of one or more visceral arteries. It represents a therapeutic challenge and diagnosis and treatment require close interdisciplinary cooperation between gastroenterologist, vascular surgeon and radiologist. Although endovascular treatment modalities have been developed, the number of restenoses ultimately resulting in treatment failure is high. In patients fit for open surgery, the visceral arteries should be revascularized conventionally. These patients will then experience long term relief from the symptoms, a better quality of life and a better overall survival. PMID:23539677

  14. Spinal cord ischemia resulting in paraplegia following extrapleural pneumonectomy.

    PubMed

    Ural, Kelly; Jakob, Kyle; Lato, Scott; Gilly, George; Landreneau, Rodney

    2014-08-01

    A patient undergoing radical extrapleural pneumonectomy for epithelioid malignant mesothelioma developed acute paraplegia postoperatively related to long-segment spinal cord ischemia. The usual area of concern for this complication is the T9 to T12 area where the artery of Adamkiewicz is most likely to originate. In this patient, there was ligation of only upper thoracic, ipsilateral segmental arteries from the T3 to T6 level, yet he still developed paraplegia. Our hypothesis is variant mid-thoracic vascular anatomy. Previously unreported, to our knowledge, this should be understood as a rare complication of this surgery.

  15. [Pharmacological properties of phosphorylacetohydrazides in experimental myocardial ischemia].

    PubMed

    Balashov, V P; Al'miasheva, M I; Tarasova, R I; Rusina, I F; Kul'kova, N P; Kurmysheva, T V; Voskresenskaia, O V

    2007-01-01

    It is shown that 2-chloroethoxy-para-N-dimethylphosphorylacetohydrazide and N-acethylhydrazide-para-dimethylaminophenyl-2-chloroethoxyphosphorylacetic acid reliably reduce ischemia-induced depression of inotropic functions of the left ventricle in cats with experimental myocardial infarction model. The effect of both compounds can be explained by the maintenance of viability of the injured myocardium via a delay of the development of acidosis and the support of oxygen recycling in the ischemized zone. Both compounds show pronounced antiradical properties with a non-standard mechanism of action.

  16. Current and emerging treatment options for spinal cord ischemia.

    PubMed

    Nardone, Raffaele; Pikija, Slaven; Mutzenbach, J Sebastian; Seidl, Martin; Leis, Stefan; Trinka, Eugen; Sellner, Johann

    2016-10-01

    Spinal cord infarction (SCI) is a rare but disabling disorder caused by a wide spectrum of conditions. Given the lack of randomized-controlled trials, contemporary treatment concepts are adapted from guidelines for cerebral ischemia, atherosclerotic vascular disease, and acute traumatic spinal cord injury. In addition, patients with SCI are at risk for several potentially life-threatening but preventable systemic and neurologic complications. Notably, there is emerging evidence from preclinical studies for the use of neuroprotection in acute ischemic injury of the spinal cord. In this review, we discuss the current state of the art for the therapy and prevention of SCI and highlight potential emerging treatment concepts awaiting translational adoption.

  17. Ischemia Activates Neutrophils But Inhibits Their Local and Remote Diapedesis.

    DTIC Science & Technology

    2007-11-02

    mediated polymorphonuclear leukocyte (PMN) activation and diapedesis . Anesthetized rabbits were subjected to three hours of hindlimb ischemia (n = 8) or...introduced into an abraded skin chamber or intratracheally induced diapedesis in non-ischemic animals. PMN accumulations in the+skin chamber were...exp 4) PMN/mm(exp 3) compared to 5 +/- 1 X 10(exp 4) PMN/mm(exp 3) with sham plasma (n = 4, pɘ.05). Diapedesis was completely prevented (0-3 PMN/mm(exp

  18. Incomplete Relaxation between Beats after Myocardial Hypoxia and Ischemia

    PubMed Central

    Weisfeldt, Myron L.; Armstrong, Paul; Scully, Hugh E.; Sanders, Charles A.; Daggett, Willard M.

    1974-01-01

    Recovery from hypoxia has been shown to prolong cardiac muscle contraction, particularly the relaxation phase. The present studies were designed to examine whether incomplete relaxation between beats can result from this prolongation of contraction and relaxation in isolated muscle after hypoxia and in the canine heart after both hypoxia and acute ischemia. The relationship between heart rate and the extent of incomplete relaxation is emphasized in view of the known enhancement of the velocity of contraction caused by increasing heart rate. The extent of incomplete relaxation during 10-s periods of pacing at increasing rates was examined before and after hypoxia in isometric cat right ventricular papillary muscle (12-120 beats/min) and in the canine isovolumic left ventricle (120-180 beats/min). Incomplete relaxation was quantified by measuring the difference between the lowest diastolic tension or pressure during pacing and the true resting tension or pressure determined by interruption of pacing at each rate. In eight cat papillary muscles (29°C), there was significantly greater incomplete relaxation 5 min after hypoxia at rates of 96 and 120 beats/min (P < 0.02 vs. before hypoxia). In seven canine isovolumic left ventricles, recovery from hypoxia and higher heart rates also resulted in incomplete relaxation. Incomplete relaxation before hypoxia at a rate of 180 beats/min was 0.8±0.5 cm H2O and at 5 min of recovery from hypoxia was 12.6±3.5 cm H2O (P < 0.01). 12 hearts were subjected to a 1.5-3-min period of acute ischemia and fibrillation. There was significant incomplete relaxation at a rate of 140 beats/min for 5 min after defibrillation and reperfusion. These data indicate that incomplete relaxation is an important determinant of diastolic hemodynamics during recovery from ischemia or hypoxia. The extent of incomplete relaxation appears to be a function of the rate of normalization of the velocity of relaxation and tension development after ischemia or

  19. SURGICAL TREATMENT FOR INFECTED LONG BONE DEFECTS AFTER LIMB-THREATENING TRAUMA: APPLICATION OF LOCKED PLATE AND AUTOGENOUS CANCELLOUS BONE GRAFT

    PubMed Central

    KAWAKAMI, RYOICHI; KONNO, SHIN-ICHI; EJIRI, SOICHI; HATASHITA, SATOSHI

    2015-01-01

    ABSTRACT Background: Treatment strategies for bone defects include free bone grafting, distraction osteogenesis, and vascularized bone grafting. Because bone defect morphology is often irregular, selecting treatment strategies may be difficult. With the Masquelet technique, a fracture site is bridged and fixed with a locking plate after treating deep infection with antibiotic-containing cement, and a free cancellous bone-graft is concomitantly placed into the defects. This procedure avoids excessive bone resection. Methods:We studied 6 patients who underwent surgical treatment for deep infection occurring after extremity trauma (2004 through 2009). Ages at surgery ranged from 29 to 59 years (largest age group: 30 s). Mean follow-up was 50.7 months (minimum/maximum: 36/72 months). One patient had complete amputation of the upper extremity, 3 open forearm fractures, 1 closed supracondylar femur fracture, and 1 open tibia fracture. In all patients, bone defects were filled with antibiotic-containing cement beads after infected site debridement. If bacterial culture of infected sites during curettage was positive, surgery was repeated to refill bone defects with antibiotic-containing cement beads. After confirmation of negative bacterial culture, osteosynthesis was performed, in which bone defects were bridged and fixed with locking plates. Concomitantly, crushed cancellous bone grafts harvested from the autogenous ilium was placed in the bone defects. Results: Time from bone grafting and plate fixation to bone union was at least 3 and at most 6 months, 4 months on average. Infection relapsed in one patient with methicillin-resistant Staphylococcus aureus, necessitating vascularized fibular grafting which achieved bone union. No patients showed implant loosening or breakage or infection relapse after the last surgery during follow-up. Conclusion: The advantage of cancellous bone grafting include applicability to relatively large bone defects, simple surgical procedure, bone graft adjustability to bone defect morphology, rapid bone graft revascularization resulting in high resistance to infection, and excellent osteogenesis. PMID:26377029

  20. Activation of Chymotrypsin-Like Activity of the Proteasome during Ischemia Induces Myocardial Dysfunction and Death.

    PubMed

    Sanchez, Gina; Berrios, Daniela; Olmedo, Ivonne; Pezoa, Javier; Riquelme, Jaime A; Montecinos, Luis; Pedrozo, Zully; Donoso, Paulina

    2016-01-01

    Inhibitors of the ubiquitin-proteasome system improve hemodynamic parameters and decrease the infarct size after ischemia reperfusion. The molecular basis of this protection is not fully understood since most available data report inhibition of the 26 proteasome after ischemia reperfusion. The decrease in cellular ATP levels during ischemia leads to the dissociation of the 26S proteasome into the 19S regulatory complex and the 20S catalytic core, which results in protein degradation independently of ubiquitination. There is scarce information on the activity of the 20S proteasome during cardiac ischemia. Accordingly, the aim of this work was to determine the effects of 30 minutes of ischemia, or 30 min of ischemia followed by 60 minutes of reperfusion on the three main peptidase activities of the 20S proteasome in Langendorff perfused rat hearts. We found that 30 min of ischemia produced a significant increase in the chymotrypsin-like activity of the proteasome, without changes in its caspase-like or trypsin-like activities. In contrast, all three activities were decreased upon reperfusion. Ixazomib, perfused before ischemia at a concentration that reduced the chymotrypsin-like activity to 50% of the control values, without affecting the other proteasomal activities, improved the hemodynamic parameters upon reperfusion and decreased the infarct size. Ixazomib also prevented the 50% reduction in RyR2 content observed after ischemia. The protection was lost, however, when simultaneous inhibition of chymotrypsin-like and caspase-like activities of the proteasome was achieved at higher concentration of ixazomib. Our results suggest that selective inhibition of chymotrypsin-like activity of the proteasome during ischemia preserves key proteins for cardiomyocyte function and exerts a positive impact on cardiac performance after reperfusion.

  1. Activation of Chymotrypsin-Like Activity of the Proteasome during Ischemia Induces Myocardial Dysfunction and Death

    PubMed Central

    Sanchez, Gina; Berrios, Daniela; Olmedo, Ivonne; Pezoa, Javier; Riquelme, Jaime A.; Montecinos, Luis; Pedrozo, Zully; Donoso, Paulina

    2016-01-01

    Inhibitors of the ubiquitin-proteasome system improve hemodynamic parameters and decrease the infarct size after ischemia reperfusion. The molecular basis of this protection is not fully understood since most available data report inhibition of the 26 proteasome after ischemia reperfusion. The decrease in cellular ATP levels during ischemia leads to the dissociation of the 26S proteasome into the 19S regulatory complex and the 20S catalytic core, which results in protein degradation independently of ubiquitination. There is scarce information on the activity of the 20S proteasome during cardiac ischemia. Accordingly, the aim of this work was to determine the effects of 30 minutes of ischemia, or 30 min of ischemia followed by 60 minutes of reperfusion on the three main peptidase activities of the 20S proteasome in Langendorff perfused rat hearts. We found that 30 min of ischemia produced a significant increase in the chymotrypsin-like activity of the proteasome, without changes in its caspase-like or trypsin-like activities. In contrast, all three activities were decreased upon reperfusion. Ixazomib, perfused before ischemia at a concentration that reduced the chymotrypsin-like activity to 50% of the control values, without affecting the other proteasomal activities, improved the hemodynamic parameters upon reperfusion and decreased the infarct size. Ixazomib also prevented the 50% reduction in RyR2 content observed after ischemia. The protection was lost, however, when simultaneous inhibition of chymotrypsin-like and caspase-like activities of the proteasome was achieved at higher concentration of ixazomib. Our results suggest that selective inhibition of chymotrypsin-like activity of the proteasome during ischemia preserves key proteins for cardiomyocyte function and exerts a positive impact on cardiac performance after reperfusion. PMID:27529620

  2. Tachycardic vs. pharmacologic stress myocardial perfusion imaging: differential implications in multi-vessel ischemia

    PubMed Central

    Nguyen, Thanh H; Horowitz, John D; Unger, Steven A

    2012-01-01

    Background In patients unable to exercise, potential methods of induction of reversible myocardial ischemia include physiological heart rate acceleration via pacing or dobutamine infusion and asymmetric coronary vasodilatation using dipyridamole. Although their bases for induction of ischemia are widely disparate, no direct comparison of these techniques has previously been reported. Methods We performed a randomised, paired comparison of dipyridamole and pacing myocardial perfusion imaging (MPI) in 28 patients in whom exercise stress imaging was precluded, comparing the detection, localisation and quantitation of ischemia. Results Reversible myocardial ischemia was detected in 21 patients, concordantly in 13 (p = 0.042). There was a high degree of concordance (p < 0.0001) regarding locations of sites of ischemia. While there was a good correlation (r = 0.74, p < 0.0001) between size of total ischemic zones with dipyridamole and pacing, the magnitude of ischemia tended to be greater with dipyridamole (mean percentage of left ventricular myocardium ± SD, 9.4 ± 11.0% vs. 7.0 ± 9.0%, p = 0.091). Furthermore, this difference resulted from accentuation of the primary ischemic zone with dipyridamole in patients with multi-vessel ischemia (mean ± SD, 28.1 ± 21.1% vs. 18.7 ± 16.1%, p = 0.046). Conclusions Despite major differences in mechanism(s) of induction of ischemia, dipyridamole and pacing produce similar results regarding detection, localisation and severity of ischemia. However, dipyridamole accentuates ischemia in primary (vs. secondary) ischemic zones, consistent with known induction of coronary “steal". This should be taken into account in interpretation of scan results. PMID:22254212

  3. Changes in Retinal Morphology, Electroretinogram and Visual Behavior after Transient Global Ischemia in Adult Rats

    PubMed Central

    Zhao, Ying; Yu, Bo; Xiang, Yong-Hui; Han, Xin-Jia; Xu, Ying; So, Kwok-Fai; Xu, An-Ding; Ruan, Yi-Wen

    2013-01-01

    The retina is a light-sensitive tissue of the central nervous system that is vulnerable to ischemia. The pathological mechanism underlying retinal ischemic injury is not fully understood. The purpose of this study was to investigate structural and functional changes of different types of rat retinal neurons and visual behavior following transient global ischemia. Retinal ischemia was induced using a 4-vessel occlusion model. Compared with the normal group, the number of βIII-tubulin positive retinal ganglion cells and calretinin positive amacrine cells were reduced from 6 h to 48 h following ischemia. The number of recoverin positive cone bipolar cells transiently decreased at 6 h and 12 h after ischemia. However, the fluorescence intensity of rhodopsin positive rod cells and fluorescent peanut agglutinin positive cone cells did not change after reperfusion. An electroretinogram recording showed that the a-wave, b-wave, oscillatory potentials and the photopic negative response were completely lost during ischemia. The amplitudes of the a- and b-waves were partially recovered at 1 h after ischemia, and returned to the control level at 48 h after reperfusion. However, the amplitudes of oscillatory potentials and the photopic negative response were still reduced at 48 h following reperfusion. Visual behavior detection showed there was no significant change in the time spent in the dark chamber between the control and 48 h group, but the distance moved, mean velocity in the black and white chambers and intercompartmental crosses were reduced at 48 h after ischemia. These results indicate that transient global ischemia induces dysfunction of retinal ganglion cells and amacrine cells at molecular and ERG levels. However, transient global ischemia in a 17 minute duration does not appear to affect photoreceptors. PMID:23776500

  4. Novel Injury Site Targeted Fusion Protein Comprising Annexin V and Kunitz Inhibitor Domains Ameliorates Ischemia-Reperfusion Injury and Promotes Survival of Ischemic Rat Abdominal Skin Flaps.

    PubMed

    Shyu, Victor Bong-Hang; Hsu, Chung En; Wen, Chih-Jen; Wun, Tze-Chein; Tang, Rui; Achilefu, Samuel; Wei, Fu-Chan; Cheng, Hui-Yun

    2017-03-01

    Appropriate antithrombotic therapy is critical for successful outcomes in reconstructive microsurgical procedures involving free tissue transfer. The annexin V-6L15 (ANV-6L15) fusion protein was developed as a targeted antithrombotic reagent. Annexin V specifically binds to exposed phosphatidylserine on apoptotic or injured cells, and prevents coagulation and cell adhesion, whereas 6L15 inhibits tissue factor-VIIa pathway within the coagulation cascade. The treatment efficacy of ANV-6L15 on rat island muscle and pedicled abdominal fasciocutaneous flaps following ischemic injury and ischemia-reperfusion injury (IRI) was evaluated.

  5. Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia.

    PubMed

    Candelario-Jalil, Eduardo; González-Falcón, Armando; García-Cabrera, Michel; Alvarez, Dalia; Al-Dalain, Said; Martínez, Gregorio; León, Olga Sonia; Springer, Joe E

    2003-08-01

    We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor rofecoxib (20 mg/kg) relative to the COX-1 inhibitor valeryl salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia.

