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Sample records for hind limb ischemia

  1. Treatment of hind limb ischemia using angiogenic peptide nanofibers.

    PubMed

    Kumar, Vivek A; Liu, Qi; Wickremasinghe, Navindee C; Shi, Siyu; Cornwright, Toya T; Deng, Yuxiao; Azares, Alon; Moore, Amanda N; Acevedo-Jake, Amanda M; Agudo, Noel R; Pan, Su; Woodside, Darren G; Vanderslice, Peter; Willerson, James T; Dixon, Richard A; Hartgerink, Jeffrey D

    2016-08-01

    For a proangiogenic therapy to be successful, it must promote the development of mature vasculature for rapid reperfusion of ischemic tissue. Whole growth factor, stem cell, and gene therapies have yet to achieve the clinical success needed to become FDA-approved revascularization therapies. Herein, we characterize a biodegradable peptide-based scaffold engineered to mimic VEGF and self-assemble into a nanofibrous, thixotropic hydrogel, SLanc. We found that this injectable hydrogel was rapidly infiltrated by host cells and could be degraded while promoting the generation of neovessels. In mice with induced hind limb ischemia, this synthetic peptide scaffold promoted angiogenesis and ischemic tissue recovery, as shown by Doppler-quantified limb perfusion and a treadmill endurance test. Thirteen-month-old mice showed significant recovery within 7 days of treatment. Biodistribution studies in healthy mice showed that the hydrogel is safe when administered intramuscularly, subcutaneously, or intravenously. These preclinical studies help establish the efficacy of this treatment for peripheral artery disease due to diminished microvascular perfusion, a necessary step before clinical translation. This peptide-based approach eliminates the need for cell transplantation or viral gene transfection (therapies currently being assessed in clinical trials) and could be a more effective regenerative medicine approach to microvascular tissue engineering.

  2. Therapeutic effect of human adipose-derived stromal cells cluster in rat hind-limb ischemia.

    PubMed

    Park, In-Su; Kang, Jo A; Kang, Jungmi; Rhie, Jong-Won; Kim, Sang-Heon

    2014-12-01

    We investigated whether transplantation of three-dimensional cell masses (3DCM) of human adipose-derived stromal cells (hASCs) cultured on a basic fibroblast growth factor-immobilized substrate improved hind limb functional recovery by stimulating angiogenesis in an immune-competent rat ischemic limb model. In vitro experiments confirmed that cells within 3DCMs differentiate toward the endothelial lineage one day after culture in normal medium. The therapeutic effect of 3DCMs was evaluated by transplanting hASCs, phosphate-buffered saline alone, and the 3DCM into rat ischemic hind limbs. Blood flow was enhanced in the ischemic hind limb in the 3DCM-injected group compared with the other groups. The ratio of human nuclear antigen (HNA) and hVEGF-positive cells was significantly higher in the 3DCM-injected group compared to hASC-injected group. Human VEGF was observed in most HNA-positive cells. Many hCD31 and hSMA-positive cells were observed in vessel-like structures in the 3DCM-injected group. The 3DCM transplantation improved cell retention and angiogenic effects compared with ASC transplantation. These findings suggest that transplantation of 3DCMs may be an effective stem cell therapy for hind limb ischemia.

  3. Imaging receptor for advanced glycation end product expression in mouse model of hind limb ischemia

    PubMed Central

    2013-01-01

    Background The purpose of this study is to image the effect of diabetes on expression of receptor for advanced glycation endproducts (RAGE) in limb ischemia in live animals. Methods Male wild-type C57BL/6 mice were either made diabetic or left as control. Two months later, diabetic and non-diabetic mice underwent left femoral artery ligation. The right leg served as lesion control. Five days later, mice were injected with 15.1 ± 4.4 MBq 99mTc-anti-RAGE F(ab’)2 and 4 to 5 h later (blood pool clearance) underwent SPECT/CT imaging. At the completion of imaging, mice were euthanized, hind limbs counted and sectioned, and scans reconstructed. Regions of interest were drawn on serial transverse sections comprising the hind limbs and activity in millicuries summed and divided by the injected dose (ID). Quantitative histology was performed for RAGE staining and angiogenesis. Results Uptake of 99mTc-anti-RAGE F(ab')2 as %ID × 10−3 was higher in the left (ischemic) limbs for the diabetic mice (n = 8) compared to non-diabetic mice (n = 8) (1.20 ± 0.44% vs. 0.49 ± 0.40%; P = 0.0007) and corresponded to less angiogenesis in the diabetic mice. Uptake was also higher in the right limbs of diabetic compared to non-diabetic animals (0.82 ± 0.33% vs. 0.40 ± 0.14%; P = 0.0004). Conclusions These data show the feasibility of imaging and quantifying the effect of diabetes on RAGE expression in limb ischemia. PMID:23663412

  4. P2Y2 nucleotide receptor mediates arteriogenesis in a murine model of hind limb ischemia.

    PubMed

    McEnaney, Ryan M; Shukla, Ankur; Madigan, Michael C; Sachdev, Ulka; Tzeng, Edith

    2016-01-01

    Arteriogenesis represents the maturation of preformed vascular connections in response to flow changes and shear stress. These collateral vessels can restore up to 60% of the native blood flow. Shear stress and vascular injury can induce the release of nucleotides from vascular smooth muscle cells and platelets that can serve as signaling ligands, suggesting they may be involved in mediating arteriogenesis. The P2Y2 nucleotide receptor (P2Y2R) has also been shown to mediate smooth muscle migration and arterial remodeling. Thus, we hypothesize that P2Y2R mediates arteriogenesis in response to ischemia. Hind limb ischemia was induced by femoral artery ligation (FAL) in C57Bl/6NJ or P2Y2R negative mice (P2Y2(-/-)). Hind limb perfusion was measured with laser Doppler perfusion imaging and compared with the sham-operated contralateral limb immediately and at 3, 7, 14, 21, and 28 days after ligation. Collateral vessel size was measured by Microfil casting. Muscle specimens were harvested and analyzed with immunohistochemistry for Ki67, vascular cell adhesion molecule, macrophages, and muscle viability by hematoxylin and essoin stain. Hind limb ischemia induced by FAL in C57Bl/6NJ mice resulted in significant ischemia as measured by laser Doppler perfusion imaging. There was rapid recovery to nearly normal levels of perfusion by 2 weeks. FAL in P2Y2(-/-) mice resulted in severe ischemia with greater tissue loss. Recovery of perfusion was impaired, achieving only 40% compared with wild-type mice by 28 days. Collateral vessels in the P2Y2(-/-) mice were underdeveloped, with reduced vascular cell proliferation and smaller vessel size. The collaterals were ∼65% the size of wild-type collateral vessels (P = .011). Angiogenesis at 28 days in the ischemic muscle, however, was greater in the P2Y2(-/-) mice (P < .001), possibly related to persistent ischemia leading and angiogenic drive. Early macrophage recruitment was reduced by nearly 70% in P2Y2(-/-) despite significantly

  5. p66(ShcA) and oxidative stress modulate myogenic differentiation and skeletal muscle regeneration after hind limb ischemia.

    PubMed

    Zaccagnini, Germana; Martelli, Fabio; Magenta, Alessandra; Cencioni, Chiara; Fasanaro, Pasquale; Nicoletti, Carmine; Biglioli, Paolo; Pelicci, Pier Giuseppe; Capogrossi, Maurizio C

    2007-10-26

    Oxidative stress plays a pivotal role in ischemic injury, and p66(ShcA)ko mice exhibit both lower oxidative stress and decreased tissue damage following hind limb ischemia. Thus, it was investigated whether tissue regeneration following acute hind limb ischemia was altered in p66(ShcA)ko mice. Upon femoral artery dissection, muscle regeneration started earlier and was completed faster than in wild-type (WT) control. Moreover, faster regeneration was associated with decreased oxidative stress. Unlike ischemia, cardiotoxin injury induced similar skeletal muscle damage in both genotypes. However, p66(ShcA)ko mice regenerated faster, in agreement with the regenerative advantage upon ischemia. Since no difference between p66(ShcA)wt and knock-out (ko) mice was found in blood perfusion recovery after ischemia, satellite cells (SCs), a resident population of myogenic progenitors, were examined. Similar SCs numbers were present in WT and ko mice. However, in vitro cultured p66(ShcA)ko SCs displayed lower oxidative stress levels and higher proliferation rate and differentiated faster than WT. Furthermore, when exposed to sublethal H(2)O(2) doses, p66(ShcA)ko SCs were resistant to H(2)O(2)-induced inhibition of differentiation. Finally, myogenic conversion induced by MyoD overexpression was more efficient in p66(ShcA)ko fibroblasts compared with WT. The present work demonstrates that oxidative stress and p66(ShcA) play a crucial role in the regenerative pathways activated by acute ischemia.

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

    PubMed

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

    2017-10-01

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

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

    PubMed

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

    2013-08-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2016-06-01

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

  10. 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

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

    PubMed

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

    2014-01-01

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

  12. Fucoidan improves bioactivity and vasculogenic potential of mesenchymal stem cells in murine hind limb ischemia associated with chronic kidney disease.

    PubMed

    Lee, Jun Hee; Ryu, Jung Min; Han, Yong-Seok; Zia, Mohammad Farid; Kwon, Hyog Young; Noh, Hyunjin; Han, Ho Jae; Lee, Sang Hun

    2016-08-01

    Chronic kidney disease (CKD) is a significant risk factor for cardiovascular and peripheral vascular disease. Although mesenchymal stem cell (MSC)-based therapy is a promising strategy for treatment of ischemic diseases associated with CKD, the associated pathophysiological conditions lead to low survival and proliferation of transplanted MSCs. To address these limitations, we investigated the effects of fucoidan, a sulfated polysaccharide, on the bioactivity of adipose tissue-derived MSCs and the potential of fucoidan-treated MSCs to improve neovascularization in ischemic tissues of CKD mice. Treatment of MSCs with fucoidan increased their proliferative potential and the expression of cell cycle-associated proteins, such as cyclin E, cyclin dependent kinase (CDK) 2, cyclin D1, and CDK4, via focal adhesion kinase and the phosphatidylinositol-4,5-bisphosphate 3-kinase-Akt axis. Moreover, fucoidan enhanced the immunomodulatory activity of MSCs through the ERK-IDO-1 signal cascade. Fucoidan was found to augment the proliferation, incorporation, and endothelial differentiation of transplanted MSCs at ischemic sites in CKD mice hind limbs. In addition, transplantation of fucoidan-treated MSCs enhanced the ratio of blood flow and limb salvage in CKD mice with hind limb ischemia. To our knowledge, our findings are the first to reveal that fucoidan enhances the bioactivity of MSCs and improves their neovascularization in ischemic injured tissues of CKD. In conclusion, fucoidan-treated MSCs may provide an important pathway toward therapeutic neovascularization in patients with CKD.

  13. TLR4 Accessory Molecule RP105 (CD180) Regulates Monocyte-Driven Arteriogenesis in a Murine Hind Limb Ischemia Model

    PubMed Central

    Bastiaansen, Antonius J. N. M.; Karper, Jacco C.; Wezel, Anouk; de Boer, Hetty C.; Welten, Sabine M. J.; de Jong, Rob C. M.; Peters, Erna A. B.; de Vries, Margreet R.; van Oeveren-Rietdijk, Annemarie M.; van Zonneveld, Anton Jan; Hamming, Jaap F.