  6. Critical Viewing: Stimulant to Critical Thinking.

    ERIC Educational Resources Information Center

    O'Reilly, Kevin; Splaine, John

    This document is intended to improve the critical viewing skills and increase the understanding and appreciation of what is viewed. Included are the chapters: (1) "Critical Thinking: The Parts of an Argument," intended to develop a process to help a person judge arguments in what is read, seen, and heard; (2) "Critical Viewing:…

  7. A novel rodent model of severe renal ischemia reperfusion injury.

    PubMed

    Whalen, Henry; Shiels, Paul; Littlejohn, Marc; Clancy, Marc

    2016-11-01

    Renal ischemia reperfusion injury (IRI) is a major problem, currently without treatments in clinical use. This reflects the failure of animal models to mimic the severity of IRI observed in clinical practice. Most described models lack both the ability to inflict a permanent reduction in renal function and the sensitivity to demonstrate the protective efficacy of different therapies in vivo. To test novel cell-based therapies, we have developed a model of renal IRI in Fisher 344 rats. Animals were subjected to 120 min of unilateral warm ischemia, during which they underwent an intra-renal artery infusion of therapeutic agents or vehicle. At either 2 or 6 weeks post-surgery, animals underwent terminal glomerular filtration rate (GFR) studies by inulin clearance to most accurately quantify renal function. Harvested kidneys underwent histological analysis. Compared to sham operations, saline treated animals suffered a long-term reduction in GFR of ≈50%. Histology revealed short- and long-term disruption of renal architecture. Despite the injury severity, post-operative animal losses are <5%. This model produces a severe, consistent renal injury that closely replicates the pathological processes encountered in clinical medicine. Renal artery infusion mimics the route likely employed in clinical transplantation, where the renal artery is accessible. Inulin clearance characterizes GFR, allowing full assessment of therapeutic intervention. This model is useful for screening therapeutic agents prior to testing in a transplant model. This reduces animal numbers needed to test drugs for clinical transplantation and allows for refinement of dosing schedules.

  8. [Heart failure due to ischemia--the adaptive mechanisms].

    PubMed

    Mitu, M; Mitu, F

    1999-01-01

    Chronic myocardial ischemia is the leading cause of disturbances in myocardial contractility (myocardial infarction) or hemodynamic overload upon the left ventricle. The heart reactions consist in a series of adaptative mechanisms in order to maintain its pump function: Frank-Starling mechanism, myocardial hypertrophy and neurohumoral activation. In heart failure, the cardiac output is maintained by an increase of the preload which enhances the contractility (Frank-Starling law). Myocardial ischemia influences the systolic and diastolic function. The decrease of cardiac output leads to neurohumoral responses which, in the initial stages of cardiac failure are compensatory; along with the progression of the disease, they exert adverse effects. Increased activity of the sympathetic nervous system induces high cardiac rates, chronotropic incompetence. Activation of the renin-angiotensin system held to myocardial and vascular hypertrophy, vasoconstriction, fluid retention. Endothelin is the most powerful vasoconstrictor; its plasmatic concentrations correlate with the severity of the disease. Vasodilator mediators released in cardiac failure are the natriuretic peptide, nitric oxide, dopamine, prostacicline, bradikinin.

  9. Chlorpromazine confers neuroprotection against brain ischemia by activating BKCa channel.

    PubMed

    Li, Hua-Juan; Zhang, Yu-Jiao; Zhou, Li; Han, Feng; Wang, Ming-Yan; Xue, Mao-Qiang; Qi, Zhi

    2014-07-15

    Chlorpromazine (CPZ) is a well-known antipsychotic drug, still widely being used to treat symptoms of schizophrenia, psychotic depression and organic psychoses. We have previously reported that CPZ activates the BKCa (KCa1.1) channel at whole cell level. In the present study, we demonstrated that CPZ increased the single channel open probability of the BKCa channels without changing its single channel amplitude. As BKCa channel is one of the molecular targets of brain ischemia, we explored a possible new use of this old drug on ischemic brain injury. In middle cerebral artery occlusion (MCAO) focal cerebral ischemia, a single intraperitoneal injection of CPZ at several dosages (5mg/kg, 10mg/kg and 20mg/kg) could exert a significant neuroprotective effect on the brain damage in a dose- and time-dependent manner. Furthermore, blockade of BKCa channels abolished the neuroprotective effect of CPZ on MCAO, suggesting that the effect of CPZ is mediated by activation of the BKCa channel. These results demonstrate that CPZ could reduce focal cerebral ischemic damage through activating BKCa channels and merits exploration as a potential therapeutic agent for treating ischemic stroke.

  10. Adult midgut malrotation presented with acute bowel obstruction and ischemia

    PubMed Central

    Zengin, Akile; Uçar, Bercis İmge; Düzgün, Şükrü Aydın; Bayhan, Zülfü; Zeren, Sezgin; Yaylak, Faik; Şanal, Bekir; Bayhan, Nilüfer Araz

    2016-01-01

    Introduction Intestinal malrotation refers to the partial or complete failure of rotation of midgut around the superior mesenteric vessels in embryonic life. Arrested midgut rotation results due to narrow-based mesentery and increases the risk of twisting midgut and subsequent obstruction and necrosis. Presentation of case 40 years old female patient admitted to emergency service with acute abdomen and computerized tomography scan showed dilated large and small intestine segments with air-fluid levels and twisted mesentery around superior mesenteric artery and vein indicating “whirpool sign”. Discussion Malrotation in adults is a rare cause of midgut volvulus as though it should be considered in differential diagnosis in patients presented with acute abdomen and intestinal ischemia. Even though clinical symptoms are obscure, adult patients usually present with vomiting and recurrent abdominal pain due to chronic partial obstruction. Contrast enhanced radiograph has been shown to be the most accurate method. Typical radiological signs are corkscrew sign, which is caused by the dilatation of various duodenal segments at different levels and the relocation of duodenojejunal junction due to jejunum folding. As malrotation commonly causes intestinal obstruction, patients deserve an elective laparotomy. Conclusion Malrotation should be considered in differential diagnosis in patients presented with acute abdomen and intestinal ischemia. Surgical intervention should be prompt to limit morbidity and mortality. PMID:27015011

  11. Protective Effects of HDL Against Ischemia/Reperfusion Injury.

    PubMed

    Gomaraschi, Monica; Calabresi, Laura; Franceschini, Guido

    2016-01-01

    Several lines of evidence suggest that, besides being a strong independent predictor of the occurrence of primary coronary events, a low plasma high density lipoprotein (HDL) cholesterol level is also associated with short- and long-term unfavorable prognosis in patients, who have recovered from a myocardial infarction, suggesting a direct detrimental effect of low HDL on post-ischemic myocardial function. Experiments performed in ex vivo and in vivo models of myocardial ischemia/reperfusion (I/R) injury have clearly shown that HDL are able to preserve cardiac function when given before ischemia or at reperfusion; the protective effects of HDL against I/R injury have been also confirmed in other tissues and organs, as brain and hind limb. HDL were shown to act on coronary endothelial cells, by limiting the increase of endothelium permeability and promoting vasodilation and neoangiogenesis, on white blood cells, by reducing their infiltration into the ischemic tissue and the release of pro-inflammatory and matrix-degrading molecules, and on cardiomyocytes, by preventing the activation of the apoptotic cascade. Synthetic HDL retains the cardioprotective activity of plasma-derived HDL and may become a useful adjunctive therapy to improve clinical outcomes in patients with acute coronary syndromes or undergoing coronary procedures.

  12. Stable angina pectoris: the medical management of symptomatic myocardial ischemia.

    PubMed

    Parker, John D; Parker, John O

    2012-01-01

    Coronary artery disease (CAD) remains an important cause of morbidity and mortality and is a serious public health problem. Over the last 4 decades there have been dramatic advances in the both the prevention and treatment of CAD. The management of CAD was revolutionized by the development of effective surgical and percutaneous revascularization techniques. In this review we discuss the importance of the medical management of symptomatic, stable angina. Medical management approaches to both the treatment and prevention of symptomatic myocardial ischemia are summarized. In Canada, organic nitrates, β-adrenergic blocking agents, and calcium channel antagonists have been available for the therapy of angina for more than 25 years. All 3 classes are of proven benefit in the improvement of symptoms and exercise capacity in patients with stable angina. Although there is no clear first choice within these classes of anti-anginal agents, the presence of prior or concurrent conditions (for example, prior myocardial infarction and/or hypertension) plays an important role in the choice of anti-anginal class in individual patients. For some patients, combinations of different anti-anginal agents can be effective; however it is recommended that this approach be individualized. Although not currently available in Canada, other classes of anti-anginal agents have been developed; their mechanism of action and clinical efficacy is discussed. Patients with stable angina have an excellent prognosis. Patients in this category who obtain relief from symptomatic myocardial ischemia may do well without invasive intervention.

  13. X-Chromosome Dosage and the Response to Cerebral Ischemia

    PubMed Central

    Turtzo, L. Christine; Siegel, Chad; McCullough, Louise D.

    2011-01-01

    Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and EdaTa). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes, nor the parent of origin of the remaining X chromosome, had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice. PMID:21917808

  14. Endovascular Treatment of Chronic Mesenteric Ischemia: Results in 14 Patients

    SciTech Connect

    Chahid, Tamam; Alfidja, Agaicha T.; Biard, Marie; Ravel, Anne; Garcier, Jean Marc; Boyer, L.

    2004-11-15

    We evaluated immediate and long-term results of percutaneous transluminal angioplasty (PTA) and stent placement to treat stenotic and occluded arteries in patients with chronic mesenteric ischemia. Fourteen patients were treated by 3 exclusive celiac artery (CA) PTAs (2 stentings), 3 cases with both Superior Mesenteric Artery (SMA) and CA angioplasties, and 8 exclusive SMA angioplasties (3 stentings). Eleven patients had atheromatous stenoses with one case of an early onset atheroma in an HIV patient with antiphospholipid syndrome. The other etiologies of mesenteric arterial lesions were Takayashu arteritis (2 cases) and a postradiation stenoses (1 case). Technical success was achieved in all cases. Two major complications were observed: one hematoma and one false aneurysm occurring at the brachial puncture site (14.3%). An immediate clinical success was obtained in all patients. During a follow-up of 1-83 months (mean: 29 months), 11 patients were symptom free; 3 patients had recurrent pain; in one patient with inflammatory syndrome, pain relief was obtained with medical treatment; in 2 patients abdominal pain was due to restenosis 36 and 6 months after PTA, respectively. Restenosis was treated by PTA (postirradiation stenosis), and by surgical bypass (atheromatous stenosis). Percutaneous endovascular techniques are safe and accurate. They are an alternative to surgery in patients with chronic mesenteric ischemia due to short and proximal occlusive lesions of SMA and CA.

  15. Real-time monitoring of ischemia inside stomach.

    PubMed

    Tahirbegi, Islam Bogachan; Mir, Mònica; Samitier, Josep

    2013-02-15

    The low pH in the gastric juice of the stomach makes it difficult to fabricate stable and functional all-solid-state pH ISE sensors to sense ischemia, mainly because of anion interference and adhesion problem between the ISE membrane and the electrode surface. In this work, the adhesion of ISE membrane on solid surface at low pH was improved by modifying the surface with a conductive substrate containing hydrophilic and hydrophobic groups. This creates a stable and robust candidate for low pH applications. Moreover, anion interference problem at low pH was solved by integration of all-solid-state ISE and internal reference electrodes on an array. So, the same tendencies of anion interferences for all-solid-state ISE and all-solid-state reference electrodes cancel each other in differential potentiometric detection. The developed sensor presents a novel all-solid-state potentiometric, miniaturized and mass producible pH ISE sensor for detecting ischemia on the stomach tissue on an array designed for endoscopic applications.

  16. Mechanisms Underlying Acute Protection from Cardiac Ischemia-Reperfusion Injury

    PubMed Central

    Murphy, Elizabeth; Steenbergen, Charles

    2009-01-01

    Mitochondria play an important role in cell death and cardioprotection. During ischemia, when ATP is progressively deleted, ion pumps cannot function resulting in a rise in calcium (Ca2+), which further accelerates ATP depletion. The rise in Ca2+ during ischemia and reperfusion leads to mitochondrial Ca2+ accumulation, particularly during reperfusion when oxygen is reintroduced. Reintroduction of oxygen allows generation of ATP; however damage to electron transport chain results in increased mitochondrial generation of reactive oxygen species (ROS). Mitochondrial Ca2+ overload, and increased ROS can result in opening of the mitochondrial permeability transition pore, which further compromises cellular energetics. The resultant low ATP and altered ion homeostasis result in rupture of the plasma membrane and cell death. Mitochondria have long been proposed as central players in cell death, since the mitochondria are central to synthesis of both ATP and ROS and since mitochondrial and cytosolic Ca2+ overload are key components of cell death. Many cardioprotective mechanisms converge on the mitochondria to reduce cell death. Reducing Ca2+ overload and reducing ROS have both been reported to reduce ischemic injury. Preconditioning activates a number of signaling pathways that reduce Ca2+ overload and reduce activation of the mitochondrial permeability transition pore. The mitochondrial targets of cardioprotective signals will be discussed in detail. PMID:18391174

  17. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    SciTech Connect

    Khodanovich, M. Yu.

    2015-11-17

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

  18. Membrane Lipid Interactions in Intestinal Ischemia/reperfusion-induced Injury

    PubMed Central

    Slone, Emily Archer; Fleming, Sherry D.

    2014-01-01

    Ischemia, lack of blood flow, and reperfusion, return of blood flow, is a common phenomenon affecting millions of Americans each year. Roughly 30,000 Americans per year experience intestinal ischemia-reperfusion (IR), which is associated with a high mortality rate. Previous studies of the intestine established a role for neutrophils, eicosanoids, the complement system and naturally occurring antibodies in IR-induced pathology. Furthermore, data indicate involvement of a lipid or lipid-like moiety in mediating IR-induced damage. It has been proposed that exposure of neo-antigens are recognized by antibodies, triggering action of the complement cascade. While it is evident that the pathophysiology of IR-induced injury is complex and multi-factorial, we focus this review on the involvement of eicosanoids, phospholipids and neo-antigens in the early pathogenesis. Lipid changes occurring in response to IR, neo-antigens exposed and the role of a phospholipid transporter, phospholipid scramblase 1 will be discussed. PMID:24814240

  19. Lindnera (Pichia) fabianii blood infection after mesenteric ischemia.

    PubMed

    Gabriel, Frederic; Noel, Thierry; Accoceberry, Isabelle

    2012-04-01

    Lindnera (Pichia) fabianii (teleomorph of Candida fabianii) is a yeast species rarely involved in human infections. This report describes the first known human case of a Lindnera fabianii blood infection after mesenteric ischemia. The 53-year-old patient was hospitalized in the intensive care unit after a suicide attempt and was suffering from a mesenteric ischemia and acute renal failure. Lindnera fabianii was recovered from an oropharyngeal swab, then isolated from stool and urine samples before the diagnosis of the blood infection. Caspofungin intravenous treatment was associated with a successful outcome. Final unequivocal identification of the strain was done by sequencing the internal transcribed spacer (ITS) region, and regions of 18S rDNA gene and of the translation elongation factor-1α gene. Until our work, the genomic databases did not contain the complete ITS region of L. fabianii as a single nucleotide sequence (encompassing ITS1, the 5.8S rDNA and ITS2), and misidentification with other yeast species, e.g., Lindnera (Pichia) mississippiensis, could have occurred. Our work demonstrates that the usual DNA barcoding method based on sequencing of the ITS region may fail to provide the correct identification of some taxa, and that partial sequencing of the EF1α gene may be much more effective for the accurate delineation and molecular identification of new emerging opportunistic yeast pathogens.

  20. Thallium-201 myocardial scintigraphy in acute myocardial infarction and ischemia

    SciTech Connect

    Wackers, F.J.

    1982-04-01

    Thallium-201 scintigraphy provides a sensitive and reliable method of detecting acute myocardial infarction and ischemia when imaging is performed with understanding of the temporal characteristics and accuracy of the technique. The results of scintigraphy are related to the time interval between onset of symptoms and time of imaging. During the first 6 hr after chest pain almost all patients with acute myocardial infarction and approximately 50% of the patients with unstable angina will demonstrate /sup 201/TI pefusion defects. Delayed imaging at 2-4 hr will permit distinction between ischemia and infarction. In patients with acute myocardial infarction, the size of the perfusion defect accurately reflects the extent of the infarcted and/or jeopardized myocardium, which may be used for prognostic stratification. In view of the characteristics of /sup 201/TI scintigraphy, the most practical application of this technique is in patients in whom myocardial infarction has to be ruled out, and for early recognition of patients at high risk for complications.

  1. Coronary vasodilator reserve persists despite tachycardia and myocardial ischemia

    SciTech Connect

    Bristow, J.D.; McFalls, E.O.; Anselone, C.G.; Pantely, G.A. )

    1987-08-01

    During myocardial ischemia, the authors tested whether coronary blood flow measured with radioactive microspheres labeled with {sup 141}Ce, {sup 51}Cr, {sup 103}Ru, and {sup 95}Nb would increase in response to tachycardia thereby employing known coronary flow reserve. The authors instrumented the left anterior descending (LAD) coronary circulation in anesthetized pigs and performed three sets of experiments while coronary pressure was controlled and several heart rate increases were produced. (1) Pacing-induced tachycardia at normal LAD pressure was characterized by increased LAD flow and myocardial oxygen consumption, without production of lactate. (2) Tachycardia at a mean LAD pressure of 38 mmHg was associated with a lower, fixed coronary flow and oxygen consumption. Lactate was produced at all rates and local myocardial function declined progressively. (3) Coronary flow at low LAD pressure doubled during tachycardia when intracoronary adenosine was added. The increase to the subepicardium was >100%, whereas subendocardial flow changed little. There is persistent coronary flow reserve during moderately severe myocardial ischemia, even when metabolic demand is increased by tachycardia. This reserve, however, is predominantly subepicardial.

  2. Inhibiting Cytochrome C Oxidase Leads to Alleviated Ischemia Reperfusion Injury

    PubMed Central

    Yang, Zhaoyun; Duan, Zhongxin; Yu, Tian; Xu, Junmei

    2017-01-01

    Background and Objectives The overall purpose of this study was to investigate the role of cytochrome C oxidase (CcO) in preventing ischemia reperfusion-induced cardiac injury through gaseous signaling molecule pathways. Materials and Methods We used CcO inhibitor, potassium cyanide (KCN) to mimic the pre-treatment of gaseous signaling molecules in a global ischemia/reperfusion (IR) injury model in rats. Intracellular reactive oxygen species (ROS) was determined by measuring mitochondrial H2O2 and mitochondrial complex activity. Results KCN pre-treatment led to decreased infarction area after IR injury and improved cardiac function. KCN pre-treated group challenged with IR injury was associated with reduced ROS production through inhibition of activity and not downregulation of CcO expression. In addition, KCN pre-treatment was associated with enhanced expression and activity of mitochondrial antioxidase, suggesting the role of CcO in regulating IR injury through oxidative stress. Conclusion KCN pre-treatment reduced the severity of IR injury. The potential mechanism could be increased endogenous anti-oxidase activity and consequently, the enhanced clearance of ROS. PMID:28382074

  3. Blood biomarkers in the early stage of cerebral ischemia.

    PubMed

    Maestrini, I; Ducroquet, A; Moulin, S; Leys, D; Cordonnier, C; Bordet, R

    2016-03-01

    In ischemic stroke patients, blood-based biomarkers may be applied for the diagnosis of ischemic origin and subtype, prediction of outcomes and targeted treatment in selected patients. Knowledge of the pathophysiology of cerebral ischemia has led to the evaluation of proteins, neurotransmitters, nucleic acids and lipids as potential biomarkers. The present report focuses on the role of blood-based biomarkers in the early stage of ischemic stroke-within 72h of its onset-as gleaned from studies published in English in such patients. Despite growing interest in their potential role in clinical practice, the application of biomarkers for the management of cerebral ischemia is not currently recommended by guidelines. However, there are some promising clinical biomarkers, as well as the N-methyl-d-aspartate (NMDA) peptide and NMDA-receptor (R) autoantibodies that appear to identify the ischemic nature of stroke, and the glial fibrillary acidic protein (GFAP) that might be able to discriminate between acute ischemic and hemorrhagic strokes. Moreover, genomics and proteomics allow the characterization of differences in gene expression, and protein and metabolite production, in ischemic stroke patients compared with controls and, thus, may help to identify novel markers with sufficient sensitivity and specificity. Additional studies to validate promising biomarkers and to identify novel biomarkers are needed.

  4. Isorhamnetin protects rat ventricular myocytes from ischemia and reperfusion injury.

    PubMed

    Zhang, Najuan; Pei, Fei; Wei, Huaying; Zhang, Tongtong; Yang, Chao; Ma, Gang; Yang, Chunlei

    2011-01-01

    Ischemia/reperfusion (I/R) has been known to cause damages to ventricular myocytes. Isorhamnetin, one member of flavonoid compounds, has cardioprotective effect, the effect that suggests a possible treatment for I/R damages. In the present investigation, we found that isorhamnetin could significantly promote the viability of neonatal rat ventricular myocytes that were exposed to ischemia/reperfusion (I/R) in vitro. Ventricular myocytes were obtained from neonatal SD rats, and then were divided randomly into three groups, namely I/R-/isor-, I/R+/isor- and I/R+/isor+ group. Before the whole experiment, the most appropriate concentration of isorhamnetin (4 μM) was determined by MTT assay. Our results showed that isorhamnetin could alleviate the damages of I/R to ventricular myocytes through inhibiting lactate dehydrogenase (LDH) activity, and repressing apoptosis. Compared with the counterpart of the I/R+/isor- group, LDH activity in the isorhamnetin-treated group weakened, halving from 24.1 ± 2.3 to 11.4 ± 1.2U/L. Additionally, flow cytometry showed the apparently increased apoptosis rate induced by I/R, the result that was further confirmed by transmission electron microscope. Administration of isorhamnetin, however, assuaged the apoptosis induced by I/R. Corresponding to the reduced apoptosis rate in the I/R+/isor+ group, western blotting assay showed increased amount of Bcl-2 and p53, decreased amount of Bax, and nuclear accumulation of NF-κB/p65.

  5. Nonlinear Dynamic Theory of Acute Cell Injuries and Brain Ischemia

    NASA Astrophysics Data System (ADS)

    Taha, Doaa; Anggraini, Fika; Degracia, Donald; Huang, Zhi-Feng

    2015-03-01

    Cerebral ischemia in the form of stroke and cardiac arrest brain damage affect over 1 million people per year in the USA alone. In spite of close to 200 clinical trials and decades of research, there are no treatments to stop post-ischemic neuron death. We have argued that a major weakness of current brain ischemia research is lack of a deductive theoretical framework of acute cell injury to guide empirical studies. A previously published autonomous model based on the concept of nonlinear dynamic network was shown to capture important facets of cell injury, linking the concept of therapeutic to bistable dynamics. Here we present an improved, non-autonomous formulation of the nonlinear dynamic model of cell injury that allows multiple acute injuries over time, thereby allowing simulations of both therapeutic treatment and preconditioning. Our results are connected to the experimental data of gene expression and proteomics of neuron cells. Importantly, this new model may be construed as a novel approach to pharmacodynamics of acute cell injury. The model makes explicit that any pro-survival therapy is always a form of sub-lethal injury. This insight is expected to widely influence treatment of acute injury conditions that have defied successful treatment to date. This work is supported by NIH NINDS (NS081347) and Wayne State University President's Research Enhancement Award.

  6. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    NASA Astrophysics Data System (ADS)

    Khodanovich, M. Yu.

    2015-11-01

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

  7. Sulodexide pretreatment attenuates renal ischemia-reperfusion injury in rats.

    PubMed

    Yin, Jianyong; Chen, Weibin; Ma, Fenfen; Lu, Zeyuan; Wu, Rui; Zhang, Guangyuan; Wang, Niansong; Wang, Feng

    2017-02-07

    Sulodexide is a potent antithrombin agent, however, whether it has beneficial effects on renal ischemia-reperfusion injury (IRI) remains unknown. In the present study, we assessed the therapeutic effects of sulodexide in renal IRI and tried to investigate the potential mechanism. One dose of sulodexide was injected intravenously in Sprague-Dawley rats 30 min before bilateral kidney ischemia for 45 min. The animals were sacrificed at 3h and 24h respectively. Our results showed that sulodexide pretreatment improved renal dysfunction and alleviated tubular pathological injury at 24h after reperfusion, which was accompanied with inhibition of oxidative stress, inflammation and cell apoptosis. Moreover, we noticed that antithrombin III (ATIII) was activated at 3h after reperfusion, which preceded the alleviation of renal injury. For in vitro study, hypoxia/reoxygenation (H/R) injury model for HK2 cells was carried out and apoptosis and reactive oxygen species (ROS) levels were evaluated after sulodexide pretreatment. Consistently, sulodexide pretreatment could reduce apoptosis and ROS level in HK2 cells under H/R injury. Taken together, sulodexide pretreatment might attenuate renal IRI through inhibition of inflammation, oxidative stress and apoptosis, and activation of ATIII.

  8. Transient cerebral ischemia. Association of apoptosis induction with hypoperfusion.

    PubMed Central

    Vexler, Z S; Roberts, T P; Bollen, A W; Derugin, N; Arieff, A I

    1997-01-01

    Apoptosis is thought to be important in the pathogenesis of cerebral ischemia. The mechanism of apoptosis induction remains unclear but several studies suggest that it is preferentially triggered by mild/moderate microcirculatory disturbances. We examined in cats whether induction of apoptosis after 2.5 h of unilateral middle cerebral artery occlusion plus 10 h of reperfusion is influenced by the degree of cerebral microcirculatory disturbance. Quantitative monitoring over time of the disturbances of cerebral microcirculation in ischemic brain areas and evaluation of cytotoxic edema associated with perfusion deficits was achieved by using two noninvasive magnetic resonance imaging techniques: (a) high-speed echo planar imaging combined with a bolus of magnetic susceptibility contrast agent; and (b) diffusion-weighted imaging. Apoptosis-positive cells were counted in anatomic areas with different severity of ischemic injury characterized by magnetic resonance imaging, triphenyltetrazolium chloride, and hemotoxylin and eosin staining. The number of apoptosis-positive cells was significantly higher in anatomic areas with severe perfusion deficits during occlusion and detectable histologic changes 10 h after reperfusion. In contrast, in areas where perfusion was reduced but maintained during occlusion there were no detectable histological changes and significantly fewer apoptosis-positive cells. A similar number of cells that undergo apoptosis were shown in regions with transient or prolonged subtotal perfusion deficits. These results suggest that the apoptotic process is induced in the ischemic core and contributes significantly in the degeneration of neurons associated with transient ischemia. PMID:9077555

  9. Application of laser therapy in the treatment of brain ischemia

    NASA Astrophysics Data System (ADS)

    Zalesskaya, G. A.; Nechipurenko, N. I.; Musienko, J. I.; Kuchinsky, A. V.

    2007-06-01

    Intravenous laser irradiation of blood (ILIB) by helium-neon laser (HNL) with λ=632.8 nm, 2.5-4.5 mW at the light guide outlet was employed to investigate ILIB influence on blood oxygen transport (BOT), hydro-ion balance for normal rabbits and after modeling of local ischemia of brain (LIB). Marked improvement of disturbances typical for ischemia was revealed for both hydro-ion balance characteristics and BOT parameters such as oxygen tension (p vO II), oxygen hemoglobin saturation (s vO II), p vO II of blood under its 50% saturation by O II (p50) and tendency was found to their normalization. To identify the molecular photoacceptors and the mechanisms of primary photoreactions the spectral data were used both in visible and infrared regions. On the basis of spectral analysis hemoglobin was discussed as a possible photoacceptor when blood is irradiated with HNL radiation. Variations in the redox properties of respiratory chain components were considered as primary mechanisms of light action on photoacceptor molecules that initiated a cascade of secondary reactions controlling cellular homeostasis parameters.

  10. Specific expression of heme oxygenase-1 by myeloid cells modulates renal ischemia-reperfusion injury.

    PubMed

    Rossi, Maxime; Thierry, Antoine; Delbauve, Sandrine; Preyat, Nicolas; Soares, Miguel P; Roumeguère, Thierry; Leo, Oberdan; Flamand, Véronique; Le Moine, Alain; Hougardy, Jean-Michel

    2017-03-15

    Renal ischemia-reperfusion injury (IRI) is a major risk factor for delayed graft function in renal transplantation. Compelling evidence exists that the stress-responsive enzyme, heme oxygenase-1 (HO-1) mediates protection against IRI. However, the role of myeloid HO-1 during IRI remains poorly characterized. Mice with myeloid-restricted deletion of HO-1 (HO-1(M-KO)), littermate (LT), and wild-type (WT) mice were subjected to renal IRI or sham procedures and sacrificed after 24 hours or 7 days. In comparison to LT, HO-1(M-KO) exhibited significant renal histological damage, pro-inflammatory responses and oxidative stress 24 hours after reperfusion. HO-1(M-KO) mice also displayed impaired tubular repair and increased renal fibrosis 7 days after IRI. In WT mice, HO-1 induction with hemin specifically upregulated HO-1 within the CD11b(+) F4/80(lo) subset of the renal myeloid cells. Prior administration of hemin to renal IRI was associated with significant increase of the renal HO-1(+) CD11b(+) F4/80(lo) myeloid cells in comparison to control mice. In contrast, this hemin-mediated protection was abolished in HO-1(M-KO) mice. In conclusion, myeloid HO-1 appears as a critical protective pathway against renal IRI and could be an interesting therapeutic target in renal transplantation.

  11. Myocardial ischemia/reperfusion impairs neurogenesis and hippocampal-dependent learning and memory.

    PubMed

    Evonuk, Kirsten S; Prabhu, Sumanth D; Young, Martin E; DeSilva, Tara M

    2017-03-01

    The incidence of cognitive impairment in cardiovascular disease (CVD) patients has increased, adversely impacting quality of life and imposing a significant economic burden. Brain imaging of CVD patients has detected changes in the hippocampus, a brain region critical for normal learning and memory. However, it is not clear whether adverse cardiac events or other associated co-morbidities impair cognition. Here, using a murine model of acute myocardial ischemia/reperfusion (I/R), where the coronary artery was occluded for 30min followed by reperfusion, we tested the hypothesis that acute myocardial infarction triggers impairment in cognitive function. Two months following cardiac I/R, behavioral assessments specific for hippocampal cognitive function were performed. Mice subjected to cardiac I/R performed worse in the fear-conditioning paradigm as well as the object location memory behavioral test compared to sham-operated mice. Reactive gliosis was apparent in the hippocampal subregions CA1, CA3, and dentate gyrus 72h post-cardiac I/R as compared with sham, which was sustained two months post-cardiac I/R. Consistent with the inflammatory response, the abundance of doublecortin positive newborn neurons was decreased in the dentate gyrus 72h and 2months post-cardiac I/R as compared with sham. Therefore, we conclude that following acute myocardial infarction, rapid inflammatory responses negatively affect neurogenesis, which may underlie long-term changes in learning and memory.

  12. The role of the microcirculation in delayed cerebral ischemia and chronic degenerative changes after subarachnoid hemorrhage

    PubMed Central

    Østergaard, Leif; Aamand, Rasmus; Karabegovic, Sanja; Tietze, Anna; Blicher, Jakob Udby; Mikkelsen, Irene Klærke; Iversen, Nina Kerting; Secher, Niels; Engedal, Thorbjørn Søndergaard; Anzabi, Mariam; Jimenez, Eugenio Gutierrez; Cai, Changsi; Koch, Klaus Ulrik; Næss-Schmidt, Erhard Trillingsgaard; Obel, Annette; Juul, Niels; Rasmussen, Mads; Sørensen, Jens Christian Hedemann

    2013-01-01

    The mortality after aneurysmal subarachnoid hemorrhage (SAH) is 50%, and most survivors suffer severe functional and cognitive deficits. Half of SAH patients deteriorate 5 to 14 days after the initial bleeding, so-called delayed cerebral ischemia (DCI). Although often attributed to vasospasms, DCI may develop in the absence of angiographic vasospasms, and therapeutic reversal of angiographic vasospasms fails to improve patient outcome. The etiology of chronic neurodegenerative changes after SAH remains poorly understood. Brain oxygenation depends on both cerebral blood flow (CBF) and its microscopic distribution, the so-called capillary transit time heterogeneity (CTH). In theory, increased CTH can therefore lead to tissue hypoxia in the absence of severe CBF reductions, whereas reductions in CBF, paradoxically, improve brain oxygenation if CTH is critically elevated. We review potential sources of elevated CTH after SAH. Pericyte constrictions in relation to the initial ischemic episode and subsequent oxidative stress, nitric oxide depletion during the pericapillary clearance of oxyhemoglobin, vasogenic edema, leukocytosis, and astrocytic endfeet swelling are identified as potential sources of elevated CTH, and hence of metabolic derangement, after SAH. Irreversible changes in capillary morphology and function are predicted to contribute to long-term relative tissue hypoxia, inflammation, and neurodegeneration. We discuss diagnostic and therapeutic implications of these predictions. PMID:24064495

  13. Roles of Calcium Regulating MicroRNAs in Cardiac Ischemia-Reperfusion Injury

    PubMed Central

    Choi, Eunhyun; Cha, Min-Ji; Hwang, Ki-Chul

    2014-01-01

    Cardiac Ca2+ cycling and signaling are closely associated with cardiac function. Changes in cellular Ca2+ homeostasis may lead to aberrant cardiac rhythm and may play a critical role in the pathogenesis of cardiac diseases, due to their exacerbation of heart failure. MicroRNAs (miRNAs) play a key role in the regulation of gene expression at the post-transcriptional level and participate in regulating diverse biological processes. The emerging evidence indicates that the expression profiles of miRNAs vary among human diseases, including cardiovascular diseases. Cardiac Ca2+-handling and signaling proteins are also regulated by miRNAs. Given the relationship between cardiac Ca2+ homeostasis and signaling and miRNA, Ca2+-related miRNAs may serve as therapeutic targets during the treatment of heart failure. In this review, we summarize the knowledge currently available regarding the role of Ca2+ in cardiac function, as well as changes in Ca2+ cycling and homeostasis and the handling of these processes by miRNAs during cardiac ischemia-reperfusion injury. PMID:25216032

  14. Design and fabrication of nanowire electrodes on a flexible substrate for detection of myocardial ischemia

    NASA Astrophysics Data System (ADS)

    Ramachandran, Vasuda; Yoon, Hargsoon; Varadan, Vijay K.