    2014-01-01

    Aims We investigated the role of the TLR4-accessory molecule RP105 (CD180) in post-ischemic neovascularization, i.e. arteriogenesis and angiogenesis. TLR4-mediated activation of pro-inflammatory Ly6Chi monocytes is crucial for effective neovascularization. Immunohistochemical analyses revealed that RP105+ monocytes are present in the perivascular space of remodeling collateral arterioles. As RP105 inhibits TLR4 signaling, we hypothesized that RP105 deficiency would lead to an unrestrained TLR4-mediated inflammatory response and hence to enhanced blood flow recovery after ischemia. Methods and Results RP105−/− and wild type (WT) mice were subjected to hind limb ischemia and blood flow recovery was followed by Laser Doppler Perfusion Imaging. Surprisingly, we found that blood flow recovery was severely impaired in RP105−/− mice. Immunohistochemistry showed that arteriogenesis was reduced in these mice compared to the WT. However, both in vivo and ex vivo analyses showed that circulatory pro-arteriogenic Ly6Chi monocytes were more readily activated in RP105−/− mice. FACS analyses showed that Ly6Chi monocytes became activated and migrated to the affected muscle tissues in WT mice following induction of hind limb ischemia. Although Ly6Chi monocytes were readily activated in RP105−/− mice, migration into the ischemic tissues was hampered and instead, Ly6Chi monocytes accumulated in their storage compartments, bone marrow and spleen, in RP105−/− mice. Conclusions RP105 deficiency results in an unrestrained inflammatory response and monocyte over-activation, most likely due to the lack of TLR4 regulation. Inappropriate, premature systemic activation of pro-inflammatory Ly6Chi monocytes results in reduced infiltration of Ly6Chi monocytes in ischemic tissues and in impaired blood flow recovery. PMID:24945347

  14. Low Energy Shock Wave Therapy Induces Angiogenesis in Acute Hind-Limb Ischemia via VEGF Receptor 2 Phosphorylation

    PubMed Central

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

    2014-01-01

    Objectives Low energy shock waves have been shown to induce angiogenesis, improve left ventricular ejection fraction and decrease angina symptoms in patients suffering from chronic ischemic heart disease. Whether there is as well an effect in acute ischemia was not yet investigated. Methods Hind-limb ischemia was induced in 10–12 weeks old male C57/Bl6 wild-type mice by excision of the left femoral artery. Animals were randomly divided in a treatment group (SWT, 300 shock waves at 0.1 mJ/mm2, 5 Hz) and untreated controls (CTR), n = 10 per group. The treatment group received shock wave therapy immediately after surgery. Results Higher gene expression and protein levels of angiogenic factors VEGF-A and PlGF, as well as their receptors Flt-1 and KDR have been found. This resulted in significantly more vessels per high-power field in SWT compared to controls. Improvement of blood perfusion in treatment animals was confirmed by laser Doppler perfusion imaging. Receptor tyrosine kinase profiler revealed significant phosphorylation of VEGF receptor 2 as an underlying mechanism of action. The effect of VEGF signaling was abolished upon incubation with a VEGFR2 inhibitor indicating that the effect is indeed VEGFR 2 dependent. Conclusions Low energy shock wave treatment induces angiogenesis in acute ischemia via VEGF receptor 2 stimulation and shows the same promising effects as known from chronic myocardial ischemia. It may therefore develop as an adjunct to the treatment armentarium of acute muscle ischemia in limbs and myocardium. PMID:25093816

  15. Effects of intravenous ibuprofen and lornoxicam on erythrocyte deformability in rats undergoing hind limb ischemia reperfusion injury.

    PubMed

    Sivgin, V; Kucuk, A; Comu, F M; Kosem, B; Kartal, S; Turgut, H C; Arpaci, H; Aydin, M E; Koc, D S; Ozer, A; Arslan, M; Alkan, M

    2016-01-01

    Acute hind limb ischemia reperfusion (I/R) injury is a common consequence of abdominal aorta cross‑clamping during aortic surgery. Erythrocyte deformability is affected by I/R process and may lead to increased tissue and organ injury. Lornoxicam and intravenous ibuprofen are becoming commonly used as non-steroidal anti-inflammatory drugs (NSAID) for postoperative analgesia. In this study, we aimed to investigate the effects of lornoxicam (2 mg/kg iv) and intravenous ibuprofen (30 mg/kg iv) on erythrocyte deformability in I/R model in rats. Four study groups, each containing 6 Wistar rats were created. Laparotomy was performed in all groups under general anesthesia with ketamine and xylazine. In all groups except sham group, ischemia and reperfusion were achieved by clamping and declamping the infrarenal abdominal aorta for 120 minutes. Rats in Group IR+L received intravenous infusion of lornoxicam (2 mg/kg) while rats in Group IR+I received intravenous infusion of ibubrofen (30 mg/kg) following 2 hours of ischemic period. At the end of reperfusion period, erythrocyte packs were prepared from heparinized blood samples. Erythrocyte suspensions with hematocrit at a concentration of 5% in a phosphate‑buffered saline (PBS) were used in order to perform deformability measurements. The value of p<0.05 was considered statistically significant. Relative resistance has increased in ischemia reperfusion group when compared to control group (p < 0.0001). Lornoxicam or ibuprofen intravenous treatments did not change the erythrocyte deformability during ischemia reperfusion period in rats (p=0.851, p=0.690). Intravenous ibuprofen or lornoxicam administrations during ischemia reperfusion period in rats have no negative effect on erythrocyte deformability. The findings of the study should be supported with more detailed and extensive clinical/experimental studies in the future (Fig. 1, Ref. 18).

  16. FACS-purified myoblasts producing controlled VEGF levels induce safe and stable angiogenesis in chronic hind limb ischemia.

    PubMed

    Wolff, Thomas; Mujagic, Edin; Gianni-Barrera, Roberto; Fueglistaler, Philipp; Helmrich, Uta; Misteli, Heidi; Gurke, Lorenz; Heberer, Michael; Banfi, Andrea

    2012-01-01

    We recently developed a method to control the in vivo distribution of vascular endothelial growth factor (VEGF) by high throughput Fluorescence-Activated Cell Sorting (FACS) purification of transduced progenitors such that they homogeneously express specific VEGF levels. Here we investigated the long-term safety of this method in chronic hind limb ischemia in nude rats. Primary myoblasts were transduced to co-express rat VEGF-A(164) (rVEGF) and truncated ratCD8a, the latter serving as a FACS-quantifiable surface marker. Based on the CD8 fluorescence of a reference clonal population, which expressed the desired VEGF level, cells producing similar VEGF levels were sorted from the primary population, which contained cells with very heterogeneous VEGF levels. One week after ischemia induction, 12 × 10(6) cells were implanted in the thigh muscles. Unsorted myoblasts caused angioma-like structures, whereas purified cells only induced normal capillaries that were stable after 3 months. Vessel density was doubled in engrafted areas, but only approximately 0.1% of muscle volume showed cell engraftment, explaining why no increase in total blood flow was observed. In conclusion, the use of FACS-purified myoblasts granted the cell-by-cell control of VEGF expression levels, which ensured long-term safety in a model of chronic ischemia. Based on these results, the total number of implanted cells required to achieve efficacy will need to be determined before a clinical application. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

  17. Effect of picroside II on erythrocyte deformability and lipid peroxidation in rats subjected to hind limb ischemia reperfusion injury

    PubMed Central

    Çomu, Faruk Metin; Kılıç, Yiğit; Özer, Abdullah; Kirişçi, Mehmet; Dursun, Ali Doğan; Tatar, Tolga; Zor, Mustafa Hakan; Kartal, Hakan; Küçük, Ayşegül; Boyunağa, Hakan; Arslan, Mustafa

    2016-01-01

    Background Ischemia reperfusion injury (I/R) in hind limb is a frequent and important clinical phenomenon. Many structural and functional damages are observed in cells and tissues in these kinds of injuries. In this study, we aimed to evaluate the effect of picroside II on lipid peroxidation and erythrocyte deformability during I/R in rats. Methods Rats were randomly divided into four groups – each containing six animals (sham, I/R, sham + picroside II, and I/R + picroside II). The infrarenal section of the abdominal aorta was occluded with an atraumatic microvascular clamp in I/R groups. The clamp was removed after 120 minutes and reperfusion was provided for a further 120 minutes. Picroside II (10 mg·kg−1) was administered intraperitoneally to the animals in the appropriate groups (sham + picroside II, I/R + picroside II groups). All rats were euthanized by intraperitoneal administration of ketamine (100 mg·kg−1) and taking blood from the abdominal aorta. Erythrocytes were extracted from heparinized complete blood samples. Buffer (PT) and then erythrocytes (PE) were passed through the filtration system and the changes in pressure were measured to investigate the role of serum malondialdehyde and nitric oxide (NO) in lipid peroxidation and erythrocyte deformability index. Results Deformability index was significantly increased in the I/R group compared to groups sham, sham + picroside-II, and I/R + picroside-II (P<0.0001, P<0.0001, and P=0.007). Malondialdehyde (MDA) and NO levels were evaluated. MDA level and NO activity were also higher in the I/R group than in the other groups. Picroside II treatment before hind limb I/R prevented these changes. Conclusion These results support that deformability of erythrocytes is decreased in I/R injury and picroside II plays a critical role to prevent these alterations. Further experimental and clinical studies are needed to evaluate and clarify the molecular mechanisms of action and clinical importance of these

  18. The Impact of Prophylactic Fasciotomy Following Porcine (Sus scrofa) Hind Limb Ischemia/Reperfusion Injury

    DTIC Science & Technology

    2012-03-23

    the 14-day survival period to calculate the composite physiologic model of recovery ( PMR ). Necropsy was performed for evaluation of nerve and...muscle histology. Results: In hemorrhage alone, according to the PMR the recovery was 94+/-28%, 63+/- 37% and 55+/-44% at 0, 3 and 6 hours of ischemia...hours. , , . v w and compared to baseline to create the Physiologic Model of Recovery ( PMR ). On day 14, necropsy was performed and

  19. Functional MMP-10 is required for efficient tissue repair after experimental hind limb ischemia.

    PubMed

    Gomez-Rodriguez, Violeta; Orbe, Josune; Martinez-Aguilar, Esther; Rodriguez, Jose A; Fernandez-Alonso, Leopoldo; Serneels, Jens; Bobadilla, Miriam; Perez-Ruiz, Ana; Collantes, Maria; Mazzone, Massimiliano; Paramo, Jose A; Roncal, Carmen

    2015-03-01

    We studied the role of matrix metalloproteinase-10 (MMP-10) during skeletal muscle repair after ischemia using a model of femoral artery excision in wild-type (WT) and MMP-10 deficient (Mmp10(-/-)) mice. Functional changes were analyzed by small animal positron emission tomography and tissue morphology by immunohistochemistry. Gene expression and protein analysis were used to study the molecular mechanisms governed by MMP-10 in hypoxia. Early after ischemia, MMP-10 deficiency resulted in delayed tissue reperfusion (10%, P < 0.01) and in increased necrosis (2-fold, P < 0.01), neutrophil (4-fold, P < 0.01), and macrophage (1.5-fold, P < 0.01) infiltration. These differences at early time points resulted in delayed myotube regeneration in Mmp10(-/-) soleus at later stages (regenerating myofibers: 30 ± 9% WT vs. 68 ± 10% Mmp10(-/-), P < 0.01). The injection of MMP-10 into Mmp10(-/-) mice rescued the observed phenotype. A molecular analysis revealed higher levels of Cxcl1 mRNA (10-fold, P < 0.05) and protein (30%) in the ischemic Mmp10(-/-) muscle resulting from a lack of transcriptional inhibition by MMP-10. This was further confirmed using siRNA against MMP-10 in vivo. Our results demonstrate an important role of MMP-10 for proper muscle repair after ischemia, and suggest that chemokine regulation such as Cxcl1 by MMP-10 is involved in muscle regeneration. © FASEB.

  20. Calcium-dependent signalling is essential during collateral growth in the pig hind limb-ischemia model.

    PubMed

    Troidl, C; Nef, H; Voss, S; Schilp, A; Kostin, S; Troidl, K; Szardien, S; Rolf, A; Schmitz-Rixen, T; Schaper, W; Hamm, C W; Elsässer, A; Möllmann, H

    2010-07-01

    We investigated the effect of pharmacological activation of the Ca(2+)-channel transient receptor potential cation channel, subfamily V, member 4 (TRPV4) on collateral growth in a pig hind limb-ischemia model thereby identifying subcellular mechanisms. Domestic pigs received femoral artery ligature and were randomly assigned to one of the following groups (each n=6): (1) 4alpha-phorbol 12,13-didecanoate (4alphaPDD) treatment; (2) treatment with an arterio-venous shunt (AV-shunt) distal to the occlusion; or (3) implantation of NaCl-filled minipump. Six sham-operated pigs acted as controls. Aortic and peripheral mean arterial pressure (MAP) measurements were performed to assess the collateral flow index (CFI). Tissue was isolated from M. quadriceps for immunohistochemistry and from isolated collateral arteries for quantitative real time PCR (qRT-PCR). Shortly after ligature the CFI dropped from 0.96+/-0.02 to 0.21+/-0.02 in all ligature-treated groups. In ligature-only-treated pigs CFI increased to 0.56+/-0.03 after 7days. Treatment with 4alphaPDD led to an enhancement of CFI compared with ligature alone (0.73+/-0.03). CD31-staining showed improved arteriolar density. Increased Ki67 staining in collaterals indicated proliferation. qRT-PCR and Western blot analysis showed upregulation or modulation of Ca(2+)-dependent transcription factors nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), Kv channel interacting protein 3, calsenilin (KCNIP3/CSEN/DREAM), and myocyte enhancer factor 2C (MEF2C) in 4alphaPDD- and AV-shunt-treated pigs compared with controls. Improved CFI after 4alphaPDD treatment identifies TRPV4 as an initial fluid shear-stress sensor and collateral remodelling and growth trigger. Subcellularly, modulation of Ca(2+)-dependent transcription factors indicates a pivotal role for Ca(2+)-signalling during arteriogenesis.