    2009-03-01

    According to a report by the American Heart Association, there are approximately 3-4 million Americans that may experience silent Myocardial Ischemia (MI). Silent MI is a serious heart condition that can progress to a severe heart attack without any warning and the consequences of such an event can turn fatal quickly. Therefore, there is a strong need for a sensor that can continuously monitor the onset of the condition to prevent high risk individuals from deadly heart attacks. An increase in extracellular potassium levels is the first sign of MI and timely sensing with an implantable potassium sensing biosensor could play a critical role in detecting and expediting care. There are challenges in the development of an implantable potassium sensing electrode one of which includes signal drift. The incorporation of novel nanostructures and smarter materials hold the potential to combat these problems. This paper presents a unique design for an all-solid-state potassium sensing device which offers miniaturization along with enhanced signal transduction. These characteristics are important when it comes to implantable devices and signal drift. Sensor design details along with fabrication processes and sensing results are discussed.

  15. Exogenous NAD+ administration significantly protects against myocardial ischemia/reperfusion injury in rat model

    PubMed Central

    Zhang, Youjun; Wang, Ban; Fu, Xingli; Guan, Shaofeng; Han, Wenzheng; Zhang, Jie; Gan, Qian; Fang, Weiyi; Ying, Weihai; Qu, Xinkai

    2016-01-01

    Acute myocardial infarction is one of the leading causes for death around the world. Although essential for successful interventional therapy, it is inevitably complicated by reperfusion injury. Thus effective approaches to reduce ischemia/reperfusion (I/R) injury are still critically needed. To test our hypothesis that intravenous administration of NAD+ can attenuate I/R injury by reducing apoptotic damage and enhancing antioxidant capacity, we used a rat mode of myocardial I/R. Our study found that administration of 10-20 mg/kg NAD+ can dose dependently reduce myocardial infarct induced by I/R, with an approximately 85% reduction of the infarct at the dosage of 20 mg/kg NAD+. We further found that the injection of NAD+ can significantly decrease I/R-induced apoptotic damage in the heart: NAD+ administration can both decrease the TUNEL signals, Bax, cleaved caspase-3 levels and increase the Bcl-XL levels in the rats that are subjected to myocardial I/R injury. NAD+ administration can also significantly attenuate I/R-induced decreases in SOD activity and SOD-2 protein levels in the hearts. NAD+ can profoundly decrease myocardial I/R injury at least partially by attenuating apoptotic damage and enhancing the antioxidant capacity, thus suggesting that NAD+ may become a promising therapeutic agent for myocardial I/R injury. PMID:27648125

  16. Hydrogen peroxide-activatable antioxidant prodrug as a targeted therapeutic agent for ischemia-reperfusion injury

    PubMed Central

    Lee, Dongwon; Park, Seunggyu; Bae, Soochan; Jeong, Dahee; Park, Minhyung; Kang, Changsun; Yoo, Wooyoung; Samad, Mohammed A.; Ke, Qingen; Khang, Gilson; Kang, Peter M.

    2015-01-01

    Overproduction of hydrogen peroxide (H2O2) causes oxidative stress and is the main culprit in the pathogenesis of ischemia/reperfusion (I/R) injury. Suppression of oxidative stress is therefore critical in the treatment of I/R injury. Here, we report H2O2-activatable antioxidant prodrug (BRAP) that is capable of specifically targeting the site of oxidative stress and exerting anti-inflammatory and anti-apoptotic activities. BRAP with a self-immolative boronic ester protecting group was designed to scavenge H2O2 and release HBA (p-hydroxybenzyl alcohol) with antioxidant and anti-inflammatory activities. BRAP exerted potent antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)- and H2O2-stimulated cells by suppressing the generation of ROS and pro-inflammatory cytokines. In mouse models of hepatic I/R and cardiac I/R, BRAP exerted potent antioxidant, anti-inflammatory and anti-apoptotic activities due to the synergistic effects of H2O2-scavenging boronic esters and therapeutic HBA. In addition, administration of high doses of BRAP daily for 7 days showed no renal or hepatic function abnormalities. Therefore BRAP has tremendous therapeutic potential as H2O2-activatable antioxidant prodrug for the treatment of I/R injuries. PMID:26563741

  17. Effect of maternal exercise on biochemical parameters in rats submitted to neonatal hypoxia-ischemia.

    PubMed

    Marcelino, Thiago Beltram; de Lemos Rodrigues, Patrícia Idalina; Miguel, Patrícia Maidana; Netto, Carlos Alexandre; Pereira Silva, Lenir Orlandi; Matté, Cristiane

    2015-10-05

    Pregnancy is a critical period for brain metabolic programming, being affected by individual environment, such as nutrition, stress, and physical exercise. In this context, we previously reported a cerebral antioxidant upregulation and mitochondrial biogenesis in the offspring delivered from exercised mothers, which could provide neuroprotection against neonatal insults. Hypoxia-ischemia (HI) encephalopathy is one of the most studied models of neonatal brain injury; disrupting motor, cognitive, and learning abilities. Physiopathology includes oxidative stress, allied to mitochondria energy production failure, glutamatergic excitotoxicity, and cell death. In this study we evaluated the effect of maternal swimming during pregnancy on offspring׳s brain oxidative status evaluated fourteen days after HI stablishment. Swimming exercise was performed by female adult rats one week before and during pregnancy, in controlled environment. Their offspring was submitted to HI on postnatal day 7, and the brain samples for biochemical assays were obtained in the weaning. Contrary to our expectations, maternal exercise did not prevent the oxidative alterations observed in brain from HI-rats. In a general way, we found a positive modulation in the activities of antioxidant enzymes, measured two weeks after HI, in hippocampus, striatum, and cerebellum of pups delivered from exercised mothers. Reactive species levels were modulated differently in each structure evaluated. Considering the scenery presented, we concluded that HI elicited a neurometabolic adaptation in both brain hemispheres, particularly in hippocampus, parietal cortex, and cerebellum; while striatum appears to be most damaged. The protocol of aerobic maternal exercise was not enough to fully prevent HI-induced brain damages.

  18. Mitochondrial targets for volatile anesthetics against cardiac ischemia-reperfusion injury

    PubMed Central

    Agarwal, Bhawana; Stowe, David F.; Dash, Ranjan K.; Bosnjak, Zeljko J.; Camara, Amadou K. S.

    2014-01-01

    Mitochondria are critical modulators of cell function and are increasingly recognized as proximal sensors and effectors that ultimately determine the balance between cell survival and cell death. Volatile anesthetics (VA) are long known for their cardioprotective effects, as demonstrated by improved mitochondrial and cellular functions, and by reduced necrotic and apoptotic cell death during cardiac ischemia and reperfusion (IR) injury. The molecular mechanisms by which VA impart cardioprotection are still poorly understood. Because of the emerging role of mitochondria as therapeutic targets in diseases, including ischemic heart disease, it is important to know if VA-induced cytoprotective mechanisms are mediated at the mitochondrial level. In recent years, considerable evidence points to direct effects of VA on mitochondrial channel/transporter protein functions and electron transport chain (ETC) complexes as potential targets in mediating cardioprotection. This review furnishes an integrated overview of targets that VA impart on mitochondrial channels/transporters and ETC proteins that could provide a basis for cation regulation and homeostasis, mitochondrial bioenergetics, and reactive oxygen species (ROS) emission in redox signaling for cardiac cell protection during IR injury. PMID:25278902

  19. Alterations of interneurons of the gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin.

    PubMed

    Himeda, Toshiki; Hayakawa, Natsumi; Tounai, Hiroko; Sakuma, Mio; Kato, Hiroyuki; Araki, Tsutomu

    2005-11-01

    We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can

  20. Pluronic® L64-mediated stable HIF-1α expression in muscle for therapeutic angiogenesis in mouse hindlimb ischemia

    PubMed Central

    Song, Hongmei; Liu, Sijia; Li, Caixia; Geng, Yanyan; Wang, Gang; Gu, Zhongwei

    2014-01-01

    Intramuscular injection of plasmid DNA (pDNA) to express a therapeutic protein is a promising method for the treatment of many diseases. However, the therapeutic applications are usually hindered by gene delivery efficiency and expression level. In this study, critical factors in a pDNA-based gene therapy system, such as gene delivery materials, a therapeutic gene, and its regulatory elements, were optimized to establish an integrated system for the treatment of mouse hindlimb ischemia. The results showed that Pluronic® L64 (L64) was an efficient and safe material for gene delivery into mouse skeletal muscle. It also showed intrinsic ability to promote in vivo angiogenesis in a concentration-dependent manner, which might be through the activation of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-regulated angiogenic factors. The combination of 0.1% L64 with a hybrid gene promoter (pSC) increased the gene expression level, elongated the gene expression duration, and enhanced the number of transfected muscle fibers. In mice ischemic limbs, a gene medicine (pSC-HIF1αtri/L64) composed of L64 and pSC-based expression plasmid encoding hypoxia-inducible factor 1-alpha triple mutant (HIF-1αtri), improved the expression of stable HIF-1α, and in turn, the expression of multiple angiogenic factors. As a result, the ischemic limbs showed accelerated function recovery, reduced foot necrosis, faster blood reperfusion, and higher capillary density. These results indicated that the pSC-HIF1αtri/L64 combination presented a potential and convenient venue for the treatment of peripheral vascular diseases, especially critical limb ischemia. PMID:25092975

  1. Critical Materials Institute

    ScienceCinema

    Alex King

    2016-07-12

    Ames Laboratory Director Alex King talks about the goals of the Critical Materials Institute in diversifying the supply of critical materials, developing substitute materials, developing tools and techniques for recycling critical materials, and forecasting materials needs to avoid future shortages.

  2. Critical Materials Institute

    SciTech Connect

    Alex King

    2013-01-09

    Ames Laboratory Director Alex King talks about the goals of the Critical Materials Institute in diversifying the supply of critical materials, developing substitute materials, developing tools and techniques for recycling critical materials, and forecasting materials needs to avoid future shortages.

  3. Incidence of gastric mucosal injury as measured by reactance in critically ill patients.

    PubMed

    Beltran, Nohra E; Ceron, Ulises; Sanchez-Miranda, Gustavo; Remolina, Miguel; Godinez, Maria M; Peralta, Itzel Y; Sacristan, Emilio

    2013-01-01

    Gastric reactance has been proposed as a measure of mucosal ischemic injury in the critically ill. The purpose of this study was to evaluate the incidence of gastric mucosal injury as measured by gastric reactance in different subgroups of critical patients. We studied 100 adult patients admitted to 7 different hospital intensive care units, requiring a nasogastric tube. Gastric impedance measurements were continuously obtained from each patient for 24 hours. Patients were managed based on conventional protocols by hospital staff, blinded to the changes in gastric impedance parameters. The low-frequency central reactance (X L) reflects tissue edema caused by prolonged ischemia. The previously reported threshold of X L ≥ 13 - jΩ was used to classify injured mucosa; 80% of all patients had mean X L above this threshold. No significant differences were found in the incidence of mucosal ischemia between medical versus surgical, hemodynamic versus respiratory or neurological patients. Significant lower urine output was found in patients with X L above threshold (P < .01); also, there was a significant effect of fluid balance in those patients (P < .05). More complicated patients had higher average reactance. This study shows that gastric ischemia as estimated by gastric reactance has a very high incidence in the critically ill, independently of the reason for admission. High reactance is related with higher morbidity in agreement with other reports using different methods of assessing splanchnic hypoperfusion in this patient population.

  4. Induction of Perivascular Neural Stem Cells and Possible Contribution to Neurogenesis Following Transient Brain Ischemia/Reperfusion Injury.

    PubMed

    Nakata, Masayo; Nakagomi, Takayuki; Maeda, Mitsuyo; Nakano-Doi, Akiko; Momota, Yoshihiro; Matsuyama, Tomohiro

    2017-04-01

    Recent therapeutic advances have increased the likelihood of recanalizing the obstructed brain arteries in patients with stroke. Therefore, it is important to understand the fate of neural cells under transient ischemia/reperfusion injury. Accumulating evidence shows that neurogenesis occurs in perivascular regions following brain injury, although the precise mechanism and origin of these newborn neurons under transient ischemia/reperfusion injury remain unclear. Using a mouse model of transient brain ischemia/reperfusion injury, we found that neural stem cells (NSCs) develop within injured areas. This induction of NSCs following ischemia/reperfusion injury was observed even in response to nonlethal ischemia, although massive numbers of NSCs were induced by lethal ischemia. Immunohistochemical and immunoelectron microscopic studies indicated that platelet-derived growth factor receptor beta-positive (PDGFRβ(+)) pericytes within injured areas following nonlethal ischemia began to express the NSC marker nestin as early as 3 days after transient ischemia/reperfusion. Some PDGFRβ(+) pericytes expressed the immature neuronal marker doublecortin at day 7. These findings indicate that brain pericytes are a potential source of the perivascular NSCs that generate neuronal cells under lethal and nonlethal ischemic conditions following transient ischemia/reperfusion. Thus, brain pericytes might be a target for neurogenesis mediation in patients with nonlethal and lethal ischemia following transient ischemia/reperfusion injury.

  5. Reversible recovery of neuronal structures depends on the degree of neuronal damage after global cerebral ischemia in mice.

    PubMed

    Zhu, Lirui; Wang, Lei; Ju, Furong; Khan, Akbar; Cheng, Xiaofeng; Zhang, Shengxiang

    2017-03-01

    It has been observed by in vivo imaging that damaged neuronal structures can be reversibly restored after ischemic insults with the application of timely therapeutic interventions. However, what degree of neuronal damage can be restored and the time frame for reversible recovery of neuronal structures remain unclear. Here, transcranial two-photon imaging, histological staining and electron microscopy were used to investigate the reversible recovery of neuronal structures from dendrites to soma after different durations of global cerebral ischemia in mice. Intravital imaging revealed that the damage to dendritic structures was reversible when ischemia time was <1h, but they became difficult to restore after >3h of ischemia. Data from fixed YFP brain slice and Golgi staining indicated that the damage of dendritic structures progressively extended to deeper dendritic shafts with the extension of ischemia time. Furthermore, longer duration of ischemia caused an increasing number of degenerating neurons. Importantly, significant chromatin margination and karyopyknosis of neuron were observed after 6h of ischemia. These data suggested that neuronal structures could be reversibly restored when ischemia time was <1h, but irreversible and progressive damage to neurons occurred with longer duration of ischemia. Consistently, behavioral performance of post-ischemic animals experienced an ischemia time-dependent recovery. Taken together, our data suggested that recovery of neuronal structures following ischemia was dependent on the duration of ischemia, and prevention of neuronal loss is a key target for therapeutic interventions in ischemic stroke.

  6. Effects of an A1 adenosine receptor agonist on the neurochemical, behavioral and histological consequences of ischemia.