  1. Telomerase mediates vascular endothelial growth factor-dependent responsiveness in a rat model of hind limb ischemia.

    PubMed

    Zaccagnini, Germana; Gaetano, Carlo; Della Pietra, Linda; Nanni, Simona; Grasselli, Annalisa; Mangoni, Antonella; Benvenuto, Roberta; Fabrizi, Manuela; Truffa, Silvia; Germani, Antonia; Moretti, Fabiola; Pontecorvi, Alfredo; Sacchi, Ada; Bacchetti, Silvia; Capogrossi, Maurizio C; Farsetti, Antonella

    2005-04-15

    Telomere dysfunction contributes to reduced cell viability, altered differentiation, and impaired regenerative/proliferative responses. Recent advances indicate that telomerase activity confers a pro-angiogenic phenotype to endothelial cells and their precursors. We have investigated whether telomerase contributes to tissue regeneration following hind limb ischemia and vascular endothelial growth factor 165 (VEGF(165)) treatment. VEGF delivery induced angiogenesis and increased expression of the telomerase reverse transcriptase (TERT) and telomerase activity in skeletal muscles and satellite and endothelial cells. Adenovirus-mediated transfer of wild type TERT but not of a dominant negative mutant, TERTdn, significantly induced capillary but not arteriole formation. However, when co-delivered with VEGF, TERTdn abrogated VEGF-dependent angiogenesis, arteriogenesis, and blood flow increase. This effect was paralleled by in vitro evidence that telomerase inhibition by 3'-azido-3'-deoxythymidine in VEGF-treated endothelial cells strongly reduced capillary density and promoted apoptosis in the absence of serum. Similar results were obtained with adenovirus-mediated expression of TERTdn and AKTdn, both reducing endogenous TERT activity and angiogenesis on Matrigel. Mechanistically, neo-angiogenesis in our system involved: (i) VEGF-dependent activation of telomerase through the nitric oxide pathway and (ii) telomerase-dependent activation of endothelial cell differentiation and protection from apoptosis. Furthermore, detection of TERT in activated satellite cells identified them as VEGF targets during muscle regeneration. Because TERT behaves as an angiogenic factor and a downstream effector of VEGF signaling, telomerase activity appears required for VEGF-dependent remodeling of ischemic tissue at the capillaries and arterioles level.

  2. 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.

  3. Effects of N-acetylcysteine and pentoxifylline on remote lung injury in a rat model of hind-limb ischemia/reperfusion injury.

    PubMed

    Takhtfooladi, Hamed Ashrafzadeh; Hesaraki, Saeed; Razmara, Foad; Takhtfooladi, Mohammad Ashrafzadeh; Hajizadeh, Hadi

    2016-01-01

    To investigate the effects of N-acetylcysteine (NAC) and pentoxifylline in a model of remote organ injury after hind-limb ischemia/reperfusion (I/R) in rats, the lungs being the remote organ system. Thirty-five male Wistar rats were assigned to one of five conditions (n = 7/group), as follows: sham operation (control group); hind-limb ischemia, induced by clamping the left femoral artery, for 2 h, followed by 24 h of reperfusion (I/R group); and hind-limb ischemia, as above, followed by intraperitoneal injection (prior to reperfusion) of 150 mg/kg of NAC (I/R+NAC group), 40 mg/kg of pentoxifylline (I/R+PTX group), or both (I/R+NAC+PTX group). At the end of the trial, lung tissues were removed for histological analysis and assessment of oxidative stress. In comparison with the rats in the other groups, those in the I/R group showed lower superoxide dismutase activity and glutathione levels, together with higher malondialdehyde levels and lung injury scores (p < 0.05 for all). Interstitial inflammatory cell infiltration of the lungs was also markedly greater in the I/R group than in the other groups. In addition, I/R group rats showed various signs of interstitial edema and hemorrhage. In the I/R+NAC, I/R+PTX, and I/R+NAC+PTX groups, superoxide dismutase activity, glutathione levels, malondialdehyde levels, and lung injury scores were preserved (p < 0.05 for all). The differences between the administration of NAC or pentoxifylline alone and the administration of the two together were not significant for any of those parameters (p > 0.05 for all). Our results suggest that NAC and pentoxifylline both protect lung tissue from the effects of skeletal muscle I/R. However, their combined use does not appear to increase the level of that protection.

  4. Effects of N-acetylcysteine and pentoxifylline on remote lung injury in a rat model of hind-limb ischemia/reperfusion injury

    PubMed Central

    Takhtfooladi, Hamed Ashrafzadeh; Hesaraki, Saeed; Razmara, Foad; Takhtfooladi, Mohammad Ashrafzadeh; Hajizadeh, Hadi

    2016-01-01

    Objective : To investigate the effects of N-acetylcysteine (NAC) and pentoxifylline in a model of remote organ injury after hind-limb ischemia/reperfusion (I/R) in rats, the lungs being the remote organ system. Methods : Thirty-five male Wistar rats were assigned to one of five conditions (n = 7/group), as follows: sham operation (control group); hind-limb ischemia, induced by clamping the left femoral artery, for 2 h, followed by 24 h of reperfusion (I/R group); and hind-limb ischemia, as above, followed by intraperitoneal injection (prior to reperfusion) of 150 mg/kg of NAC (I/R+NAC group), 40 mg/kg of pentoxifylline (I/R+PTX group), or both (I/R+NAC+PTX group). At the end of the trial, lung tissues were removed for histological analysis and assessment of oxidative stress. Results : In comparison with the rats in the other groups, those in the I/R group showed lower superoxide dismutase activity and glutathione levels, together with higher malondialdehyde levels and lung injury scores (p < 0.05 for all). Interstitial inflammatory cell infiltration of the lungs was also markedly greater in the I/R group than in the other groups. In addition, I/R group rats showed various signs of interstitial edema and hemorrhage. In the I/R+NAC, I/R+PTX, and I/R+NAC+PTX groups, superoxide dismutase activity, glutathione levels, malondialdehyde levels, and lung injury scores were preserved (p < 0.05 for all). The differences between the administration of NAC or pentoxifylline alone and the administration of the two together were not significant for any of those parameters (p > 0.05 for all). Conclusions : Our results suggest that NAC and pentoxifylline both protect lung tissue from the effects of skeletal muscle I/R. However, their combined use does not appear to increase the level of that protection. PMID:26982035

  5. Co-injection of mesenchymal stem cells with endothelial progenitor cells accelerates muscle recovery in hind limb ischemia through an endoglin-dependent mechanism.

    PubMed

    Rossi, Elisa; Smadja, David; Goyard, Celine; Cras, Audrey; Dizier, Blandine; Bacha, Nour; Lokajczyk, Anna; Guerin, Coralie L; Gendron, Nicolas; Planquette, Benjamin; Mignon, Virginie; Bernabéu, Carmelo; Sanchez, Olivier; Smadja, David M

    2017-10-05

    Endothelial colony-forming cells (ECFCs) are progenitor cells committed to endothelial lineages and have robust vasculogenic properties. Mesenchymal stem cells (MSCs) have been described to support ECFC-mediated angiogenic processes in various matrices. However, MSC-ECFC interactions in hind limb ischemia (HLI) are largely unknown. Here we examined whether co-administration of ECFCs and MSCs bolsters vasculogenic activity in nude mice with HLI. In addition, as we have previously shown that endoglin is a key adhesion molecule, we evaluated its involvement in ECFC/MSC interaction. Foot perfusion increased on day 7 after ECFC injection and was even better at 14 days. Co-administration of MSCs significantly increased vessel density and foot perfusion on day 7 but the differences were no longer significant at day 14. Analysis of mouse and human CD31, and in situ hybridization of the human ALU sequence, showed enhanced capillary density in ECFC+MSC mice. When ECFCs were silenced for endoglin, coinjection with MSCs led to lower vessel density and foot perfusion at both 7 and 14 days (p<0.001). Endoglin silencing in ECFCs did not affect MSC differentiation into perivascular cells or other mesenchymal lineages. Endoglin silencing markedly inhibited ECFC adhesion to MSCs. Thus, MSCs, when combined with ECFCs, accelerate muscle recovery in a mouse model of hind limb ischemia, through an endoglin-dependent mechanism.

  6. Protective effects of erdosteine, vitamin E, and vitamin C on renal injury induced by the ischemia-reperfusion of the hind limbs in rats.

    PubMed

    Sirmali, Rana; Armağan, Abdullah; Öktem, Faruk; Uz, Efkan; Kirbas, Aynur; Dönmezs, Soner; Yilmaz, Hacı Ramazan; Silay, Mesrur Selçuk; Sirmali, Mehmet

    2015-01-01

    To compare the protective efficacy of erdosteine and vitamins C and E against renal injury caused by hind limb ischemia-reperfusion (I/R). Rats were split into 4 groups: group I as the control, group II as I/R, group III as I/R + erdosteine, and group IV as I/R + vitamins C and E. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) tissue levels were determined. MDA levels were found comparable with the control group in groups II and III. However, they were considerably decreased in group IV when compared to group II (P < 0.01). Additionally, SOD, CAT, and GSH-Px activities were considerably (P < 0.05) decreased in group II. While CAT and GSH-Px activities were restored (P <0.01) by vitamin E and C treatment, SOD activity was not significantly affected. While GSH-Px activities were higher (P < 0.05) with erdosteine administration, SOD and CAT activities were unchanged. The protective effect of vitamins C and E is higher than that of erdosteine treatment in reducing the oxidative stress after renal ischemia in this animal model.

  7. Pig specific vascular anatomy allows acute infrarenal aortic occlusion without hind limb ischemia and stepwise occlusion without clinical signs.

    PubMed

    Haacke, N; Unger, J K; Haidenhein, C; Russ, M; Hiebl, B; Niehues, S M

    2011-01-01

    EGAs for a partial collateral support of an infrarenal aortic occlusion the pig's EGA is a naturally sufficient collateral system capable to cover immediately for an acute infrarenal aortic occlusion. Further collateral enlargement even provides a permanent, sufficient hind limb perfusion in pigs. As the sufficient collateral system probably reduce pressure and shear rates in the infrarenal aortic segment after cross clamping, pigs might have a higher predisposition to produce early thrombosis related graft occlusions tan humans.

  8. Transfection of VEGF(165) genes into endothelial progenitor cells and in vivo imaging using quantum dots in an ischemia hind limb model.

    PubMed

    Yang, Han Na; Park, Ji Sun; Woo, Dae Gyun; Jeon, Su Yeon; Park, Keun-Hong

    2012-11-01

    Endothelial progenitor cells (EPCs) were transfected with fluorescently labeled quantum dot nanoparticles (QD NPs) with or without VEGF(165) plasmid DNA (pDNA) to probe the EPCs after in vivo transplantation and to test whether they presented as differentiated endothelial cells (ECs). Bare QD NPs and QD NPs coated with PEI or PEI + VEGF(165) genes were characterized by dynamic light scattering, scanning electron microscopy, and atomic force microscopy. Transfection of EPCs with VEGF(165) led to the expression of specific genes and proteins for mature ECs. A hind limb ischemia model was generated in nude mice, and VEGF(165) gene-transfected EPCs were transplanted intramuscularly into the ischemic limbs. At 28 days after transplantation, the VEGF(165) gene-transfected EPCs significantly increased the number of differentiated ECs compared with the injection of medium or bare EPCs without VEGF(165) genes. Laser Doppler imaging revealed that blood perfusion levels were increased significantly by VEGF(165) gene-transfected EPCs compared to EPCs without VEGF(165). Moreover, the transplantation of VEGF(165) gene-transfected EPCs increased the specific gene and protein expression levels of mature EC markers and angiogenic factors in the animal model.

  9. Periostin enhances adipose-derived stem cell adhesion, migration, and therapeutic efficiency in Apo E deficient mice with hind limb ischemia.

    PubMed

    Qin, Jinbao; Yuan, Fukang; Peng, Zhiyou; Ye, Kaichuang; Yang, Xinrui; Huang, Lijia; Jiang, Mier; Lu, Xinwu

    2015-07-24

    Therapeutic angiogenesis by transplantation of autologous/allogeneic adipose-derived stem cells (ADSCs) is a potential approach for severe ischemic diseases. However, poor viability, adhesion, migration and differentiation limit the therapeutic efficiency after the cells were transplanted into the targeted area. Periostin, an extracellular matrix protein, exhibits a critical role in wound repair as well as promotes cell adhesion, survival, and angiogenesis. ADSCs were obtained and genetically engineered with periostin gene (P-ADSCs). The viability, proliferation, migration, and apoptosis of P-ADSCs under hypoxia were analyzed. Moreover, P-ADSCs were implanted into Apo E deficient mice with hind limb ischemia. The Laser Doppler perfusion index, immunofluorescence, and histological pathology assay were tested to evaluate the therapeutic effects. The associated molecular mechanism of periostin on the proliferation, adhesion, migration, and differentiation of ADSCs was also analyzed. The in vitro studies have shown that periostin-transfected ADSCs (P-ADSCs) promoted viability, proliferation, and migration of ADSCs. Apoptosis of ADSCs was inhibited under hypoxic conditions. The Laser Doppler perfusion index was significantly higher in the P-ADSCs group compared with that in the ADSC and control groups after 4 weeks. Immunofluorescence and histological pathology assay showed that the P-ADSCs were in and around the ischemic sites, and some cells differentiated into capillaries and endothelium. Microvessel densities were significantly improved in P-ADSCs group compared with those in the control group. The molecular mechanisms that provide the beneficial effects of periostin were connected with the upregulated expression of integrinβ1/FAK/PI3K/Akt/eNOS signal pathway and the increased secretion of growth factors. Overexpression of periostin by gene transfection on ADSCs promotes survival, migration, and therapeutic efficiency, which will bring new insights into the

  10. 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 ...

  11. Critical Limb Ischemia (CLI)

    MedlinePlus

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

  12. Protective effects of erdosteine and vitamins C and E combination on ischemia-reperfusion-induced lung oxidative stress and plasma copper and zinc levels in a rat hind limb model.

    PubMed

    Sirmali, Mehmet; Uz, Efkan; Sirmali, Rana; Kilbaş, Aynur; Yilmaz, H Ramazan; Altuntaş, Irfan; Naziroğlu, Mustafa; Delibaş, Namik; Vural, Hüseyin

    2007-07-01

    The aim of this study was to investigate the protective effects of erdosteine and vitamins C and E (VCE) on the lungs after performing hind limb ischemia-reperfusion (I/R) by assessing oxidative stress, plasma copper (Cu), and zinc (Zn) analysis. The animals were divided randomly into four groups as nine rats each as follows: control, I/R, I/R plus erdosteine, and I/R plus VCE combination. I/R period for 60 min was performed on the both hind limbs of all the rats in the groups of I/R, erdosteine with I/R, VCE with I/R allowing 120 min of reperfusion. The animals received orally erdosteine one time in a day and 3 days before I/R in the erdosteine group. In the VCE group, the animals VCE combination received one time in a day and 3 days before I/R, although placebo was given to control and I/R group animals. Lung lipid peroxidation (malondialdehyde [MDA]) level, superoxide dismutase (SOD), and catalase activities were increased, although lung glutathione (GSH) and plasma Zn levels decreased in I/R group in lung tissue compared with the control group. Serum MDA level, creatine kinase, and lactate dehydrogenase activities were increased in I/R group compared with the control. Lung MDA and plasma Zn levels and lung SOD activity were decreased by erdosteine administration, whereas lung GSH levels after I/R increased. The plasma Zn levels and lung SOD activity were decreased by VCE administration, although the plasma Cu and lung GSH levels increased after I/R. In conclusion, erdosteine has an antioxidant role on the values in the rat model, and it has more protective affect than in VCE in attenuating I/R-induced lung injury in rats.

  13. 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

  14. Scaling and functional morphology in strigiform hind limbs

    PubMed Central

    Madan, Meena A.; Rayfield, Emily J.; Bright, Jen A.

    2017-01-01

    Strigiformes are an order of raptorial birds consisting exclusively of owls: the Tytonidae (barn owls) and the Strigidae (true owls), united by a suite of adaptations aiding a keen predatory lifestyle, including robust hind limb elements modified for grip strength. To assess variation in hind limb morphology, we analysed how the dimensions of the major hind limb elements in subfossil and modern species scaled with body mass. Comparing hind limb element length, midshaft width, and robusticity index (RI: ratio of midshaft width to maximum length) to body mass revealed that femoral and tibiotarsal width scale with isometry, whilst length scales with negative allometry, and close to elastic similarity in the tibiotarsus. In contrast, tarsometatarsus width shows strong positive allometry with body mass, whilst length shows strong negative allometry. Furthermore, the tarsometatarsi RI scales allometrically to mass0.028, whilst a weak relationship exists in femora (mass0.004) and tibiotarsi (mass0.004). Our results suggest that tarsometatarsi play a more substantial functional role than tibiotarsi and femora. Given the scaling relationship between tarsometatarsal width and robusticity to body mass, it may be possible to infer the body mass of prehistoric owls by analysing tarsometatarsi, an element that is frequently preserved in the fossil record of owls. PMID:28327549

  15. Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels.

    PubMed

    Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2016-08-01

    Remote ischemic preconditioning is a well reported therapeutic strategy that induces cardioprotective effects but the underlying intracellular mechanisms have not been widely explored. The current study was designed to investigate the involvement of TRP and especially TRPV channels in remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 alternate cycles of inflation and deflation of 5 min each) was delivered using a blood pressure cuff tied on the hind limb of the anesthetized rat. Using Langendorff's system, the heart was perfused and subjected to 30-min ischemia and 120-min reperfusion. The myocardial injury was assessed by measuring infarct size, lactate dehydrogenase (LDH), creatine kinase (CK), LVDP, +dp/dtmax, -dp/dtmin, heart rate, and coronary flow rate. Gadolinium, TRP blocker, and ruthenium red, TRPV channel blocker, were employed as pharmacological tools. Remote hind limb preconditioning significantly reduced the infarct size, LDH release, CK release and improved coronary flow rate, hemodynamic parameters including LVDP, +dp/dtmax, -dp/dtmin, and heart rate. However, gadolinium (7.5 and 15 mg kg(-1)) and ruthenium red (4 and 8 mg kg(-1)) significantly attenuated the cardioprotective effects suggesting the involvement of TRP especially TRPV channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus possibly activates TRPV channels on the heart or sensory nerve fibers innervating the heart to induce cardioprotective effects. Alternatively, remote hind limb preconditioning stimulus may also activate the mechanosensitive TRP and especially TRPV channels on the sensory nerve fibers innervating the skeletal muscles to trigger cardioprotective neurogenic signaling cascade. The cardioprotective effects of remote hind limb preconditioning may be mediated via activation of mechanosensitive TRP and especially TRPV channels.

  16. Investigating the involvement of TRPV1 ion channels in remote hind limb preconditioning-induced cardioprotection in rats.

    PubMed

    Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2017-02-01

    Remote ischemic preconditioning (RIPC) treatment strategy is a breakthrough in the field of cardiovascular pharmacology as it has the potential to attenuate myocardial ischemia-reperfusion injury. However, the underlying intracellular pathways have not been widely explored. The present study intends to explore the possible role of TRPV1 channels in mediating remote hind limb preconditioning-induced cardioprotection. Remote hind limb preconditioning stimulus (4 cycles in succession) was delivered by tying the blood pressure cuff at the inguinal level of the rat. The Langendorff system was used to perfuse the isolated heart and afterward was subjected to 30 min of global ischemia and 120 min of reperfusion. Sustained ischemia and, thereafter, reperfusion led to cardiac injury that was assessed in terms of infarct size, lactate dehydrogenase (LDH) release, creatine kinase (CK) release, left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), +dp/dtmax, -dp/dtmin, heart rate, rate pressure product, and coronary flow rate. The pharmacological modulators employed included capsaicin as TRPV1 agonist and capsazepine as TRPV1 antagonist. Remote hind limb preconditioning stimulus and capsaicin preconditioning (5 and 10 mg/kg) led to significant reduction in infarct size, LVEDP, LDH release, CK release, and significant improvement in LVDP, +dp/dtmax, -dp/dtmin, heart rate, rate pressure product, and coronary flow rate. However, remote hind limb preconditioning-induced cardioprotective effects were considerably abolished in the presence of capsazepine (2.5 and 5 mg/kg). This indicates that remote hind limb preconditioning stimulus possibly activates TRPV1 channels to produce cardioprotective effects.

  17. Pelvic and hind limb musculature of Staurikosaurus pricei (Dinosauria: Saurischia).

    PubMed

    Grillo, Orlando N; Azevedo, Sergio A K

    2011-03-01

    The study of pelvic and hind limb bones and muscles in basal dinosaurs is important for understanding the early evolution of bipedal locomotion in the group. The use of data from both extant and extinct taxa placed into a phylogenetic context allowed to make well-supported inferences concerning most of the hind limb musculature of the basal saurischian Staurikosaurus pricei Colbert, 1970 (Santa Maria Formation, Late Triassic of Rio Grande do Sul, Brazil). Two large concavities in the lateral surface of the ilium represent the origin of the muscles iliotrochantericus caudalis plus iliofemoralis externus (in the anterior concavity) and iliofibularis (in the posterior concavity). Muscle ambiens has only one head and originates from the pubic tubercle. The origin of puboischiofemoralis internus 1 possibly corresponds to a fossa in the ventral margin of the pré-acetabular iliac process. This could represent an intermediate stage prior to the origin of a true pré-acetabular fossa. Muscles caudofemorales longus et brevis were likely well developed, and Staurikosaurus is unique in bearing a posteriorly projected surface for the origin of caudofemoralis brevis.

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

    PubMed

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

    2017-02-14

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

  19. Hind-limb vascular-capacitance responses in anaesthetized dogs.

    PubMed Central

    Hainsworth, R; Karim, F; McGregor, K H; Wood, L M

    1983-01-01

    In anaesthetized dogs a hind limb was vascularly isolated, perfused through the femoral artery at either constant flow or constant pressure and drained from the femoral vein at constant pressure. Inflow and outflow were recorded. Vascular-resistance changes were calculated from changes in pressure or flow and volume changes from the differences between inflow and outflow. During constant-flow perfusion, both changes in carotid sinus pressure and direct stimulation of efferent sympathetic nerves resulted in large resistance responses. However, changes in carotid sinus pressure did not result in changes in limb blood volume and only small decreases were obtained in response to direct stimulation. During constant-pressure perfusion, both reflex and direct stimulation resulted not only in significant changes in resistance but also in significant volume changes which were much larger than those obtained during constant-flow perfusion. Similar responses were obtained when the flow rate was changed by altering the pump speed. These results indicate that changes in pressure to carotid baroreceptors do not result in active capacitance responses in the limb circulation and that only very small responses are obtained even to electrical stimulation of sympathetic nerves. The larger responses occurring during constant-pressure perfusion are thought to be secondary to changes in blood flow. PMID:6875939

  20. Bone morphology of the hind limbs in two caviomorph rodents.

    PubMed

    de Araújo, F A P; Sesoko, N F; Rahal, S C; Teixeira, C R; Müller, T R; Machado, M R F

    2013-04-01

    In order to evaluate the hind limbs of caviomorph rodents a descriptive analysis of the Cuniculus paca (Linnaeus, 1766) and Hydrochoerus hydrochaeris (Linnaeus, 1766) was performed using anatomical specimens, radiography, computed tomography (CT) and full-coloured prototype models to generate bone anatomy data. The appendicular skeleton of the two largest rodents of Neotropical America was compared with the previously reported anatomical features of Rattus norvegicus (Berkenhout, 1769) and domestic Cavia porcellus (Linnaeus, 1758). The structures were analyzed macroscopically and particular findings of each species reported. Features including the presence of articular fibular projection and lunulae were observed in the stifle joint of all rodents. Imaging aided in anatomical description and, specifically in the identification of bone structures in Cuniculus paca and Hydrochoerus hydrochaeris. The imaging findings were correlated with the anatomical structures observed. The data may be used in future studies comparing these animals to other rodents and mammalian species. © 2012 Blackwell Verlag GmbH.

  1. New Australovenator Hind Limb Elements Pertaining to the Holotype Reveal the Most Complete Neovenatorid Leg

    PubMed Central

    White, Matt A.; Benson, Roger B. J.; Tischler, Travis R.; Hocknull, Scott A.; Cook, Alex G.; Barnes, David G.; Poropat, Stephen F.; Wooldridge, Sarah J.; Sloan, Trish; Sinapius, George H. K.; Elliott, David A.