    PubMed

    Héron, A; Lekieffre, D; Le Peillet, E; Lasbennes, F; Seylaz, J; Plotkine, M; Boulu, R G

    1994-04-04

    Untreated rats and rats given the A1 receptor adenosine agonist, R-phenylisopropyladenosine (R-PIA), were subjected to four vessel ischemia. The effect of R-PIA on hippocampal amino acid release, hippocampal neuronal damage, exploratory behavior, learning capacity and global neurological score were evaluated. R-PIA decreased by half the glutamate released during ischemia and improved the global neurological scores 3, 24, 48, 78 h and 7 days after ischemia. But R-PIA had no effect on taurine/GABA release (during ischemia), hippocampal neuronal damage (7 days post-ischemia), exploratory behavior (48 h post-ischemia) or learning capacity (7 days post-ischemia). Thus, a decrease in glutamate release by R-PIA is not systematically correlated with an improvement of histological damage or learning capacity. Reduced glutamate release is not therefore a sufficient criterion on which to evaluate the neuroprotective capacity of a drug.

  7. DJ-1 protects against cell death following acute cardiac ischemia-reperfusion injury.

    PubMed

    Dongworth, R K; Mukherjee, U A; Hall, A R; Astin, R; Ong, S-B; Yao, Z; Dyson, A; Szabadkai, G; Davidson, S M; Yellon, D M; Hausenloy, D J

    2014-02-27

    Novel therapeutic targets are required to protect the heart against cell death from acute ischemia-reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia-reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1(L166P) and DJ-1(Cys106A) mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection.

  8. Cathepsin L acutely alters microvessel integrity within the neurovascular unit during focal cerebral ischemia

    PubMed Central

    Gu, Yu-Huan; Kanazawa, Masato; Hung, Stephanie Y; Wang, Xiaoyun; Fukuda, Shunichi; Koziol, James A; del Zoppo, Gregory J

    2015-01-01

    During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage. PMID:26198177

  9. Neuroprotective effects of pretreatment with minocycline on memory impairment following cerebral ischemia in rats.

    PubMed

    Naderi, Yazdan; Sabetkasaei, Masoumeh; Parvardeh, Siavash; Moini Zanjani, Taraneh

    2017-04-01

    Cerebral ischemia leads to memory impairment that is associated with loss of hippocampal CA1 pyramidal neurons. Neuroinflammation and oxidative stress may be implicated in the pathogenesis of ischemia/reperfusion damage. Minocycline has anti-inflammatory and antioxidant properties. We investigated the neuroprotective effects of minocycline in rats subjected to cerebral ischemia/reperfusion injury. Thirty male rats were divided into three groups: control, sham, and minocycline-pretreated group. Minocycline (40 mg/kg) was injected intraperitoneally immediately before surgery, and then ischemia was induced by occlusion of common carotid arteries for 20 min. Seven days after reperfusion, the Morris water-maze task was used to evaluate memory. Nissl staining was also performed to analyze pyramidal cell damage. We measured the contents of malondialdehyde and proinflammatory cytokines in the hippocampus by the thiobarbituric acid method and enzyme-linked immunosorbent assay, respectively. Microglial activation was also investigated by Iba1 immunostaining. The results showed that pretreatment with minocycline prevented memory impairment induced by cerebral ischemia/reperfusion. Minocycline pretreatment also significantly attenuated ischemia-induced pyramidal cell death and microglial activation in the CA1 region and reduced the levels of malondialdehyde and proinflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of ischemic rats. Minocycline showed neuroprotective effects on cerebral ischemia-induced memory deficit probably through its anti-inflammatory and antioxidant activities.

  10. Gastric injury induced by hemorrhage, local ischemia, and oxygen radical generation

    SciTech Connect

    Wadhwa, S.S.; Perry, M.A. )

    1987-08-01

    Gastric mucosal injury caused by local intra-arterial generation of oxygen-derived free radicals was compared with gastric injury caused by 30 min of hemorrhage-induced ischemia or local ischemia. The index of injury was the loss of {sup 51}Cr-labeled red cells across the gastric mucosa. Generation of oxygen radicals in the celiac artery caused a rapid increase in mucosal blood loss during the period of radical generation, and this loss was maintained after radical production ceased. Local ischemia produced similar mucosal injury; however, this occurred after reperfusion of the stomach and not during the ischemic episode. Hemorrhage-induced ischemia produced a threefold greater mucosal blood loss than local ischemia. The results of this study indicate that (1) oxygen radicals generated enzymatically in the blood supply to the stomach cause mucosal bleeding of similar magnitude to that observed after local ischemia and (2) that gastric ischemia induced by systemic hypotension produces more severe gastric injury than the same level of local hypotension.

  11. Isolating the segment of the mitochondrial electron transport chain responsible for mitochondrial damage during cardiac ischemia

    SciTech Connect

    Chen, Qun; Yin, Guotian; Stewart, Sarah; Hu, Ying; Lesnefsky, Edward J.

    2010-07-09

    Ischemia damages the mitochondrial electron transport chain (ETC), mediated in part by damage generated by the mitochondria themselves. Mitochondrial damage resulting from ischemia, in turn, leads to cardiac injury during reperfusion. The goal of the present study was to localize the segment of the ETC that produces the ischemic mitochondrial damage. We tested if blockade of the proximal ETC at complex I differed from blockade distal in the chain at cytochrome oxidase. Isolated rabbit hearts were perfused for 15 min followed by 30 min stop-flow ischemia at 37 {sup o}C. Amobarbital (2.5 mM) or azide (5 mM) was used to block proximal (complex I) or distal (cytochrome oxidase) sites in the ETC. Time control hearts were buffer-perfused for 45 min. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated. Ischemia decreased cytochrome c content in SSM but not in IFM compared to time control. Blockade of electron transport at complex I preserved the cytochrome c content in SSM. In contrast, blockade of electron transport at cytochrome oxidase with azide did not retain cytochrome c in SSM during ischemia. Since blockade of electron transport at complex III also prevented cytochrome c loss during ischemia, the specific site that elicits mitochondrial damage during ischemia is likely located in the segment between complex III and cytochrome oxidase.

  12. Protective effect of resveratrol against neuronal damage following transient global cerebral ischemia in mice.

    PubMed

    Hong, Jeong-Ho; Lee, Hyung; Lee, Seong-Ryong

    2016-01-01

    Resveratrol (3,5,4'-trihydroxystilbene) is a natural polyphenol which is rich in grape seeds and skin. Several studies have revealed that resveratrol possesses neuroprotective effects. In the case of global brain ischemia, there are few reports regarding the protective effect of resveratrol. Therefore, the influence of resveratrol on neuronal damage after transient global brain ischemia remains to be clarified. In the current study, C57BL/6 black mice were subjected to 20 min of transient global brain ischemia and followed by 72 h of reperfusion. Resveratrol (20 or 40 mg/kg, once daily, dissolved in 0.5% carboxymethylcellulose) was administered orally for 7 days before ischemia and daily until the mice were euthanized. The effect of lower or higher dose of resveratrol on neuronal damage, matrix metalloproteinase (MMP) activity and in situ DNA fragmentation (TUNEL) assay in the hippocampus after global ischemia was examined. Neuronal damages were remarkable in CA1 and CA2 pyramidal cell layers after global ischemia. In resveratrol-treated mice (40 mg/kg), neuronal damage was significantly reduced compared with vehicle-treated mice. Mice treated with resveratrol showed reduced MMP-9 activity. Resveratrol also inhibited TUNEL staining. These data suggest that resveratrol, a natural polyphenol, reduces hippocampal neuronal cell damage following transient global ischemia by reducing MMP-9 activity.

  13. Perioperative evaluation and outcomes of major limb replantations with ischemia periods of more than 6 hours.

    PubMed

    Tantry, Thrivikrama Padur; Kadam, Dinesh; Shenoy, Sunil P; Bhandary, Sanath; Adappa, Karunakara K

    2013-03-01

    Early revascularization is cardinal for successful replantation of proximal limb amputations. Prolonged ischemia time potentially leads to reperfusion syndrome and morbidity. The dilemma persists regarding safe duration of cold ischemia time for replantation. The study was conducted to evaluate retrospectively the outcomes of major replantation in terms of limb survival, reperfusion events, morbidity, and potential mortality with respect to the ischemia time and level of amputations. Fourteen patients with proximal amputations at the arm, elbow, and forearm with total ischemia time beyond 6 hours were replanted. All had warm ischemia time of less than 2 hours and were closely monitored to record and correct reperfusion events. Nine out of 14 limbs survived. Five patients had reperfusion events. Proximal limb amputations with larger muscle mass were at higher risk of developing reperfusion syndrome and such events had higher chances of limb loss. Major limb amputations within 2 hours of warm ischemia time even with prolonged cold ischemia can be successfully replanted with closed perioperative monitoring.

  14. Enhanced autophagy signaling in diabetic rats with ischemia-induced seizures.

    PubMed

    Xia, Luoxing; Lei, Zhigang; Shi, Zhongshan; Guo, Dave; Su, Henry; Ruan, Yiwen; Xu, Zao C

    2016-07-15

    Seizures are among the most common neurological sequelae of stroke, and ischemic insult in diabetes notably increases the incidence of seizures. Recent studies indicated that autophagy influences the outcome of stroke and involved in epileptogenesis. However, the association of autophagy and post-ischemic seizures in diabetes remains unclear. The present study aimed to reveal the involvement of autophagy in the seizures following cerebral ischemia in diabetes. Diabetes was induced in adult male Wistar rats by intraperitoneal injection of streptozotocin (STZ). The diabetic rats were subjected to transient forebrain ischemia. The neuronal damage was assessed using hematoxylin-eosin staining. Western blotting and immunohistochemistry were performed to investigate the alteration of autophagy marker microtubule-associated protein light chain 1B (LC3B). The results showed that all diabetic animals developed seizures after ischemia. However, no apparent cell death was observed in the hippocampus of seizure rats 12h after the insult. The expression of LC3B was significantly enhanced in naïve animals after ischemia and was further increased in diabetic animals after ischemia. Immunofluorescence double-labeling study indicated that LC3B was mainly increased in neurons. Our study demonstrated, for the first time, that autophagy activity is significantly increased in diabetic animals with ischemia-induced seizures. Further studies are needed to explore the role of autophagy in seizure generation after ischemia in diabetic conditions.

  15. Signaling pathway for nitric oxide generation with simulated ischemia in flow-adapted endothelial cells.

    PubMed

    Wei, Z; Al-Mehdi, A B; Fisher, A B

    2001-11-01

    Ischemia in the intact ventilated lung (oxygenated ischemia) leads to endothelial generation of reactive oxygen species (ROS) and nitric oxide (NO). This study investigated the signaling pathway for NO generation with oxygenated ischemia in bovine pulmonary artery endothelial cells (BPAEC) that were flow adapted in vitro. BPAECs were cultured in an artificial capillary system and subjected to abrupt cessation of flow (ischemia) under conditions where cellular oxygenation was maintained. Immunoblotting and dichlorofluorescein/triazolofluorescein fluorescence were used to assess extracellular signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation and ROS/NO generation, respectively. ERK1/2 phosphorylation significantly increased during ischemia, whereas total ERK1/2 did not change. ERK1/2 phosphorylation was suppressed by an inhibitor of tyrosine phosphorylation (genestein), cholesterol-binding reagents (filipin or cyclodextrin), or inhibitors of ROS (diphenyleneiodonium, N-acetylcysteine, or catalase), suggesting a role for both membrane cholesterol and ROS in ERK1/2 activation. Ischemia resulted in a 1.8-fold increase in NO generation that was suppressed by inhibitors of ERK1/2 activation (PD-98059 or U-0126). A calmodulin inhibitor (calmidizolium) or removal of Ca2+ from the medium also blocked NO generation, indicating that endothelial NO synthase (eNOS) is the activated isoform. These results indicate ischemia induces NO generation (possibly through a membrane cholesterol-sensitive flow sensor), the ERK1/2 cascade mediates signaling from the sensor to eNOS, and ROS are required for ERK activation.

  16. Ceramide is involved in triggering of cardiomyocyte apoptosis induced by ischemia and reperfusion.

    PubMed Central

    Bielawska, A. E.; Shapiro, J. P.; Jiang, L.; Melkonyan, H. S.; Piot, C.; Wolfe, C. L.; Tomei, L. D.; Hannun, Y. A.; Umansky, S. R.

    1997-01-01

    Involvement of ceramide signaling in the initiation of apoptosis induction in myocardial cells by in vitro and in vivo ischemia and reperfusion was analyzed. Synthetic cell permeable C2-ceramide induced apoptotic death of rat neonatal cardiomyocytes in vitro. In vitro ischemia (oxygen/serum/glucose deprivation) led to a progressive accumulation of ceramide in cardiomyocytes. After 16 hours of simulated in vitro reperfusion (readdition of oxygen, serum and glucose), the level of ceramide in surviving cells was found to have returned to baseline, whereas, levels in nonadherent dead cells remained high. In the rat heart left coronary artery occlusion model, ischemia with the subsequent reperfusion, but not ischemia alone, induced apoptosis in myocardial cells as demonstrated by DNA electrophoresis and measurement of soluble chromatin degradation products. The content of ceramide in ischemic area was elevated to 155% baseline levels at 30 minutes, and to 330% after 210 minutes of ischemia. Ischemia (30 minutes) followed by reperfusion (180 minutes) increased the ceramide level to 250% in the ischemic area. The combination of results obtained in both in vitro and animal models demonstrate for the first time that ceramide signaling can be involved in ischemia/reperfusion death of myocardial cells. Images Figure 2 Figure 4 PMID:9358751

  17. Role of histamine H3 receptors during ischemia/reperfusion in isolated rat hearts.

    PubMed

    Yamamoto, Satoshi; Tamai, Isao; Takaoka, Masanori; Matsumura, Yasuo

    2004-03-01

    Histamine H3 receptors are involved in regulating the release of norepinephrine (NE), in both central and peripheral nervous systems. We investigated the effect of R-alpha-methylhistamine (R-HA), a selective H3 receptor agonist, and thioperamide (Thiop), a selective H3 receptor antagonist, on ischemia/reperfusion-induced changes in carrier-mediated NE release and cardiac function in isolated rat heart. Hearts were subjected to 40-minute ischemia followed by 30-minute reperfusion. Ischemia/reperfusion evoked massive NE release, which was markedly suppressed by the treatment with desipramine (DMI), a neuronal NE transporter blocker. Ischemia/reperfusion-induced cardiac dysfunction (decreases in left ventricular developed pressure, LVDP, and the first derivative of left ventricular pressure, dP/dt, and a rise in left ventricular end diastolic pressure, LVEDP) was also improved by the DMI treatment. The treatment with R-HA also significantly decreased the excessive NE release induced by the ischemia/reperfusion, improved the recovery of LVDP and dP/dt, and suppressed the rise in LVEDP. Thiop did not affect NE release and cardiac function after the reperfusion. When R-HA was administered concomitantly with Thiop, R-HA failed to attenuate ischemia/reperfusion-induced NE release and cardiac dysfunction. Thus, it seems likely that the ischemia/reperfusion-induced carrier-mediated NE release in rat hearts is negatively regulated by the activation of H3 receptors, probably located on cardiac noradrenergic nerve endings.

  18. Tyrosol attenuates ischemia-reperfusion-induced kidney injury via inhibition of inducible nitric oxide synthase.

    PubMed

    Wang, Pengqi; Zhu, Qingjun; Wu, Nan; Siow, Yaw L; Aukema, Harold; O, Karmin

    2013-04-17

    Tyrosol is a natural phenolic antioxidant compound. Oxidative stress represents one of the important mechanisms underlying ischemia-reperfusion-induced kidney injury. The aim of this study was to investigate the effect of tyrosol against ischemia-reperfusion-induced acute kidney injury. The left kidney of Sprague-Dawley rats was subjected to 45 min of ischemia followed by reperfusion for 6 h. Ischemia-reperfusion caused an increase in peroxynitrite formation and lipid peroxidation. The level of nitric oxide (NO) metabolites and the mRNA of inducible nitric oxide synthase (iNOS) were elevated in ischemia-reperfused kidneys. Administration of tyrosol (100 mg/kg body weight) to rats prior to the induction of ischemia significantly reduced peroxynitrite formation, lipid peroxidation, and the level of NO metabolites. Tyrosol administration also attenuated ischemia-reperfusion-induced NF-κB activation and iNOS expression. Such a treatment improved kidney function. Results suggest that tyrosol may have a protective effect against acute kidney injury through inhibition of iNOS-mediated oxidative stress.

  19. GABA and benzodiazepine receptors in the gerbil brain after transient ischemia: demonstration by quantitative receptor autoradiography

    SciTech Connect

    Onodera, H.; Sato, G.; Kogure, K.