    2013-01-01

    We report new skeletal elements pertaining to the same individual which represents the holotype of Australovenator wintonensis, from the ‘Matilda Site’ in the Winton Formation (Upper Cretaceous) of western Queensland. The discovery of these new elements means that the hind limb of Australovenator is now the most completely understood hind limb among Neovenatoridae. The new hind limb elements include: the left fibula; left metatarsal IV; left pedal phalanges I-2, II-1, III-4, IV-2, IV-3; and right pedal phalanges, II-2 and III-1. The detailed descriptions are supported with three dimensional figures. These coupled with the completeness of the hind limb will increase the utility of Australovenator in comparisons with less complete neovenatorid genera. These specimens and the previously described hind limb elements of Australovenator are compared with other theropods classified as neovenatorids (including Neovenator, Chilantaisaurus, Fukuiraptor, Orkoraptor and Megaraptor). Hind limb length proportion comparisons indicate that the smaller neovenatorids Australovenator and Fukuiraptor possess more elongate and gracile hind limb elements than the larger Neovenator and Chilantaisaurus. Greater stride lengths to body size exist in both Fukuiraptor and Australovenator with the femur discovered to be proportionally shorter the rest of the hind limb length. Additionally Australovenator is identified as possessing the most elongate metatarsus. The metatarsus morphology varies with body size. The larger neoventorids possess a metatarsus with greater width but shorter length compared to smaller forms. PMID:23894328

  2. New Australovenator hind limb elements pertaining to the holotype reveal the most complete Neovenatorid leg.

    PubMed

    White, Matt A; Benson, Roger B J; Tischler, Travis R; Hocknull, Scott A; Cook, Alex G; Barnes, David G; Poropat, Stephen F; Wooldridge, Sarah J; Sloan, Trish; Sinapius, George H K; Elliott, David A

    2013-01-01

    We report new skeletal elements pertaining to the same individual which represents the holotype of Australovenator wintonensis, from the 'Matilda Site' in the Winton Formation (Upper Cretaceous) of western Queensland. The discovery of these new elements means that the hind limb of Australovenator is now the most completely understood hind limb among Neovenatoridae. The new hind limb elements include: the left fibula; left metatarsal IV; left pedal phalanges I-2, II-1, III-4, IV-2, IV-3; and right pedal phalanges, II-2 and III-1. The detailed descriptions are supported with three dimensional figures. These coupled with the completeness of the hind limb will increase the utility of Australovenator in comparisons with less complete neovenatorid genera. These specimens and the previously described hind limb elements of Australovenator are compared with other theropods classified as neovenatorids (including Neovenator, Chilantaisaurus, Fukuiraptor, Orkoraptor and Megaraptor). Hind limb length proportion comparisons indicate that the smaller neovenatorids Australovenator and Fukuiraptor possess more elongate and gracile hind limb elements than the larger Neovenator and Chilantaisaurus. Greater stride lengths to body size exist in both Fukuiraptor and Australovenator with the femur discovered to be proportionally shorter the rest of the hind limb length. Additionally Australovenator is identified as possessing the most elongate metatarsus. The metatarsus morphology varies with body size. The larger neoventorids possess a metatarsus with greater width but shorter length compared to smaller forms.

  3. 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.

  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. Architecture of the hind limb muscles of cats: functional significance.

    PubMed

    Sacks, R D; Roy, R R

    1982-08-01

    Force, velocity, and displacement properties of a muscle are determined in large part by its architectural design. The relative effect of muscle architecture on these physiological variables was studied by determining muscle weight, fiber length, average sarcomere length, and approximate angle of pinnation of 24 cat hind limb muscles. Muscle lengths ranged from 28.3 to 144 mm, whereas fiber lengths ranged from 8.4 to 105.5 mm. Generally, fiber to muscle length ratios were similar throughout a muscle. Estimated angles of pinnation of muscle fibers varied from 0 to 21 degrees with most having an angle of less than 10 degrees. The cross-sectional area of the knee extensors was similar to the knee flexors (16.43 vs. 16.83 cm2) whereas the cross-sectional area of the ankle extensors was more than six times greater than the ankle flexors (18.59 vs. 2.83 cm2). There was a 6.7-fold difference in the maximal force between muscles, when normalized to a constant weight, that could be attributed to architectural features. Ratios of wet weight to predicted maximal tetanic tension for each muscle and muscle group were calculated to compare the relative priority of muscle force versus muscle length-velocity for a given mass of muscle. These ratios varied from 0.4 to 4.84. The ratios suggest that velocity and/or displacement is a priority for the hamstrings, whereas force is a priority for the quadriceps and lower leg muscles. As much as a 12.6-fold difference in maximal velocity between muscles can be attributed to differences in fiber lengths. This can be compared to approximately a 2.5-fold difference in maximal velocity reported to occur as a result of biochemical (intrinsic) differences.

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

    PubMed Central

    2012-01-01

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

  7. 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

  8. Effect of Limb Demand Ischemia on Autophagy and Morphology in Mice

    PubMed Central

    Albadawi, Hassan; Oklu, Rahmi; Milner, John D.; Uong, Thuy P.; Yoo, Hyung-Jin; Austen, William G.; Watkins, Michael T.

    2015-01-01

    Background Obesity is a major risk factor for diabetes and peripheral arterial disease (PAD), which frequently leads to lower limb demand ischemia. Skeletal muscle autophagy and mitochondrial biogenesis are important processes for proper oxidative capacity and energy metabolism which are compromised in diabetes. This study compares autophagy, mitochondrial biogenesis, energy metabolism, and morphology in the hind limbs of obese diabetic mice subjected to demand or sedentary ischemia. Materials and Methods Unilateral hind limb demand ischemia was created in a group of diet induced obese mice following femoral artery ligation (FAL) and 4 weeks of daily exercise. A parallel group of mice underwent FAL but remained sedentary for 4 weeks. Hind limbs muscles were analyzed for markers of autophagy, mitochondrial biogenesis, ATP, and muscle tissue morphology. Results At the end of the 4-week exercise period, demand ischemia increased the autophagy mediator Beclin-1, but it did not alter the autophagy indicator LC3B-II/I ratio, or markers of mitochondrial biogenesis, Opa-1/Drp-1. In contrast, exercise significantly increased the level of mitochondrial protein-SDHA and reduced adipocyte accumulation and the percentage of centrally nucleated myofibers in the demand ischemia limb. In addition, demand ischemia resulted in decreased uncoupling protein-3 levels without altering muscle ATP or pS473-Akt levels. Conclusions Limb demand ischemia markedly decreased adipocyte accumulation and enhanced muscle regeneration in obese mice but it did not appear to enhance autophagy, mitochondrial biogenesis, energy metabolism, or insulin sensitivity. Future studies aimed at evaluating novel therapies that enhance autophagy and mitochondrial biogenesis in diabetes with PAD are warranted. PMID:25959834

  9. Effect of limb demand ischemia on autophagy and morphology in mice.

    PubMed

    Albadawi, Hassan; Oklu, Rahmi; Milner, John D; Uong, Thuy P; Yoo, Hyung-Jin; Austen, William G; Watkins, Michael T

    2015-10-01

    Obesity is a major risk factor for diabetes and peripheral arterial disease, which frequently leads to lower limb demand ischemia. Skeletal muscle autophagy and mitochondrial biogenesis are important processes for proper oxidative capacity and energy metabolism, which are compromised in diabetes. This study compares autophagy, mitochondrial biogenesis, energy metabolism, and morphology in the hind limbs of obese diabetic mice subjected to demand or sedentary ischemia. Unilateral hind limb demand ischemia was created in a group of diet-induced obese mice after femoral artery ligation and 4 wk of daily exercise. A parallel group of mice underwent femoral artery ligation but remained sedentary for 4 wk. Hind limb muscles were analyzed for markers of autophagy, mitochondrial biogenesis, adenosine triphosphate, and muscle tissue morphology. At the end of the 4-wk exercise period, demand ischemia increased the autophagy mediator Beclin-1, but it did not alter the autophagy indicator, LC3B-II/I ratio, or markers of mitochondrial biogenesis, optic atrophy/dynamin-related protein. In contrast, exercise significantly increased the level of mitochondrial protein-succinate dehydrogenase subunit-A and reduced adipocyte accumulation and the percentage of centrally nucleated myofibers in the demand ischemia limb. In addition, demand ischemia resulted in decreased uncoupling protein-3 levels without altering muscle adenosine triphosphate or pS473-Akt levels. Limb demand ischemia markedly decreased adipocyte accumulation and enhanced muscle regeneration in obese mice, but it did not appear to enhance autophagy, mitochondrial biogenesis, energy metabolism, or insulin sensitivity. Future studies aimed at evaluating novel therapies that enhance autophagy and mitochondrial biogenesis in diabetes with peripheral arterial disease are warranted. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Hind limb kinematics during therapeutic exercises in dogs with osteoarthritis of the hip joints.

    PubMed

    Bockstahler, Barbara A; Prickler, Bettina; Lewy, Elisabeth; Holler, Peter J; Vobornik, Angela; Peham, Christian

    2012-09-01

    To assess joint kinematics in dogs with osteoarthritis of the hip joints during walking up an incline or down a decline and over low obstacles and to compare findings with data for nonlame dogs. 10 dogs with osteoarthritis of the hip joints (mean ± SD age, 6.95 ± 3.17 years; mean body weight, 34.33 ± 13.58 kg) and 8 nonlame dogs (3.4 ± 2.0 years; 23.6 ± 4.6 kg). Reflective markers located on the limbs and high-speed cameras were used to record joint kinematics during walking up an incline or down a decline and over low obstacles. Maximal flexion, extension, and range of motion of the hip joints were calculated. Osteoarthritis of the hip joints reduced extension of both hip joints and flexion of the contralateral hind limb, compared with flexion of the lame hind limb, during walking down a decline. Walking up an incline resulted in decreased extension of the stifle joint in both hind limbs of osteoarthritic dogs; extension was significantly decreased for the lame hind limb. During walking over low obstacles, maximal flexion of the stifle joint was increased significantly for the contralateral hind limb. Maximal flexion was increased in both tarsal joints. Osteoarthritis of the hip joints led to complex changes in the gait of dogs, which involved more joints than the affected hip joint alone. Each exercise had specific effects on joint kinematics that must be considered when planning a rehabilitation program.

  11. Recovery of sympathetic nerve function after lumbar sympathectomy is slower in the hind limbs than in the torso.

    PubMed

    Zheng, Zhi-Fang; Liu, Yi-Shu; Min, Xuan; Tang, Jian-Bing; Liu, Hong-Wei; Cheng, Biao

    2017-07-01

    Local sympathetic denervation by surgical sympathectomy is used in the treatment of lower limb ulcers and ischemia, but the restoration of cutaneous sympathetic nerve functions is less clear. This study aims to explore the recovery of cutaneous sympathetic functions after bilateral L2-4 sympathectomy. The skin temperature of the left feet, using a point monitoring thermometer, increased intraoperatively after sympathectomy. The cytoplasm of sympathetic neurons contained tyrosine hydroxylase and dopamine β-hydroxylase, visualized by immunofluorescence, indicated the accuracy of sympathectomy. Iodine starch test results suggested that the sweating function of the hind feet plantar skin decreased 2 and 7 weeks after lumbar sympathectomy but had recovered by 3 months. Immunofluorescence and western blot assay results revealed that norepinephrine and dopamine β-hydroxylase expression in the skin from the sacrococcygeal region and hind feet decreased in the sympathectomized group at 2 weeks. Transmission electron microscopy results showed that perinuclear space and axon demyelination in sympathetic cells in the L5 sympathetic trunks were found in the sympathectomized group 3 months after sympathectomy. Although sympathetic denervation occurred in the sacrococcygeal region and hind feet skin 2 weeks after lumbar sympathectomy, the skin functions recovered gradually over 7 weeks to 3 months. In conclusion, sympathetic functional recovery may account for the recurrence of hyperhidrosis after sympathectomy and the normalization of sympathetic nerve trunks after incomplete injury. The recovery of sympathetic nerve function was slower in the limbs than in the torso after bilateral L2-4 sympathectomy.

  12. Recovery of sympathetic nerve function after lumbar sympathectomy is slower in the hind limbs than in the torso

    PubMed Central

    Zheng, Zhi-fang; Liu, Yi-shu; Min, Xuan; Tang, Jian-bing; Liu, Hong-wei; Cheng, Biao

    2017-01-01

    Local sympathetic denervation by surgical sympathectomy is used in the treatment of lower limb ulcers and ischemia, but the restoration of cutaneous sympathetic nerve functions is less clear. This study aims to explore the recovery of cutaneous sympathetic functions after bilateral L2–4 sympathectomy. The skin temperature of the left feet, using a point monitoring thermometer, increased intraoperatively after sympathectomy. The cytoplasm of sympathetic neurons contained tyrosine hydroxylase and dopamine β-hydroxylase, visualized by immunofluorescence, indicated the accuracy of sympathectomy. Iodine starch test results suggested that the sweating function of the hind feet plantar skin decreased 2 and 7 weeks after lumbar sympathectomy but had recovered by 3 months. Immunofluorescence and western blot assay results revealed that norepinephrine and dopamine β-hydroxylase expression in the skin from the sacrococcygeal region and hind feet decreased in the sympathectomized group at 2 weeks. Transmission electron microscopy results showed that perinuclear space and axon demyelination in sympathetic cells in the L5 sympathetic trunks were found in the sympathectomized group 3 months after sympathectomy. Although sympathetic denervation occurred in the sacrococcygeal region and hind feet skin 2 weeks after lumbar sympathectomy, the skin functions recovered gradually over 7 weeks to 3 months. In conclusion, sympathetic functional recovery may account for the recurrence of hyperhidrosis after sympathectomy and the normalization of sympathetic nerve trunks after incomplete injury. The recovery of sympathetic nerve function was slower in the limbs than in the torso after bilateral L2–4 sympathectomy. PMID:28852403

  13. A case report of partial bilateral hind limb adactyly in a male lamb.

    PubMed

    Rajabioun, Masoud; Kazemi Mehrjerdi, Hossein; Ghasemi, Samaneh

    2016-01-01

    Hemimelia as a congenital anomaly is a failure of development of extremities formation in embryonic period. This anomaly is defined as complete absence of the part of extremities and different forms were explained for hemimelia. Adactyly is an alternative name for transverse hemimelia and is a rare disorder in the most of animal species. A two months old male lamb with normal vital signs was referred to clinic due to both hind limbs shortness and absence of hooves from the birth day. Clinical and radiological examinations were performed and partial hemimelia was confirmed radiographically in both hind limbs. In left hind limb, total absence of the toe indicated presence of adactyly in this limb. No other congenital deformities were diagnosed in skeletal system based on clinical and radiological examinations. According to our knowledge, this is the first report of such rare conditions in a lamb. Clinical findings and radiological signs of this rare anomaly in a lamb were described in this report.

  14. Changes in the composition of hind limb lymph after chemical injury

    PubMed Central

    Boyles, Susan; Lewis, G. P.; Westcott, Barbara

    1970-01-01

    1. Lymph was collected directly from the hind limbs of rabbits and cats anaesthetized with pentobarbitone. 2. Injury to the hind limb was caused by injection of one of two chemicals; either dimethylsulphoxide (DMSO) which produced a mild injury, or croton oil which produced severe injury. 3. After subcutaneous injection (6 × 0·2 ml) into the right hind limb there was a good correlation between the changes in concentration of intracellular enzyme systems in the lymph draining the limb and the histological appearance of the injured tissue. DMSO caused an increase in cytoplasmic enzymes only, while after croton oil, which caused cell necrosis, there was an increase in the concentration of all intracellular enzymes examined. 4. There was an increased lymph flow accompanied by a fall in protein concentration after DMSO, while croton oil caused an increase in protein concentration and a variable effect on lymph flow. PMID:5485152

  15. Dynamic imaging of allogeneic adipose-derived regenerative cells transplanted in ischemic hind limb of apolipoprotein E mouse model

    PubMed Central

    Zheng, Yi; Qin, Jinbao; Wang, Xin; Peng, Zhiyou; Hou, Peiyong; Lu, Xinwu

    2017-01-01

    Background Transplantation of allogeneic adipose-derived regenerative cells (ADRCs) is a promising treatment modality for severe ischemic diseases. However, minimal information is available on the in vivo effects, fate, and migration of ADRCs, as well as the mechanisms of their therapeutic angiogenesis. Materials and methods In this study, green fluorescent protein-expressing ADRCs (GFP-ADRCs) were obtained, labeled with acetylated 3-aminopropyltrimethoxysilane (APTS)-coated iron oxide nanoparticles (APTS NPs), and injected into an old apolipoprotein E knockout (ApoE-KO) mouse model with hind limb ischemia. Then, 3.0 T magnetic resonance imaging (MRI) was performed to dynamically trace the role of ADRCs targeting hind limb ischemia in the ApoE-KO mice model. Results Labeled cells were visualized as large hypointense spots in ischemic muscles by serial 3.0 T MRI scans during a 4-week follow-up. The presence of labeled GFP-ADRCs was confirmed by Prussian blue staining and fluorescence microscopy on postmortem specimens. Conclusion This study showed that allogeneic ADRCs offer great potential application for therapeutic angiogenesis in severe ischemic disease based on the efficacy and feasibility of ADRC transplantation and on the available amounts of tissue. PMID:28053524

  16. [Effect of two types of intermittent pressure on formation of pressure ulcer in rabbit hind limbs].

    PubMed

    Liu, Jianghui; Wang, Weiping; Wang, Keke; Chen, Xilin; Li, Qiang; Dai, Qiangsheng; Wang, Yongqian; Ji, Zhongliang

    2009-08-01

    To compare the effect of two types of intermittent pressure on formation of pressure ulcer in rabbit hind limbs and to investigate the mechanism of gradually changed intermittent pressure produced by waves bed in the prevention of pressure ulcer. Gracilis (3 cm2) in both hind limbs of 12 adult Japanese white rabbits were randomly loaded with gradually changed intermittent pressure (50-160 mm Hg, 1 mm Hg = 0.133 kPa) and sustained pressure (100 mmHg) serving as the experimental group and the control group, respectively. The experiment was terminated after 4 cycles, and a single cycle included 2 hours of compression and 30 minutes of compression-release. Blood velocity of hind limbs and blood perfusion of wound were detected by bidirectional Doppler blood flow detector and laser Doppler perfusion imaging detection system before compression and at every 10 minutes in compression-release period of each cycle (0, 10, 20 and 30 minutes). After the termination, gross observation of the wound was conducted, pathomorphological changes of tissues from compressed area were observed by HE staining, and contents of NO, malondialdehyde (MDA), and superoxide dismutase (SOD) in muscle tissue were measured using colorimetry method. No significant difference was evident between two groups in terms of blood flow velocity before compression (P > 0.05); the blood flow velocity of two groups decreased significantly at 0 minute in every compression-release period of each cycle, and no significant differences were noted between two groups (P > 0.05); the blood flow velocity of the experimental group was higher than that of the control group at 10, 20 and 30 minutes (P < 0.05). No significant difference was noted between two groups in terms of wound blood perfusion before compression (P > 0.05); the wound blood perfusion of two groups decreased significantly at 0 minute in every compression-release period of each cycle, and no significant differences were noted between two groups (P > 0

  17. 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.

  18. Vascular access in critical limb ischemia.

    PubMed

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

    2016-01-01

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

  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. Evaluation of a New Surgical Treatment for Equine Hind Limb Proximal Suspensory Desmitis.

    PubMed

    Brokken, Matthew T; Schneider, Robert K; Roberts, Gregory D; Holmes, Shannon P; Gavin, Patrick R; Sampson, Sarah N; Farnsworth, Kelly D; Dahlgren, Linda A

    2016-10-01

    To evaluate the effects of a new microfracture and ligament splitting procedure on ligament healing and to examine the usefulness of magnetic resonance (MR) imaging for monitoring ligament healing over time using a collagenase model of hind limb proximal suspensory desmitis. Experimental in vivo study. Healthy adult horses (n=6). Horses were free of lameness with normal hind limb proximal suspensory ligaments (PSL). The origin of both hind limb PSL was injected with collagenase and underwent MR imaging 2 weeks later, followed by the microfracture and ligament splitting procedure on 1 limb, with the opposite limb serving as the sham-operated control. Serial lameness and MR examinations were performed. Horses were euthanatized 210 days after surgery, the PSL harvested, and histology, biochemistry, and gene expression performed on both PSL. Collagenase lesions viewed on MR images appeared similar to those seen clinically. Serial MR images demonstrated resolution of abnormal signal intensity and tissue formation in the microfracture sites within the third metatarsal bone. Treated limbs had histologic evidence of connective tissue appearing to originate from the small perforations and blending into the ligament but no statistical differences were identified. Gene expression for cartilage oligomeric matrix protein and decorin were significantly increased in treated compared to control limbs. The microfracture and ligament splitting procedure did incite a tissue response but further clinical investigation is necessary to determine if this tissue remodeling at the bone-ligament interface translates to improved clinical outcome. MR imaging may be useful to follow healing in horses with hind limb proximal suspensory desmitis. © Copyright 2016 by The American College of Veterinary Surgeons.

  1. Effects of immobilization on rat hind limb muscles under non-weight-bearing conditions

    NASA Technical Reports Server (NTRS)

    Jaspers, Stephen R.; Fagan, Julie M.; Satarug, Soisungwan; Cook, Paul H.; Tischler, Marc E.

    1988-01-01

    The effect of stretched and unstretched immobilization of a hind limb on the concentration and the metabolism of proteins in the hind-limb muscles of rats was investigated. The animals were divided into three groups: (1) weight-bearing controls, (2) tail-cast-suspended, and (3) suspended, with one hind limb immobilized with the ankle in dorsiflexion (30-40 deg angle) and the other freely moving. It was found that unloading the hind limbs for 6 days by tail cast suspension caused soleus to atrophy and reduced growth of the gastrocnemius and plantaris muscles; unloading resulted in a higher degradation rate and lower synthesis rate in both in vitro and in vivo. Chronic stretch of the unloaded soleus not only prevented its atrophy but led to significant hypertrophy, relative to weight-bearing controls, with increases in both the sarcoplasmic and myofibrillar protein fractions. Immobilizing one ankle in dorsiflexion prevented the inhibition of growth in the plantaris and gastrocnemius muscles due to unloading.

  2. Effects of immobilization on rat hind limb muscles under non-weight-bearing conditions

    NASA Technical Reports Server (NTRS)

    Jaspers, Stephen R.; Fagan, Julie M.; Satarug, Soisungwan; Cook, Paul H.; Tischler, Marc E.

    1988-01-01

    The effect of stretched and unstretched immobilization of a hind limb on the concentration and the metabolism of proteins in the hind-limb muscles of rats was investigated. The animals were divided into three groups: (1) weight-bearing controls, (2) tail-cast-suspended, and (3) suspended, with one hind limb immobilized with the ankle in dorsiflexion (30-40 deg angle) and the other freely moving. It was found that unloading the hind limbs for 6 days by tail cast suspension caused soleus to atrophy and reduced growth of the gastrocnemius and plantaris muscles; unloading resulted in a higher degradation rate and lower synthesis rate in both in vitro and in vivo. Chronic stretch of the unloaded soleus not only prevented its atrophy but led to significant hypertrophy, relative to weight-bearing controls, with increases in both the sarcoplasmic and myofibrillar protein fractions. Immobilizing one ankle in dorsiflexion prevented the inhibition of growth in the plantaris and gastrocnemius muscles due to unloading.

  3. Hind-limb paresis in a dog with paralumbar solitary T-cell lymphoma.

    PubMed

    Ortega, Maria; Castillo-Alcala, Fernanda

    2010-05-01

    A 2-year-old, neutered, male golden retriever was referred to the Ontario Veterinary College, with a 6-week history of hind limb weakness and back pain. Magnetic resonance imaging of the lumbar vertebral column, and histopathology and immunohistochemistry following euthanasia identified an uncommon solitary T-cell lymphoma in the paralumbar area.