    1987-02-01

    Quantitative receptor autoradiography was used to measure the binding of gamma-aminobutyric acid (GABA) and benzodiazepine receptors after ischemia by means of transient occlusion of bilateral common carotid arteries in the gerbil. (/sup 3/H)Muscimol was used to label the GABAA receptors and (/sup 3/H)flunitrazepam to label central type benzodiazepine receptors. In the superolateral convexities of the frontal cortices, (/sup 3/H)muscimol binding was increased in 60% of the animals killed 3 days after ischemia, and decreased in 67% of the animals killed 27 days after ischemia. Twenty-seven days after ischemia, (/sup 3/H)flunitrazepam binding in the substantia nigra pars reticulata increased to 252% of the control, though the increase in (/sup 3/H)muscimol binding was not significant. In the dorsolateral region of the caudate putamen, marked neuronal necrosis and depletion of both (/sup 3/H)muscimol and (/sup 3/H)flunitrazepam binding sites were observed 27 days after ischemia, the ventromedial region being left intact. In spite of the depletion of pyramidal cells in the CA1 region of the hippocampus, both (/sup 3/H)muscimol and (/sup 3/H)flunitrazepam binding sites were preserved 27 days after ischemia. Since our previous study revealed that adenosine A1 binding sites were depleted in the CA1 subfield of the hippocampus after ischemia correlating with neuronal damage, GABAA and benzodiazepine receptors may not be distributed predominantly on the pyramidal cells in the CA1 region.

  20. Thromboxane A2 release in ischemia and reperfusion of free flaps in rats, studied by microdialysis.

    PubMed

    Ionac, M; Schaefer, D; Geishauser, M

    2001-02-01

    Several studies have implicated enhanced eicosanoid production in reperfusion injury. The reported study investigated the use of microdialysis in the in vivo measurement of thromboxane levels during reperfusion in ischemic and reperfused experimental free muscle flaps. Microdialysis probes were inserted, via a guide, into the gracilis and semitendinosus free flap in the rat. The probe was perfused at a flow of 5 microl/min, with samples collected at intervals of 20 min, and analyzed by the ELISA technique. Animals were randomly distributed into three groups. After ischemic periods of 2, 4, and 6 hr, respectively, the free muscle flaps were revascularized on the contralateral femoral vessels. The mean thromboxane level during ischemia was 1785.34 +/- 124.81 pg/ml. The mean levels of thromboxane rose significantly (p < 0.05), compared to base level, with 151.65 percent in the 2-hr ischemia group, 192.33 percent in the 4-hr ischemia group, and 294.69 percent in the 6-hr ischemia group, and correlated well with histologic observations. The results suggest that a microdialysis technique, combined with a sensitive assay for measuring thromboxane, is a useful method for in vivo monitoring of inflammatory processes during ischemia and reperfusion. The evolution of thromboxane release following 6 hr of ischemia indicates that this mediator may be involved in facilitation of cell death, following ischemia and reperfusion, since its tissue level correlates with histologic tissue damage.

  1. Aqueous extract of Cordyceps alleviates cerebral ischemia-induced short-term memory impairment in gerbils

    PubMed Central

    Lee, Sang-Hak; Ko, Il-Gyu; Kim, Sung-Eun; Hwang, Lakkyong; Jin, Jun-Jang; Choi, Hyun-Hee; Kim, Chang-Ju

    2016-01-01

    Cerebral ischemia is caused by reduced cerebral blood flow due to a transient or permanent cerebral artery occlusion. Ischemic injury in the brain leads to neuronal cell death, and eventually causes neurological impairments. Cordyceps, the name given to the fungi on insects, has abundant useful natural products with various biological activities. Cordyceps is known to have nephroprotective, hepatoprotective, anti-inflammatory, antioxidative, and antiapoptotic effects. We investigated the effects of Cordyceps on short-term memory, neuronal apoptosis, and cell proliferation in the hippocampal dentate gyrus following transient global ischemia in gerbils. For this study, a step-down avoidance test, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3 and 5-bromo-2′-de-oxyuridine, and western blot for Bax, Bcl-2, brain-derived neurotrophic factor (BDNF), and tyrosin kinase B were performed. In the present study, Cordyceps alleviated cerebral ischemia-induced short-term memory impairment. Cordyceps showed therapeutic effects through inhibiting cerebral ischemia-induced apoptosis in the hippocampus. Cordyceps suppressed cerebral ischemia-induced cell proliferation in the hippocampal dentate gyrus due to the reduced apoptotic neuronal cell death. Cordyceps treatment also enhanced BDNF and TrkB expressions in the hippocampus of ischemic gerbils. It can be suggested that Cordyceps overcomes cerebral ischemia-induced neuronal apoptosis, thus facilitates recovery following cerebral ischemia injury. PMID:27162767

  2. Aqueous extract of Cordyceps alleviates cerebral ischemia-induced short-term memory impairment in gerbils.

    PubMed

    Lee, Sang-Hak; Ko, Il-Gyu; Kim, Sung-Eun; Hwang, Lakkyong; Jin, Jun-Jang; Choi, Hyun-Hee; Kim, Chang-Ju

    2016-04-01

    Cerebral ischemia is caused by reduced cerebral blood flow due to a transient or permanent cerebral artery occlusion. Ischemic injury in the brain leads to neuronal cell death, and eventually causes neurological impairments. Cordyceps, the name given to the fungi on insects, has abundant useful natural products with various biological activities. Cordyceps is known to have nephroprotective, hepatoprotective, anti-inflammatory, antioxidative, and antiapoptotic effects. We investigated the effects of Cordyceps on short-term memory, neuronal apoptosis, and cell proliferation in the hippocampal dentate gyrus following transient global ischemia in gerbils. For this study, a step-down avoidance test, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3 and 5-bromo-2'-de-oxyuridine, and western blot for Bax, Bcl-2, brain-derived neurotrophic factor (BDNF), and tyrosin kinase B were performed. In the present study, Cordyceps alleviated cerebral ischemia-induced short-term memory impairment. Cordyceps showed therapeutic effects through inhibiting cerebral ischemia-induced apoptosis in the hippocampus. Cordyceps suppressed cerebral ischemia-induced cell proliferation in the hippocampal dentate gyrus due to the reduced apoptotic neuronal cell death. Cordyceps treatment also enhanced BDNF and TrkB expressions in the hippocampus of ischemic gerbils. It can be suggested that Cordyceps overcomes cerebral ischemia-induced neuronal apoptosis, thus facilitates recovery following cerebral ischemia injury.

  3. Water-soluble acacetin prodrug confers significant cardioprotection against ischemia/reperfusion injury

    PubMed Central

    Liu, Hui; Yang, Lei; Wu, Hui-Jun; Chen, Kui-Hao; Lin, Feng; Li, Gang; Sun, Hai-Ying; Xiao, Guo-Sheng; Wang, Yan; Li, Gui-Rong

    2016-01-01

    The morbidity and mortality of patients with ischemic cardiomyopathy resulted from ischemia/reperfusion injury are very high. The present study investigates whether our previously synthesized water-soluble phosphate prodrug of acacetin was cardioprotective against ischemia/reperfusion injury in an in vivo rat model. We found that intravenous administration of acacetin prodrug (10 mg/kg) decreased the ventricular arrhythmia score and duration, reduced ventricular fibrillation and infarct size, and improved the impaired heart function induced by myocardial ischemia/reperfusion injury in anesthetized rats. The cardioprotective effects were further confirmed with the parent compound acacetin in an ex vivo rat regional ischemia/reperfusion heart model. Molecular mechanism analysis revealed that acacetin prevented the ischemia/reperfusion-induced reduction of the anti-oxidative proteins SOD-2 and thioredoxin, suppressed the release of inflammation cytokines TLR4, IL-6 and TNFα, and decreased myocyte apoptosis induced by ischemia/reperfusion. Our results demonstrate the novel evidence that acacetin prodrug confer significant in vivo cardioprotective effect against ischemia/reperfusion injury by preventing the reduction of endogenous anti-oxidants and the release of inflammatory cytokines, thereby inhibiting cardiomyocytes apoptosis, which suggests that the water-soluble acacetin prodrug is likely useful in the future as a new drug candidate for treating patients with acute coronary syndrome. PMID:27819271

  4. Multislice diffusion mapping for 3-D evolution of cerebral ischemia in a rat stroke model.

    PubMed

    Reith, W; Hasegawa, Y; Latour, L L; Dardzinski, B J; Sotak, C H; Fisher, M

    1995-01-01

    Diffusion-weighted magnetic resonance imaging (DWI) can quantitatively demonstrate cerebral ischemia within minutes after the onset of ischemia. The use of a DWI echo-planar multislice technique in this study and the mapping of the apparent diffusion coefficient (ADC) of water, a reliable indicator of ischemic regions, allow for the detection of the three-dimensional (3-D) evolution of ischemia in a rat stroke model. We evaluated 13 time points from 5 to 180 minutes after occlusion of the middle cerebral artery (MCA) and monitored the 3-D spread of ischemia. Within 5 minutes after the onset of ischemia, regions with reduced ADC values occurred. The core of the lesion, with the lowest absolute ADC values, first appeared in the lateral caudoputamen and frontoparietal cortex, then spread to adjacent areas. The volume of ischemic tissue was 224 +/- 48.5 mm3 (mean +/- SEM) after 180 minutes, ranging from 92 to 320 mm3, and this correlated well with the corrected infarct volume at postmortem (194 +/- 23.1 mm3, r = 0.72, p < 0.05). This experiment demonstrated that 3-D multislice diffusion mapping can detect ischemic regions noninvasively 5 minutes after MCA occlusion and follow the development of ischemia. The distribution of changes in absolute ADC values within the ischemic region can be followed over time, giving important information about the evolution of focal ischemia.

  5. Nuclear criticality safety guide

    SciTech Connect

    Pruvost, N.L.; Paxton, H.C.

    1996-09-01

    This technical reference document cites information related to nuclear criticality safety principles, experience, and practice. The document also provides general guidance for criticality safety personnel and regulators.

  6. Critical Access Hospitals (CAH)

    MedlinePlus

    ... use requirements for Critical Access Hospitals related to Electronic Health Records (EHRs)? Critical Access Hospital (CAH) are eligible for Electronic Health Record (EHR) incentive payments and can receive ...

  7. Physiological ischemia/reperfusion phenomena and their relation to endogenous melatonin production: a hypothesis.

    PubMed

    Tan, Dun-Xian; Manchester, Lucien C; Sainz, Rosa M; Mayo, Juan C; León, Josefa; Reiter, Russel J

    2005-07-01

    Ischemia/reperfusion is a frequently encountered phenomenon in organisms. Prolonged ischemia followed then by reperfusion results in severe oxidative injury in tissues and organs; however, some species can tolerate such events better than others. In nature, arousal from hibernation and resurfacing from diving causes animals to experience classic ischemia/reperfusion and, somehow, these animals cope well with the potential oxidative stress. It has been documented that during these physiological ischemia/reperfusion events, the activities of several antioxidant enzymes and the levels of some small-molecular-weight antioxidants become elevated. For example, the potent small-molecular-weight antioxidant melatonin often attains especially high levels during these physiological ischemia/reperfusion events including during arousal from hibernation or in the newborns during delivery. Highly elevated melatonin production during these physiological ischemia/reperfusion episodes exhibits several features. First, this high melatonin production is transient and fits well with the time schedule of the physiological ischemia/reperfusion period; therefore, it is not related to the normal endogenous melatonin rhythm. Yet, this transient peak protects the animals from destructive oxidative processes that occur during these transition periods. Second, these high levels of melatonin seem to derive from several organs since pinealectomy does not totally reduce circulating levels of this agent. Third, high melatonin production present at arousal from hibernation or in the newborns at birth does not appear to be controlled by light, i.e., it occurs both during the day and at night, and the amplitudes of elevated melatonin levels are equivalent at these times. The significance of these findings is discussed herein. Based on currently available data, we hypothesize that melatonin plays an important role in the physiological ischemia/reperfusion, i.e., as a member of antioxidant defense

  8. Dictionary-driven Ischemia Detection from Cardiac Phase-Resolved Myocardial BOLD MRI at Rest

    PubMed Central

    Bevilacqua, Marco; Dharmakumar, Rohan; Tsaftaris, Sotirios A.

    2016-01-01

    Cardiac Phase-resolved Blood-Oxygen-Level Dependent (CP–BOLD) MRI provides a unique opportunity to image an ongoing ischemia at rest. However, it requires post-processing to evaluate the extent of ischemia. To address this, here we propose an unsupervised ischemia detection (UID) method which relies on the inherent spatio-temporal correlation between oxygenation and wall motion to formalize a joint learning and detection problem based on dictionary decomposition. Considering input data of a single subject, it treats ischemia as an anomaly and iteratively learns dictionaries to represent only normal observations (corresponding to myocardial territories remote to ischemia). Anomaly detection is based on a modified version of One-class Support Vector Machines (OCSVM) to regulate directly the margins by incorporating the dictionary-based representation errors. A measure of ischemic extent (IE) is estimated, reflecting the relative portion of the myocardium affected by ischemia. For visualization purposes an ischemia likelihood map is created by estimating posterior probabilities from the OCSVM outputs, thus obtaining how likely the classification is correct. UID is evaluated on synthetic data and in a 2D CP–BOLD data set from a canine experimental model emulating acute coronary syndromes. Comparing early ischemic territories identified with UID against infarct territories (after several hours of ischemia), we find that IE, as measured by UID, is highly correlated (Pearson’s r = 0.84) w.r.t. infarct size. When advances in automated registration and segmentation of CP–BOLD images and full coverage 3D acquisitions become available, we hope that this method can enable pixel-level assessment of ischemia with this truly non-invasive imaging technique. PMID:26292338

  9. Myocardial ischemia is a key factor in the management of stable coronary artery disease

    PubMed Central

    Iwasaki, Kohichiro

    2014-01-01

    Previous studies demonstrated that coronary revascularization, especially percutaneous coronary intervention (PCI), does not significantly decrease the incidence of cardiac death or myocardial infarction in patients with stable coronary artery disease. Many studies using myocardial perfusion imaging (MPI) showed that, for patients with moderate to severe ischemia, revascularization is the preferred therapy for survival benefit, whereas for patients with no to mild ischemia, medical therapy is the main choice, and revascularization is associated with increased mortality. There is some evidence that revascularization in patients with no or mild ischemia is likely to result in worsened ischemia, which is associated with increased mortality. Studies using fractional flow reserve (FFR) demonstrate that ischemia-guided PCI is superior to angiography-guided PCI, and the presence of ischemia is the key to decision-making for PCI. Complementary use of noninvasive MPI and invasive FFR would be important to compensate for each method’s limitations. Recent studies of appropriateness criteria showed that, although PCI in the acute setting and coronary bypass surgery are properly performed in most patients, PCI in the non-acute setting is often inappropriate, and stress testing to identify myocardial ischemia is performed in less than half of patients. Also, some studies suggested that revascularization in an inappropriate setting is not associated with improved prognosis. Taken together, the presence and the extent of myocardial ischemia is a key factor in the management of patients with stable coronary artery disease, and coronary revascularization in the absence of myocardial ischemia is associated with worsened prognosis. PMID:24772253

  10. Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury.

    PubMed

    Ham, Ahrom; Rabadi, May; Kim, Mihwa; Brown, Kevin M; Ma, Zhe; D'Agati, Vivette; Lee, H Thomas

    2014-11-01

    Peptidyl arginine deiminase (PAD)4 is a nuclear enzyme that catalyzes the posttranslational conversion of arginine residues to citrulline. Posttranslational protein citrullination has been implicated in several inflammatory autoimmune diseases, including rheumatoid arthritis, colitis, and multiple sclerosis. Here, we tested the hypothesis that PAD4 contributes to ischemic acute kidney injury (AKI) by exacerbating the inflammatory response after renal ischemia-reperfusion (I/R). Renal I/R injury in mice increased PAD4 activity as well as PAD4 expression in the mouse kidney. After 30 min of renal I/R, vehicle-treated mice developed severe AKI with large increases in plasma creatinine. In contrast, mice pretreated with PAD4 inhibitors (2-chloroamidine or streptonigrin) had significantly reduced renal I/R injury. Further supporting a critical role for PAD4 in generating ischemic AKI, mice pretreated with recombinant human PAD4 (rPAD4) protein and subjected to mild (20 min) renal I/R developed exacerbated ischemic AKI. Consistent with the hypothesis that PAD4 regulates renal tubular inflammation after I/R, mice treated with a PAD4 inhibitor had significantly reduced renal neutrophil chemotactic cytokine (macrophage inflammatory protein-2 and keratinocyte-derived cytokine) expression and had decreased neutrophil infiltration. Furthermore, mice treated with rPAD4 had significantly increased renal tubular macrophage inflammatory protein-2 and keratinocyte-derived cytokine expression as well as increased neutrophil infiltration and necrosis. Finally, cultured mouse kidney proximal tubules treated with rPAD4 had significantly increased proinflammatory chemokine expression compared with vehicle-treated cells. Taken together, our results suggest that PAD4 plays a critical role in renal I/R injury by increasing renal tubular inflammatory responses and neutrophil infiltration after renal I/R.