  4. Comparative anatomy and muscle architecture of selected hind limb muscles in the Quarter Horse and Arab

    PubMed Central

    Crook, T C; Cruickshank, S E; McGowan, C M; Stubbs, N; Wakeling, J M; Wilson, A M; Payne, R C

    2008-01-01

    The Quarter Horse (bred for acceleration) and the Arab (bred for endurance) are situated at either end of the equine athletic spectrum. Studies into the form and function of the leg muscles in human sprint and endurance runners have demonstrated that differences exist in their muscle architecture. It is not known whether similar differences exist in the horse. Six Quarter Horse and six Arab fresh hind limb cadavers were dissected to gain information on the muscle mass and architecture of the following muscles: gluteus medius; biceps femoris; semitendinosus; vastus lateralis; gastrocnemius; tibialis cranialis and extensor digitorum longus. Specifically, muscle mass, fascicle length and pennation angle were quantified and physiological cross-sectional area (PCSA) and maximum isometric force were estimated. The hind limb muscles of the Quarter Horse were of a significantly greater mass, but had similar fascicle lengths and pennation angles when compared with those of the Arab; this resulted in the Quarter Horse hind limb muscles having greater PCSAs and hence greater isometric force potential. This study suggests that Quarter Horses as a breed inherently possess large strong hind limb muscles, with the potential to accelerate their body mass more rapidly than those of the Arab. PMID:18194205

  5. Comparative anatomy and muscle architecture of selected hind limb muscles in the Quarter Horse and Arab.

    PubMed

    Crook, T C; Cruickshank, S E; McGowan, C M; Stubbs, N; Wakeling, J M; Wilson, A M; Payne, R C

    2008-02-01

    The Quarter Horse (bred for acceleration) and the Arab (bred for endurance) are situated at either end of the equine athletic spectrum. Studies into the form and function of the leg muscles in human sprint and endurance runners have demonstrated that differences exist in their muscle architecture. It is not known whether similar differences exist in the horse. Six Quarter Horse and six Arab fresh hind limb cadavers were dissected to gain information on the muscle mass and architecture of the following muscles: gluteus medius; biceps femoris; semitendinosus; vastus lateralis; gastrocnemius; tibialis cranialis and extensor digitorum longus. Specifically, muscle mass, fascicle length and pennation angle were quantified and physiological cross-sectional area (PCSA) and maximum isometric force were estimated. The hind limb muscles of the Quarter Horse were of a significantly greater mass, but had similar fascicle lengths and pennation angles when compared with those of the Arab; this resulted in the Quarter Horse hind limb muscles having greater PCSAs and hence greater isometric force potential. This study suggests that Quarter Horses as a breed inherently possess large strong hind limb muscles, with the potential to accelerate their body mass more rapidly than those of the Arab.

  6. A Modified Heterotopic Swine Hind Limb Transplant Model for Translational Vascularized Composite Allotransplantation (VCA) Research

    PubMed Central

    Ibrahim, Zuhaib; Cooney, Damon S.; Shores, Jaimie T.; Sacks, Justin M.; Wimmers, Eric G.; Bonawitz, Steven C.; Gordon, Chad; Ruben, Dawn; Schneeberger, Stefan; Lee, W. P. Andrew; Brandacher, Gerald

    2013-01-01

    Vascularized Composite Allotransplantation (VCA) such as hand and face transplants represent a viable treatment option for complex musculoskeletal trauma and devastating tissue loss. Despite favorable and highly encouraging early and intermediate functional outcomes, rejection of the highly immunogenic skin component of a VCA and potential adverse effects of chronic multi-drug immunosuppression continue to hamper widespread clinical application of VCA. Therefore, research in this novel field needs to focus on translational studies related to unique immunologic features of VCA and to develop novel immunomodulatory strategies for immunomodulation and tolerance induction following VCA without the need for long term immunosuppression. This article describes a reliable and reproducible translational large animal model of VCA that is comprised of an osteomyocutaneous flap in a MHC-defined swine heterotopic hind limb allotransplantation. Briefly, a well-vascularized skin paddle is identified in the anteromedial thigh region using near infrared laser angiography. The underlying muscles, knee joint, distal femur, and proximal tibia are harvested on a femoral vascular pedicle. This allograft can be considered both a VCA and a vascularized bone marrow transplant with its unique immune privileged features. The graft is transplanted to a subcutaneous abdominal pocket in the recipient animal with a skin component exteriorized to the dorsolateral region for immune monitoring. Three surgical teams work simultaneously in a well-coordinated manner to reduce anesthesia and ischemia times, thereby improving efficiency of this model and reducing potential confounders in experimental protocols. This model serves as the groundwork for future therapeutic strategies aimed at reducing and potentially eliminating the need for chronic multi-drug immunosuppression in VCA. PMID:24145603

  7. Delivery system for autologous growth factors fabricated with low-molecular-weight heparin and protamine to attenuate ischemic hind-limb loss in a mouse model.

    PubMed

    Nakamura, Shingo; Takikawa, Megumi; Ishihara, Masayuki; Nakayama, Takefumi; Kishimoto, Satoko; Isoda, Susumu; Ozeki, Yuichi; Sato, Masahiro; Maehara, Tadaaki

    2012-12-01

    Frozen and thawed platelet-rich plasma (PRP) contains high concentrations of various growth factors, such as fibroblast growth factor (FGF)-2, vascular endothelial growth factor, and hepatocyte growth factor. We previously reported that low-molecular-weight heparin/protamine microparticles (LH/P MPs) are useful as biodegradable carriers for the controlled release of FGF-2. In this study, we examined the ability of PRP/LH/P MPs to prevent limb loss in an induced ischemic hind-limb model that used adult BALB/c-nu/nu male mice. One day after inducing ischemia, intramuscular injections of a PRP/LH/P MPs solution were administered into several sites of the ischemic hind limb. Seven days and onward after the injections, the PRP/LH/P MPs-treated and PRP-treated groups recovered from ischemia, as reflected by the improved oxygen saturation. In the PRP-treated group, however, the level of recovery of oxygen saturation after ischemia decreased after 14 days. From the 21st day onward, there was a significant difference between those two groups. In the LH/P MPs-treated group, a partial recovery occurred only in the early period. The saline-treated group (i.e., the control) and the noninjection group (i.e., ischemia only) exhibited no recovery. The limb survival rate at 1 year in the ischemia-induced mice injected with PRP/LH/P MPs was approximately 25 % (two of eight mice) but was absent in the other groups.

  8. Use of kinetic gait analysis for detection, quantification, and differentiation of hind limb lameness and spinal ataxia in horses.

    PubMed

    Ishihara, Akikazu; Reed, Stephen M; Rajala-Schultz, Päivi J; Robertson, James T; Bertone, Alicia L

    2009-03-01

    To evaluate use of kinetic gait analysis for detection, quantification, and differentiation of hind limb lameness and spinal ataxia in horses. Prospective clinical study. 36 horses. Procedures-Kinetic gait analysis with a force plate was performed for 12 clinically normal horses, 12 horses with hind limb lameness, and 12 horses with spinal ataxia. Kinetic variables were compared among groups, correlated to subjective grading, and used to build predictive models to assess the accuracy of discrimination. Subsets of kinetic variables were characteristically altered in ataxic and lame gaits. Ataxic horses had significantly increased lateral force peak and variation in vertical force peaks in both hind limbs. Lame horses had significantly decreased vertical force peak and increased variation in vertical force peaks only in the lame hind limb. These variables were used to differentiate between spinal ataxia and hind limb lameness with excellent accuracy. There were significant correlations between a subset of kinetic variables and subjective lameness and neurologic grades. Kinetic gait variables, specifically lateral force peak and the variation in vertical force, can be used to support the differential diagnosis between spinal ataxia and hind limb lameness in horses. Kinetic gait analysis may also be applied for quantification of equine hind limb gait abnormalities as well as confirming lack of lameness and ataxia in soundness examinations.

  9. A case report of partial bilateral hind limb adactyly in a male lamb

    PubMed Central

    Rajabioun, Masoud; Kazemi Mehrjerdi, Hossein; Ghasemi, Samaneh

    2016-01-01

    Hemimelia as a congenital anomaly is a failure of development of extremities formation in embryonic period. This anomaly is defined as complete absence of the part of extremities and different forms were explained for hemimelia. Adactyly is an alternative name for transverse hemimelia and is a rare disorder in the most of animal species. A two months old male lamb with normal vital signs was referred to clinic due to both hind limbs shortness and absence of hooves from the birth day. Clinical and radiological examinations were performed and partial hemimelia was confirmed radiographically in both hind limbs. In left hind limb, total absence of the toe indicated presence of adactyly in this limb. No other congenital deformities were diagnosed in skeletal system based on clinical and radiological examinations. According to our knowledge, this is the first report of such rare conditions in a lamb. Clinical findings and radiological signs of this rare anomaly in a lamb were described in this report. PMID:28144430

  10. Hind limb malformations in free-living northern leopard frogs (Rana pipiens) from Maine, Minnesota, and Vermont suggest multiple etiologies

    USGS Publications Warehouse

    Meteyer, C.U.; Loeffler, I.K.; Fallon, J.F.; Converse, K.A.; Green, E.; Helgen, J.C.; Kersten, S.; Levey, R.; Eaton-Poole, L.; Burkhart, J.G.

    2000-01-01

    Background Reports of malformed frogs have increased throughout the North American continent in recent years. Most of the observed malformations have involved the hind limbs. The goal of this study was to accurately characterize the hind limb malformations in wild frogs as an important step toward understanding the possible etiologies. Methods During 1997 and 1998, 182 recently metamorphosed northern leopard frogs (Rana pipiens) were collected from Minnesota, Vermont, and Maine. Malformed hind limbs were present in 157 (86%) of these frogs, which underwent necropsy and radiographic evaluation at the National Wildlife Health Center. These malformations are described in detail and classified into four major categories: (1) no limb (amelia); (2) multiple limbs or limb elements (polymelia, polydactyly, polyphalangy); (3) reduced limb segments or elements (phocomelia, ectromelia, ectrodactyly, and brachydactyly; and (4) distally complete but malformed limb (bone rotations, bridging, skin webbing, and micromelia). Results Amelia and reduced segments and/or elements were the most common finding. Frogs with bilateral hind limb malformations were not common, and in only eight of these 22 frogs were the malformations symmetrical. Malformations of a given type tended to occur in frogs collected from the same site, but the types of malformations varied widely among all three states, and between study sites within Minnesota. Conclusions Clustering of malformation type suggests that developmental events may produce a variety of phenotypes depending on the timing, sequence, and severity of the environmental insult. Hind limb malformations in free-living frogs transcend current mechanistic explanations of tetrapod limb development.

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

    PubMed Central

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

    2016-01-01

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

  12. Reinnervation of hind limb extremity after lumbar dorsal root ganglion injury.

    PubMed

    Liu, Song; Bréjot, Thomas; Cressant, Arnaud; Bacci, Josette; Saïd, Gérard; Tadié, Marc; Heard, Jean Michel

    2005-12-01

    Loss of dorsal root ganglion neuron, or injury to dorsal roots, induces permanent somatosensory defect without therapeutic option. We explored an approach to restoring hind limb somatosensory innervation after elimination of L4, L5 and L6 dorsal root ganglion neurons in rats. Somatosensory pathways were reconstructed by connecting L4, L5 and L6 lumbar dorsal roots to T10, T11 and T12 intercostal nerves, respectively, thus allowing elongation of thoracic ganglion neuron peripheral axons into the sciatic nerve. Connection of thoracic dorsal root ganglion neurons to peripheral tissues was documented 4 and 7 months after injury. Myelinated and unmyelinated fibers regrew in the sciatic nerve. Nerve terminations expressing calcitonin-gene-related-peptide colonized the footpad skin. Retrograde tracing showed that T10, T11 and T12 dorsal root ganglion neurons expressing calcitonin-gene-related-peptide or the neurofilament RT97 projected axons to the sciatic nerve and the footpad skin. Recording of somatosensory evoked potentials in the upper spinal cord indicated connection between the sciatic nerve and the central nervous system. Hind limb retraction in response to nociceptive stimulation of the reinnervated footpads and reversion of skin lesions suggested partial recovery of sensory function. Proprioceptive defects persisted. Delayed somatosensory reinnervation of the hind limb after destruction of lumbar dorsal root neurons in rats indicates potential approaches to reduce chronic disability after severe injury to somatosensory pathways.

  13. A new model for the immobilization of the rat hind limb.

    PubMed

    Coutinho, E L; Gomes, A R S; Franca, C N; Salvini, T F

    2002-11-01

    An alternative device for the immobilization of the hind limb of the rat was developed to study the effects of chronic disuse on the soleus and tibialis anterior muscles, maintained for 3 weeks in the shortening and the stretching positions, respectively. The proposed device is made of steel mesh and cotton materials, and has some advantages when compared to cast or plaster cast: it is cheaper, lighter (12 g or 4% of the body weight of the rat) and the same unit can be easily adjusted and used several times in the same animal or in animals of similar size. Immobilization is also useful to restrain the movements of the hip, knee, and ankle joints. Male rats (291 +/- 35 g and aged 14 +/- 2 weeks) were used to develop and test the model. The soleus muscle of 18 rats was maintained in a shortened position for 21 consecutive days and lost 19 +/- 7% of its length (P = 0.008) and 44 +/- 6% of its weight (P = 0.002) compared to the contralateral intact muscle. No difference (P = 0.67) was found in the stretched tibialis anterior of the same hind limb when compared to the contralateral muscle. No ulcer, sore or foot swelling was observed in the animals. Immobilization was effective in producing chronic muscle disuse in the hind limbs of rats and is an acceptable alternative to the traditional methods of immobilization such as cast or plaster cast.