  11. Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury

    PubMed Central

    Ham, Ahrom; Rabadi, May; Kim, Mihwa; Brown, Kevin M.; Ma, Zhe; D'Agati, Vivette

    2014-01-01

    Peptidyl arginine deiminase (PAD)4 is a nuclear enzyme that catalyzes the posttranslational conversion of arginine residues to citrulline. Posttranslational protein citrullination has been implicated in several inflammatory autoimmune diseases, including rheumatoid arthritis, colitis, and multiple sclerosis. Here, we tested the hypothesis that PAD4 contributes to ischemic acute kidney injury (AKI) by exacerbating the inflammatory response after renal ischemia-reperfusion (I/R). Renal I/R injury in mice increased PAD4 activity as well as PAD4 expression in the mouse kidney. After 30 min of renal I/R, vehicle-treated mice developed severe AKI with large increases in plasma creatinine. In contrast, mice pretreated with PAD4 inhibitors (2-chloroamidine or streptonigrin) had significantly reduced renal I/R injury. Further supporting a critical role for PAD4 in generating ischemic AKI, mice pretreated with recombinant human PAD4 (rPAD4) protein and subjected to mild (20 min) renal I/R developed exacerbated ischemic AKI. Consistent with the hypothesis that PAD4 regulates renal tubular inflammation after I/R, mice treated with a PAD4 inhibitor had significantly reduced renal neutrophil chemotactic cytokine (macrophage inflammatory protein-2 and keratinocyte-derived cytokine) expression and had decreased neutrophil infiltration. Furthermore, mice treated with rPAD4 had significantly increased renal tubular macrophage inflammatory protein-2 and keratinocyte-derived cytokine expression as well as increased neutrophil infiltration and necrosis. Finally, cultured mouse kidney proximal tubules treated with rPAD4 had significantly increased proinflammatory chemokine expression compared with vehicle-treated cells. Taken together, our results suggest that PAD4 plays a critical role in renal I/R injury by increasing renal tubular inflammatory responses and neutrophil infiltration after renal I/R. PMID:25164081

  12. Productive criticism. Part 1: Criticism that works.

    PubMed

    Weisinger, H D

    1995-01-01

    Criticism affects almost all aspects of your job: the quality of work you do, how you feel about your performance, and your relationships with your boss, coworkers, and subordinates. Used productively, criticism is a powerful tool that helps you improve your work, enhance your working relationships, increase your job satisfaction, and achieve better overall results. Improperly used, it impedes performance, demoralizes you, discourages you from wanting to try again, and creates friction in the workplace. In short, the ability to give and take criticism significantly determines how well you do on the job. In Part I, we will examine the traditional negative approach to criticism and develop new management tools to turn criticism into an opportunity for growth and education. By explaining new evaluation and communication techniques, we will show the reader how to use productive criticism to increase job performance and satisfaction.

  13. Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury.

    PubMed

    Yan, Xiao-Ge; Cheng, Bao-Hua; Wang, Xin; Ding, Liang-Cai; Liu, Hai-Qing; Chen, Jing; Bai, Bo

    2015-05-01

    Apelin-13 inhibits neuronal apoptosis caused by hydrogen peroxide, yet apoptosis following cerebral ischemia-reperfusion injury has rarely been studied. In this study, Apelin-13 (0.1 μg/g) was injected into the lateral ventricle of middle cerebral artery occlusion model rats. TTC, TUNEL, and immunohistochemical staining showed that compared with the cerebral ischemia/reperfusion group, infarct volume and apoptotic cell number at the ischemic penumbra region were decreased in the Apelin-13 treatment group. Additionally, Apelin-13 treatment increased Bcl-2 immunoreactivity and decreased caspase-3 immunoreactivity. Our findings suggest that Apelin-13 is neuroprotective against cerebral ischemia/reperfusion injury through inhibition of neuronal apoptosis.

  14. [The comparative efficacy of emoxipine and sodium oxybutyrate in experimental myocardial ischemia].

    PubMed

    Afanas'ev, S A; Alekseeva, E D; Bardamova, I B; Bogomaz, S A

    1994-01-01

    The efficacy of emoxypine (2-ethyl-6-methyl-3-hydroxypyridine chlorohydrate) versus sodium hydroxybutyrate in total and local ischemia followed by reperfusion was studied in the experiments on rat isolated hearts. Emoxypine in a dose of 1 nM in total ischemia was shown to have a protective action, by decreasing reperfusion contracture. In local ischemia, emoxypine, unlike sodium hydroxybutyrate, did not favour greater restoration of the amplitude of isolated heart contractions, but restored coronary flow and stabilized contraction frequency better than did sodium hydroxybutyrate.

  15. Intracranial dermoid cyst rupture-related brain ischemia

    PubMed Central

    Jin, Hang; Guo, Zhen-Ni; Luo, Yun; Zhao, Ren; Sun, Ming-Shuo; Yang, Yi

    2017-01-01

    Abstract Rationale: Spontaneous rupture of intracranial dermoid cyst is a rare but serious clinical event that can result in cerebral ischemia. Cerebral vasospasm and vasculitis are considered as potential mechanisms of dermoid cyst rupture-related cerebral ischemia. However, the hemodynamic mechanisms between cerebral ischemia and dermoid cyst rupture are not well known. Patient concerns: A 55-year-old, right-handed man was admitted to our hospital with sudden receptive aphasia and right-sided hypoalgesia. Brain magnetic resonance imaging (MRI) revealed a ruptured dermoid cyst and watershed infarcts in the left hemisphere. Then brain magnetic resonance angiography disclosed mild stenosis in the left middle cerebral artery (MCA), and further high-resolution MRI demonstrated it was caused by an unstable atherosclerosis plaque. Transcranial Doppler of the patient showed a decreasing tendency of peak systolic velocity (PSV) of the left MCA at different time points after the stroke (from 290cm/s at day 6 to 120cm/s at day 30), indicating a transient vasospasm. However, the time course of dynamic cerebral autoregulation (dCA) seemed different from the PSV. The patient's dCA reached its lowest point at day 8 and was restored at day 10. The time course of dCA indicated a “called procedure” of a cerebrovascular regulating function to deal with the stimulation in subarachnoid space. Diagnoses: A dermoid cyst rupture-related cerebral infarction was diagnosed in this patient. Interventions: Aspirin (100 mg/d) and atorvastatin (20 mg/d) were given to the patient. A neurosurgical operation was strongly recommended to minimize the risk of further injury of the ruptured dermoid cyst; however, the patient refused the recommended treatment. Outcomes: The neurological deficit of the patient was significantly improved on 30 days follow-up. Lessons: We found that the spread of cyst contents through the subarachnoid and/or ventricular system can induce a vasospasm. Then, dCA was

  16. Effects of hypothermia on skeletal ischemia reperfusion injury in rats

    PubMed Central

    Kaldırım, Ümit; Akyıldız, Faruk; Bilgiç, Serkan; Koca, Kenan; Poyrazoğlu, Yavuz; Uysal, Ozgür Selim; Turğut, Hasan; Türkkan, Selim; Erşen, Ömer; Topal, Turgut; Ozkan, Huseyin

    2015-01-01

    Objective The aim of this study was to investigate the effect of hypothermia (H) on skeletal ischemia-reperfusion (IR) injury in rats by measuring malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), nitric oxide (NO), and interleukin-1 beta (IL-1β) in muscle, and measureing immunohistochemical-inducible nitric oxide synthase (iNOS) staining of skeletal muscle. Materials and Methods Eighteen Wistar Albino rats were divided randomly into three groups (sham, IR, hypothermia) (n=6). The sham group had all procedures without the IR period. The lower right extremity of rats in the IR and hypothermia groups was subjected to 2 hours of ischemia and 22 hours of reperfusion by applying a clamp on the common iliac artery and a rubber-band at the level of the lesser trochanter under general anesthesia. Rats in the hypothermia group underwent 4 hours of hypothermia during the first four hours of reperfusion in addition to a 2-hour ischemia and 22-hour reperfusion period. All rats were sacrificed at end of the IR period using a high dose of anesthesia. The tibialis anterior muscles were preserved. Immunohistochemical iNOS staining was performed, and MDA, SOD, GSH-Px, NO, and IL-1β were measured in the muscle. Results The level of MDA, NO, and IL-1β in muscle was increased in the IR group compared with that in the sham group, but these parameters were decreased in the hypothermia group compared with the IR group. The activities of SOD and GSH-Px in muscle were decreased in the IR group; however, these parameters were increased in the hypothermia group. The score and intensity of iNOS staining of skeletal muscle was dens in IR group, mild in hypothermia group, and weak in sham group. Conclusion The present study has shown that hypothermia reduced IR injury in the skeletal muscle by decreasing the levels of MDA, NO, and IL-1β, and increasing the activities of SOD and GSH-Px. In addition, hypothermia attenuated the score and intensity of i

  17. Diosmin Protects Rat Retina from Ischemia/Reperfusion Injury

    PubMed Central

    Tong, Nianting; Zhang, Zhenzhen; Gong, Yuanyuan; Yin, Lili

    2012-01-01

    Abstract Objective Diosmin, a natural flavone glycoside, possesses antioxidant activity and has been used to alleviate ischemia/reperfusion (I/R) injury. The aim of this study was to clarify whether the administration of diosmin has a protective effect against I/R injury induced using the high intraocular pressure (IOP) model in rat retina, and to determine the possible antioxidant mechanisms involved. Methods Retinal I/R injury was induced in the rats by elevating the IOP to 110 mmHg for 60 min. Diosmin (100 mg/kg) or vehicle solution was administered intragastrically 30 min before the onset of ischemia and then daily after I/R injury until the animals were sacrificed. The levels of malondialdehyde (MDA) and the activities of total-superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in the retinal tissues were determined 24 h after I/R injury. At 7 days post-I/R injury, electroretinograms (ERGs) were recorded, and the density of surviving retinal ganglion cells (RGCs) was estimated by counting retrograde tracer-labeled cells in whole-mounted retinas. Retinal histological changes were also examined and quantified using light microscopy. Results Diosmin significantly decreased the MDA levels and increased the activities of T-SOD, GSH-Px, and CAT in the retina of rats compared with the ischemia group (P<0.05), and suppressed the I/R-induced reduction in the a- and b-wave amplitudes of the ERG (P<0.05). The thickness of the entire retina, inner nuclear layer, inner plexiform layer, and outer retinal layer and the number of cells in the ganglion cell layer were significantly less after I/R injury (P<0.05), and diosmin remarkably ameliorated these changes on retinal morphology. Diosmin also attenuated the I/R-induced loss of RGCs of the rat retina (P<0.05). Conclusion Diosmin protected the retina from I/R injury, possibly via a mechanism involving the regulation of oxidative parameters. PMID:22509733

  18. The protective effect of cilostazol on isolated rabbit femoral arteries under conditions of ischemia and reperfusion: the role of the nitric oxide pathway

    PubMed Central

    Santos, Mariana R.G.A.; Celotto, Andréa C; Capellini, Verena K; Evora, Paulo R B; Piccinato, Carlos E; Joviliano, Edwaldo E

    2012-01-01

    OBJECTIVES: The clinical significance of ischemia/reperfusion of the lower extremities demands further investigation to enable the development of more effective therapeutic alternatives. This study investigated the changes in the vascular reactivity of the rabbit femoral artery and nitric oxide metabolites under partial ischemia/reperfusion conditions following cilostazol administration. METHODS: Ischemia was induced using infrarenal aortic clamping. The animals were randomly divided into seven groups: Control 90 minutes, Ischemia/Reperfusion 90/60 minutes, Control 120 minutes, Ischemia/Reperfusion 120/90 minutes, Cilostazol, Cilostazol before Ischemia/Reperfusion 120/90 minutes, and Ischemia 120 minutes/Cilostazol/Reperfusion 90 minutes. Dose-response curves for sodium nitroprusside, acetylcholine, and the calcium ionophore A23187 were obtained in isolated femoral arteries. The levels of nitrites and nitrates in the plasma and skeletal muscle were determined using chemiluminescence. RESULTS: Acetylcholine- and A23187-induced relaxation was reduced in the Ischemia/Reperfusion 120/90 group, and treatment with cilostazol partially prevented this ischemia/reperfusion-induced endothelium impairment. Only cilostazol treatment increased plasma levels of nitrites and nitrates. An elevation in the levels of nitrites and nitrates was observed in muscle tissues in the Ischemia/Reperfusion 120/90, Cilostazol/Ischemia/Reperfusion, and Ischemia/Cilostazol/Reperfusion groups. CONCLUSION: Hind limb ischemia/reperfusion yielded an impaired endothelium-dependent relaxation of the femoral artery. Furthermore, cilostazol administration prior to ischemia exerted a protective effect on endothelium-dependent vascular reactivity under ischemia/reperfusion conditions. PMID:22358243

  19. Critical Thinking Skills.

    ERIC Educational Resources Information Center

    Word's Worth: A Quarterly Newsletter of the Lifelong Learning Network, 1998

    1998-01-01

    This issue of a quarterly newsletter focuses on the theme of critical thinking skills. "Critical Thinking Skills: An Interview with Dr. Richard Paul" (Barbara Christopher) is the text of an interview in which the director of research at Sonoma State University's Center for Critical Thinking examines the meaning of critical thinking and…

  20. A Critical Humanist Curriculum

    ERIC Educational Resources Information Center

    Magill, Kevin; Rodriguez, Arturo

    2015-01-01

    This essay is a critical humanist discussion of curriculum; a departure from the technicist view of education [education meant to support a global capitalist economy] and an analysis of curriculum considering critical humanism, political economy and critical race theory among other modes of critical analysis and inquiry. Our discussion supports a…

  1. Role of Hydrogen Sulfide in Ischemia-Reperfusion Injury

    PubMed Central

    Wu, Dongdong; Wang, Jun; Li, Hui; Xue, Mengzhou; Ji, Ailing; Li, Yanzhang

    2015-01-01

    Ischemia-reperfusion (I/R) injury is one of the major causes of high morbidity, disability, and mortality in the world. I/R injury remains a complicated and unresolved situation in clinical practice, especially in the field of solid organ transplantation. Hydrogen sulfide (H2S) is the third gaseous signaling molecule and plays a broad range of physiological and pathophysiological roles in mammals. H2S could protect against I/R injury in many organs and tissues, such as heart, liver, kidney, brain, intestine, stomach, hind-limb, lung, and retina. The goal of this review is to highlight recent findings regarding the role of H2S in I/R injury. In this review, we present the production and metabolism of H2S and further discuss the effect and mechanism of H2S in I/R injury. PMID:26064416

  2. Acute digital ischemia: A rare presentation of antisynthetase syndrome

    PubMed Central

    Chan, Jin Ei; Palakodeti, Sandeep; Koster, Matthew J.

    2017-01-01

    Antisynthetase syndrome (ASS) is recognized as a subgroup of idiopathic inflammatory myopathies (IIMs). It is associated with autoantibodies directed against aminoacyl-transfer ribonucleic acid (tRNA) synthetase enzymes. We report the first case of anti-PL-7/anti-SSA 52kD ASS presenting as acute digital ischemia, an association not described previously. Occlusive vasculopathy is a rare but serious manifestation that can be seen at presentation in patients with ASS and may herald the onset of severe interstitial lung disease (ILD). Comprehensive evaluation should be performed to confirm the presence of subclinical myositis. Extensive myositis-specific antibody testing is strongly recommended even if initial screening autoimmune serologies are unrevealing. PMID:28293456

  3. Transgenerational effects of neonatal hypoxia-ischemia in progeny.

    PubMed

    Infante, Smitha K; Rea, Harriett C; Perez-Polo, J R

    2013-10-01

    Neonatal hypoxia-ischemia (HI) affects 60% of low birth weight infants and up to 40% of preterm births. Cell death and brain injury after HI have been shown to cause long-lasting behavioral deficits. By using a battery of behavioral tests on second generation 3-week-old rodents, we found that neonatal HI is associated with behavioral outcomes in the progeny of HI-affected parents. Our results suggest an epigenetic transfer mechanism of some of the neurological symptoms associated with neonatal HI. Elucidating the transfer of brain injury to the next generation after HI calls attention to the risks associated with HI injury and the need for proper treatment to reverse these effects. Assessing the devastating extent of HI's reach serves as a cautionary tale to the risks associated with neonatal HI, and provides an incentive to create improved therapeutic measures to treat HI.

  4. Release of Adenosine and ATP During Ischemia and Epilepsy

    PubMed Central

    Dale, Nicholas; Frenguelli, Bruno G

    2009-01-01

    Eighty years ago Drury & Szent-Györgyi described the actions of adenosine, AMP (adenylic acid) and ATP (pyrophosphoric or diphosphoric ester of adenylic acid) on the mammalian cardiovascular system, skeletal muscle, intestinal and urinary systems. Since then considerable insight has been gleaned on the means by which these compounds act, not least of which in the distinction between the two broad classes of their respective receptors, with their many subtypes, and the ensuing diversity in cellular consequences their activation invokes. These myriad actions are of course predicated on the release of the purines into the extracellular milieu, but, surprisingly, there is still considerable ambiguity as to how this occurs in various physiological and pathophysiological conditions. In this review we summarise the release of ATP and adenosine during seizures and cerebral ischemia and discuss mechanisms by which the purines adenosine and ATP may be released from cells in the CNS under these conditions. PMID:20190959

  5. Acute digital ischemia: A rare presentation of antisynthetase syndrome.

    PubMed

    Chan, Jin Ei; Palakodeti, Sandeep; Koster, Matthew J

    2017-03-01

    Antisynthetase syndrome (ASS) is recognized as a subgroup of idiopathic inflammatory myopathies (IIMs). It is associated with autoantibodies directed against aminoacyl-transfer ribonucleic acid (tRNA) synthetase enzymes. We report the first case of anti-PL-7/anti-SSA 52kD ASS presenting as acute digital ischemia, an association not described previously. Occlusive vasculopathy is a rare but serious manifestation that can be seen at presentation in patients with ASS and may herald the onset of severe interstitial lung disease (ILD). Comprehensive evaluation should be performed to confirm the presence of subclinical myositis. Extensive myositis-specific antibody testing is strongly recommended even if initial screening autoimmune serologies are unrevealing.

  6. Alternative Interventions to Prevent Oxidative Damage following Ischemia/Reperfusion

    PubMed Central

    Rodríguez-Lara, Simón Quetzalcoatl; Ramírez-Lizardo, Ernesto Javier; Totsuka-Sutto, Sylvia Elena; Castillo-Romero, Araceli; García-Cobián, Teresa Arcelia

    2016-01-01

    Ischemia/reperfusion (I/R) lesions are a phenomenon that occurs in multiple pathological states and results in a series of events that end in irreparable damage that severely affects the recovery and health of patients. The principal therapeutic approaches include preconditioning, postconditioning, and remote ischemic preconditioning, which when used separately do not have a great impact on patient mortality or prognosis. Oxidative stress is known to contribute to the damage caused by I/R; however, there are no pharmacological approaches to limit or prevent this. Here, we explain the relationship between I/R and the oxidative stress process and describe some pharmacological options that may target oxidative stress-states. PMID:28116037

  7. Ergotism with ischemia in all four extremities: a case report.

    PubMed

    Jeong, Seok-Young; Lim, Eui-Seong; Shin, Byoung-Soo; Seo, Man-Wook; Kim, Young-Hyun; Kwak, Hyo-Sung; Chung, Gyung-Ho; Jeong, Seul-Ki

    2006-12-01

    Here we describe a case of ergotism that presented with ischemia in all four extremities. A 48-year-old man was admitted for pain and weakness in both upper extremities. He had a long history of migraine and had taken 3 mg of ergotamine daily for more than 21 years. Angiography demonstrated vasospasm involving all four extremities, which resolved partially following intra-arterial prostaglandin infusion. Intravenous nitroprusside was administered, and the patient stopped smoking and stopped taking ergotamine in an attempt to counteract the vasospasm. Follow-up computed tomography angiogram revealed that both brachial arteries had normalized. Thus, in this case of ergotism, severe vasospasm in all of the extremities was resolved with appropriate management.

  8. Management of delayed cerebral ischemia after subarachnoid hemorrhage.

    PubMed

    Francoeur, Charles L; Mayer, Stephan A

    2016-10-14

    For patients who survive the initial bleeding event of a ruptured brain aneurysm, delayed cerebral ischemia (DCI) is one of the most important causes of mortality and poor neurological outcome. New insights in the last decade have led to an important paradigm shift in the understanding of DCI pathogenesis. Large-vessel cerebral vasospasm has been challenged as the sole causal mechanism; new hypotheses now focus on the early brain injury, microcirculatory dysfunction, impaired autoregulation, and spreading depolarization. Prevention of DCI primarily relies on nimodipine administration and optimization of blood volume and cardiac performance. Neurological monitoring is essential for early DCI detection and intervention. Serial clinical examination combined with intermittent transcranial Doppler ultrasonography and CT angiography (with or without perfusion) is the most commonly used monitoring paradigm, and usually suffices in good grade patients. By contrast, poor grade patients (WFNS grades 4 and 5) require more advanced monitoring because stupor and coma reduce sensitivity to the effects of ischemia. Greater reliance on CT perfusion imaging, continuous electroencephalography, and invasive brain multimodality monitoring are potential strategies to improve situational awareness as it relates to detecting DCI. Pharmacologically-induced hypertension combined with volume is the established first-line therapy for DCI; a good clinical response with reversal of the presenting deficit occurs in 70 % of patients. Medically refractory DCI, defined as failure to respond adequately to these measures, should trigger step-wise escalation of rescue therapy. Level 1 rescue therapy consists of cardiac output optimization, hemoglobin optimization, and endovascular intervention, including angioplasty and intra-arterial vasodilator infusion. In highly refractory cases, level 2 rescue therapies are also considered, none of which have been validated. This review provides an overview of

  9. Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy.

    PubMed

    Martin, Elizabeth A; Barresi, Rita; Byrne, Barry J; Tsimerinov, Evgeny I; Scott, Bryan L; Walker, Ashley E; Gurudevan, Swaminatha V; Anene, Francine; Elashoff, Robert M; Thomas, Gail D; Victor, Ronald G

    2012-11-28

    Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin's rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived NO attenuates local α-adrenergic vasoconstriction, thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective-causing functional muscle ischemia-in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. We report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled crossover trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation is fully restored in the muscles of men with BMD by boosting NO-cGMP (guanosine 3',5'-monophosphate) signaling with a single dose of the drug tadalafil, a phosphodiesterase 5A inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD.

  10. Arginase 2 promotes neurovascular degeneration during ischemia/reperfusion injury

    PubMed Central

    Shosha, Esraa; Xu, Zhimin; Yokota, Harumasa; Saul, Alan; Rojas, Modesto; Caldwell, R William; Caldwell, Ruth B; Narayanan, S Priya

    2016-01-01

    Retinal ischemia is a major cause of visual impairment and blindness and is involved in various disorders including diabetic retinopathy, glaucoma, optic neuropathies and retinopathy of prematurity. Neurovascular degeneration is a common feature of these pathologies. Our lab has previously reported that the ureahydrolase arginase 2 (A2) is involved in ischemic retinopathies. Here, we are introducing A2 as a therapeutic target to prevent neurovascular injury after retinal ischemia/reperfusion (I/R) insult. Studies were performed with mice lacking both copies of A2 (A2−/−) and wild-type (WT) controls (C57BL6J). I/R insult was conducted on the right eye and the left eye was used as control. Retinas were collected for analysis at different times (3 h–4 week after injury). Neuronal and microvascular degeneration were evaluated using NeuN staining and vascular digests, respectively. Glial activation was evaluated by glial fibrillary acidic protein expression. Necrotic cell death was studied by propidium iodide labeling and western blot for RIP-3. Arginase expression was determined by western blot and quantitative RT-PCR. Retinal function was determined by electroretinography (ERG). A2 mRNA and protein levels were increased in WT I/R. A2 deletion significantly reduced ganglion cell loss and microvascular degeneration and preserved retinal morphology after I/R. Glial activation, reactive oxygen species formation and cell death by necroptosis were significantly reduced by A2 deletion. ERG showed improved positive scotopic threshold response with A2 deletion. This study shows for the first time that neurovascular injury after retinal I/R is mediated through increased expression of A2. Deletion of A2 was found to be beneficial in reducing neurovascular degeneration after I/R. PMID:27882947

  11. Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons

    PubMed Central

    McClendon, Evelyn; Chen, Kevin; Gong, Xi; Sharifnia, Elica; Hagen, Matthew; Cai, Victor; Shaver, Daniel C.; Riddle, Art; Dean, Justin M.; Gunn, Alistair J.; Mohr, Claudia; Kaplan, Joshua S.; Rossi, David J.; Kroenke, Christopher D.; Hohimer, A. Roger; Back, Stephen A.

    2014-01-01

    Objective Recently we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry and Golgi staining defined CN growth, cell death, proliferation and dendritic maturation in preterm fetal sheep four weeks after HI. Patch-clamping recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Neither was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity. PMID:24395459

  12. Ellagic acid ameliorates lung injury after intestinal ischemia-reperfusion

    PubMed Central

    Böyük, Abdullah; Önder, Akin; Kapan, Murat; Gümüş, Metehan; Fιrat, Uğur; Başaralι, Mustafa Kemal; Alp, Harun

    2011-01-01

    Background: The aim of this study was to investigate the possible protective role of antioxidant treatment with ellagic acid (EA) on lung injury after intestinal ischemia-reperfusion (I/R) injury using biochemical and histopatological approaches. Materials and Methods: Forty rats were divided into four groups as control, control + EA, I/R, and I/R + EA. The control and control + EA groups were also anesthetized and subjected to laparotomy, but without clamp application. The control + EA and I/R + EA groups were given EA (85 mg/kg) orally prior to experiment. The I/R and I/R + EA groups underwent 30 minutes of intestinal ischemia and 1 hour of reperfusion. In all groups, serum total antioxidant capacity (TAC) and malondialdehyde (MDA) levels were determined. TAC, total oxidative status (TOS), and oxidative stress index (OSI) in lung tissue were measured. Lung tissue histopathology was also evaluated by light microscopy. Results: TAC levels were higher in control, EA, and I/R + EA groups while TOS, OSI, and MDA levels were lower in these groups compared with I/R group. Serum MDA levels were significantly higher in I/R + EA group than that of control group. Lung tissue TAC levels were lower in I/R + EA group while OSI values were higher in that groups compared with EA group. Histological tissue damage was milder in the EA treatment group than in the I/R group. Conclusion: These results suggest that EA treatment protected the rats lung tissue against intestinal I/R injury. PMID:21969793

  13. Revalorizing the Critical Attitude for Critical Education

    ERIC Educational Resources Information Center

    Amsler, Sarah S.

    2011-01-01

    This article argues that at a moment of crisis in education, the defence of critical pedagogy is vitally important. However, it also suggests that such a defence should be more than a "cri de coeur" that asserts principles and methods of criticality against those of neoliberal or conservative education policy. Narratives of a totalising "crisis of…

  14. Vasoconstrictor prostanoids may be involved in reduced coronary reactive hyperemia after ischemia-reperfusion in anesthetized goats.

    PubMed

    Climent, Belén; Fernández, Nuria; Sánchez, Ana; García-Villalón, Angel-Luis; Monge, Luis; Diéguez, Godofredo

    2006-01-20

    To examine coronary vasodilator reserve after ischemia-reperfusion, reactive hyperemia was determined during reperfusion after partial and total, brief and prolonged ischemia. To this, left circumflex coronary artery flow was electromagnetically measured, and partial (60 min) or total (15 and 60 min) occlusions of this artery were induced, followed in each case by 60-min reperfusion in anesthetized goats untreated and treated with N(W)-nitro-l-arginine methyl ester (l-NAME) or meclofenamate. In untreated and treated animals, coronary flow was decreased during reperfusion after the three types of ischemia. In hyperemic responses to 5- and 10-s coronary occlusions, repayment of debt decreased during reperfusion after the three types of ischemia in untreated animals, and this decrease was not affected by l-NAME. This decrease during reperfusion after partial and total, 60-min ischemia, but not after total, 15-min ischemia, reversed with meclofenamate. Peak hyperemic flow/control flow ratio decreased only during reperfusion after total 60-min occlusion in untreated animals and it was normalized by meclofenamate. These results show that ischemia-reperfusion reduces hyperemic response (vasodilator reserve); this diminution being dependent on duration and severity of ischemia. The hyperemic responses reduction during reperfusion after prolonged ischemia, but not after brief ischemia may be related at least in part to increased production of vasoconstrictor prostanoids.

  15. Being Critical of Criticality in the Brain

    PubMed Central

    Beggs, John M.; Timme, Nicholas

    2012-01-01

    Relatively recent work has reported that networks of neurons can produce avalanches of activity whose sizes follow a power law distribution. This suggests that these networks may be operating near a critical point, poised between a phase where activity rapidly dies out and a phase where activity is amplified over time. The hypothesis that the electrical activity of neural networks in the brain is critical is potentially important, as many simulations suggest that information processing functions would be optimized at the critical point. This hypothesis, however, is still controversial. Here we will explain the concept of criticality and review the substantial objections to the criticality hypothesis raised by skeptics. Points and counter points are presented in dialog form. PMID:22701101

  16. Monocarboxylate transporter 4 plays a significant role in the neuroprotective mechanism of ischemic preconditioning in transient cerebral ischemia

    PubMed Central

    Hong, Seongkweon; Ahn, Ji Yun; Cho, Geum-Sil; Kim, In Hye; Cho, Jeong Hwi; Ahn, Ji Hyeon; Park, Joon Ha; Won, Moo-Ho; Chen, Bai Hui; Shin, Bich-Na; Tae, Hyun-Jin; Park, Seung Min; Cho, Jun Hwi; Choi, Soo Young; Lee, Jae-Chul

    2015-01-01

    Monocarboxylate transporters (MCTs), which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ischemic preconditioning (IPC) on MCT4 immunoreactivity after 5 minutes of transient cerebral ischemia in the gerbil. Animals were randomly designated to four groups (sham-operated group, ischemia only group, IPC + sham-operated group and IPC + ischemia group). A serious loss of neuron was found in the stratum pyramidale of the hippocampal CA1 region (CA1), not CA2/3, of the ischemia-only group at 5 days post-ischemia; however, in the IPC + ischemia groups, neurons in the stratum pyramidale of the CA1 were well protected. Weak MCT4 immunoreactivity was found in the stratum pyramidale of the CA1 in the sham-operated group. MCT4 immunoreactivity in the stratum pyramidale began to decrease at 2 days post-ischemia and was hardly detected at 5 days post-ischemia; at this time point, MCT4 immunoreactivity was newly expressed in astrocytes. In the IPC + sham-operated group, MCT4 immunoreactivity in the stratum pyramidale of the CA1 was increased compared with the sham-operated group, and, in the IPC + ischemia group, MCT4 immunoreactivity was also increased in the stratum pyramidale compared with the ischemia only group. Briefly, present findings show that IPC apparently protected CA1 pyramidal neurons and increased or maintained MCT4 expression in the stratum pyramidale of the CA1 after transient cerebral ischemia. Our findings suggest that MCT4 appears to play a significant role in the neuroprotective mechanism of IPC in the gerbil with transient cerebral ischemia. PMID:26692857

  17. Antioxidant Vitamins and Trace Elements in Critical Illness.

    PubMed

    Koekkoek, W A C Kristine; van Zanten, Arthur R H

    2016-08-01

    This comprehensive narrative review summarizes relevant antioxidant mechanisms, the antioxidant status, and effects of supplementation in critically ill patients for the most studied antioxidant vitamins A, C, and E and the enzyme cofactor trace elements selenium and zinc. Over the past 15 years, oxidative stress-mediated cell damage has been recognized to be fundamental to the pathophysiology of various critical illnesses such as acute respiratory distress syndrome, ischemia-reperfusion injury, and multiorgan dysfunction in sepsis. Related to these conditions, low plasma levels of antioxidant enzymes, vitamins, and trace elements have been frequently reported, and thus supplementation seems logical. However, low antioxidant plasma levels per se may not indicate low total body stores as critical illness may induce redistribution of antioxidants. Furthermore, low antioxidant levels may even be beneficial as pro-oxidants are essential in bacterial killing. The reviewed studies in critically ill patients show conflicting results. This may be due to different patient populations, study designs, timing, dosing regimens, and duration of the intervention and outcome measures evaluated. Therefore, at present, it remains unclear whether supplementation of antioxidant micronutrients has any clinical benefit in critically ill patients as some studies show clear benefits, whereas others demonstrate neutral outcomes and even harm. Combination therapy of antioxidants seems logical as they work in synergy and function as elements of the human antioxidant network. Further research should focus on defining the normal antioxidant status for critically ill patients and to study optimal supplement combinations either by nutrition enrichment or by enteral or parenteral pharmacological interventions.

  18. 3-N-butylphthalide improves neuronal morphology after chronic cerebral ischemia