  14. Insulin resistance of hind-limb tissues in vivo in lactating sheep.

    PubMed Central

    Vernon, R G; Faulkner, A; Hay, W W; Calvert, D T; Flint, D J

    1990-01-01

    1. The effects of varying the plasma insulin concentration by infusion while maintaining euglycaemia by infusion of glucose on nutrient arterio-venous differences across the hind-limb and mammary gland in lactating and non-lactating sheep were investigated. 2. Insulin infusion increased the glucose arterio-venous difference across the hind-limb; this effect of insulin was decreased by lactation, suggesting that lactation induces insulin resistance in skeletal muscle. 3. Lactation increased but insulin infusion decreased the plasma concentrations of acetate, beta-hydroxybutyrate and non-esterified fatty acids. 4. Insulin infusion decreased the arterio-venous differences of acetate and hydroxybutyrate across the hind-limb; this effect of insulin is probably indirect, resulting from the decrease in plasma concentrations of these metabolites. 5. Infusion of insulin had no effect on the glucose arterio-venous difference across the mammary gland, but did decrease the oxygen arterio-venous difference. 6. The results suggest that lactation results in insulin resistance in skeletal muscle, at least with respect to glucose utilization; this should facilitate the preferential utilization of glucose by the mammary gland. PMID:2241910

  15. Identifying risk factors for poor hind limb cleanliness in Danish loose-housed dairy cows.

    PubMed

    Nielsen, B H; Thomsen, P T; Sørensen, J T

    2011-08-01

    The objective of this study was to identify possible risk factors for poor cow hind limb cleanliness in Danish loose-housed, lactating dairy cows. The study was conducted as a cross-sectional study of 1315 cows in 42 commercial Danish dairy herds with primarily Danish Holstein cows. The effect of four cow-level factors (parity, days in milk, daily lying time and lameness) and eight herd-level factors (herd size, milk production, milking system, floor type, access to pasture grazing, floor scraping frequency, hoof bathing frequency and hoof washing frequency) on the risk of having dirtier hind limbs were analysed using ordinal logistic regression fitting a proportional odds model. Cow hind limb cleanliness was scored using an ordinal score from 1 to 4: 1 being clean and 4 being covered in dirt. The odds ratios (ORs) estimated from the proportional odds model depict the effect of a risk factor on the odds of having a higher rather than a lower cleanliness score. First parity cows had an increased risk of being dirtier compared with third parity or older cows (OR=1.70). Compared with late lactation, early and mid lactation were associated with an increased risk of being dirtier (OR=2.07 and 1.33, respectively). Decreasing the daily time lying by 30 min was associated with an increased risk of being dirtier (OR=1.05). Furthermore, an increased risk of being dirtier was found in herds with no pasture access (OR=3.75).

  16. Ontogenetic scaling of fore- and hind limb posture in wild chacma baboons (Papio hamadryas ursinus).

    PubMed

    Patel, Biren A; Horner, Angela M; Thompson, Nathan E; Barrett, Louise; Henzi, S Peter

    2013-01-01

    Large-scale interspecific studies of mammals ranging between 0.04-280 kg have shown that larger animals walk with more extended limb joints. Within a taxon or clade, however, the relationship between body size and joint posture is less straightforward. Factors that may affect the lack of congruence between broad and narrow phylogenetic analyses of limb kinematics include limited sampling of (1) ranges of body size, and/or (2) numbers of individuals. Unfortunately, both issues are inherent in laboratory-based or zoo locomotion research. In this study, we examined the relationship between body mass and elbow and knee joint angles (our proxies of fore- and hind limb posture, respectively) in a cross-sectional ontogenetic sample of wild chacma baboons (Papio hamadryas ursinus) habituated in the De Hoop Nature Reserve, South Africa. Videos were obtained from 33 individuals of known age (12 to ≥ 108 months) and body mass (2-29.5 kg) during walking trials. Results show that older, heavier baboons walk with significantly more extended knee joints but not elbow joints. This pattern is consistent when examining only males, but not within the female sample. Heavier, older baboons also display significantly less variation in their hind limb posture compared to lighter, young animals. Thus, within this ontogenetic sample of a single primate species spanning an order of magnitude in body mass, hind limb posture exhibited a postural scaling phenomenon while the forelimbs did not. These findings may further help explain 1) why younger mammals (including baboons) tend to have relatively stronger bones than adults, and 2) why humeri appear relatively weaker than femora (in at least baboons). Finally, this study demonstrates how field-acquired kinematics can help answer fundamental biomechanical questions usually addressed only in animal gait laboratories.

  17. Ontogenetic Scaling of Fore- and Hind Limb Posture in Wild Chacma Baboons (Papio hamadryas ursinus)

    PubMed Central

    Patel, Biren A.; Horner, Angela M.; Thompson, Nathan E.; Barrett, Louise; Henzi, S. Peter

    2013-01-01

    Large-scale interspecific studies of mammals ranging between 0.04–280 kg have shown that larger animals walk with more extended limb joints. Within a taxon or clade, however, the relationship between body size and joint posture is less straightforward. Factors that may affect the lack of congruence between broad and narrow phylogenetic analyses of limb kinematics include limited sampling of (1) ranges of body size, and/or (2) numbers of individuals. Unfortunately, both issues are inherent in laboratory-based or zoo locomotion research. In this study, we examined the relationship between body mass and elbow and knee joint angles (our proxies of fore- and hind limb posture, respectively) in a cross-sectional ontogenetic sample of wild chacma baboons (Papio hamadryas ursinus) habituated in the De Hoop Nature Reserve, South Africa. Videos were obtained from 33 individuals of known age (12 to ≥108 months) and body mass (2–29.5 kg) during walking trials. Results show that older, heavier baboons walk with significantly more extended knee joints but not elbow joints. This pattern is consistent when examining only males, but not within the female sample. Heavier, older baboons also display significantly less variation in their hind limb posture compared to lighter, young animals. Thus, within this ontogenetic sample of a single primate species spanning an order of magnitude in body mass, hind limb posture exhibited a postural scaling phenomenon while the forelimbs did not. These findings may further help explain 1) why younger mammals (including baboons) tend to have relatively stronger bones than adults, and 2) why humeri appear relatively weaker than femora (in at least baboons). Finally, this study demonstrates how field-acquired kinematics can help answer fundamental biomechanical questions usually addressed only in animal gait laboratories. PMID:23923046

  18. Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms.

    PubMed

    Klafke, J Z; da Silva, M A; Rossato, M F; de Prá, S Dal Toé; Rigo, F K; Walker, C I B; Bochi, G V; Moresco, R N; Ferreira, J; Trevisan, G

    2016-02-01

    Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain.

  19. Norepinephrine stimulates mobilization of endothelial progenitor cells after limb ischemia.

    PubMed

    Jiang, Qijun; Ding, Shifang; Wu, Jianxiang; Liu, Xing; Wu, Zonggui

    2014-01-01

    During several pathological processes such as cancer progression, thermal injury, wound healing and hindlimb ischemia, the mobilization of endothelial progenitor cells (EPCs) mobilization was enhanced with an increase of sympathetic nerve activity and norepinephrine (NE) secretion, yet the cellular and molecular mechanisms involved in the effects of NE on EPCs has less been investigated. EPCs from BMs, peripheral circulation and spleens, the VEGF concentration in BM, skeletal muscle, peripheral circulation and spleen and angiogenesis in ischemic gastrocnemius were quantified in mice with hindlimbs ischemia. Systemic treatment of NE significantly increased EPCs number in BM, peripheral circulation and spleen, VEGF concentration in BM and skeletal muscle and angiogenesis in ischemic gastrocnemius in mice with hind limb ischemia, but did not affair VEGF concentration in peripheral circulation and spleen. EPCs isolated from healthy adults were cultured with NE in vitro to evaluate proliferation potential, migration capacity and phosphorylations of Akt and eNOS signal moleculars. Treatment of NE induced a significant increase in number of EPCs in the S-phase in a dose-dependent manner, as well as migrative activity of EPCs in vitro (p<0.05). The co-treatment of Phentolamine, I127, LY294002 and L-NAME with NE blocked the effects of NE on EPCs proliferation and migration. Treatment with NE significantly increased phosphorylation of Akt and eNOS of EPCs. Addition of phentolamine and I127 attenuated the activation of Akt/eNOS pathway, but metoprolol could not. Pretreatment of mice with either Phentolamine or I127 significantly attenuated the effects of NE on EPCs in vivo, VEGF concentration in BM, skeletal muscle and angiogenesis in ischemic gastrocnemius, but Metoprolol did not. These results unravel that sympathetic nervous system regulate EPCs mobilization and their pro-angiogenic capacity via α adrenoceptor, β 2 adrenoceptor and meanwhile Akt/eNOS signaling pathway.

  20. 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

  1. Disparate Igf1 expression and growth in the fore- and hind limbs of a marsupial mammal (Monodelphis domestica).

    PubMed

    Sears, Karen E; Patel, Ankit; Hübler, Merla; Cao, Xiaoyi; Vandeberg, John L; Zhong, Sheng

    2012-06-01

    Proper regulation of growth is essential to all stages of life, from development of the egg into an embryo to the maintenance of normal cell cycle progression in adults. However, despite growth's importance to basic biology and health, little is known about how mammalian growth is regulated. In this study, we investigated the molecular basis of the highly disparate growth of opossum fore- and hind limbs in utero. We first used a novel, opossum-specific microarray to identify several growth-related genes that are differentially expressed in opossum fore- and hind limbs of comparable developmental stages. These genes included Igf1. Given Igf1's role in the growth of other systems, we further investigated the role of Igf1 in opossum limb growth. Supporting the microarray results, RT-PCR indicated that Igf1 levels are approximately two times higher in opossum fore- than hind limbs. Consistent with this, while Igf1 transcripts were readily detectable in opossum forelimbs using whole-mount in situ hybridization, they were not detectable in opossum hind limbs. Furthermore, opossum limbs treated with exogenous Igf1 protein experienced significantly greater cellular proliferation and growth than control limbs in vitro. Taken together, results suggest that the differential expression of Igf1 in developing opossum limbs contributes to their divergent rate of growth, and the unique limb phenotype of opossum newborns. This study establishes the opossum limb as a new mammalian model system for study of organ growth.

  2. 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.

  3. 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.

  4. Hind limb unloading, a model of spaceflight conditions, leads to decreased B lymphopoiesis similar to aging.

    PubMed

    Lescale, Chloé; Schenten, Véronique; Djeghloul, Dounia; Bennabi, Meriem; Gaignier, Fanny; Vandamme, Katleen; Strazielle, Catherine; Kuzniak, Isabelle; Petite, Hervé; Dosquet, Christine; Frippiat, Jean-Pol; Goodhardt, Michele

    2015-02-01

    Within the bone marrow, the endosteal niche plays a crucial role in B-cell differentiation. Because spaceflight is associated with osteoporosis, we investigated whether changes in bone microstructure induced by a ground-based model of spaceflight, hind limb unloading (HU), could affect B lymphopoiesis. To this end, we analyzed both bone parameters and the frequency of early hematopoietic precursors and cells of the B lineage after 3, 6, 13, and 21 d of HU. We found that limb disuse leads to a decrease in both bone microstructure and the frequency of B-cell progenitors in the bone marrow. Although multipotent hematopoietic progenitors were not affected by HU, a decrease in B lymphopoiesis was observed as of the common lymphoid progenitor (CLP) stage with a major block at the progenitor B (pro-B) to precursor B (pre-B) cell transition (5- to 10-fold decrease). The modifications in B lymphopoiesis were similar to those observed in aged mice and, as with aging, decreased B-cell generation in HU mice was associated with reduced expression of B-cell transcription factors, early B-cell factor (EBF) and Pax5, and an alteration in STAT5-mediated IL-7 signaling. These findings demonstrate that mechanical unloading of hind limbs results in a decrease in early B-cell differentiation resembling age-related modifications in B lymphopoiesis.

  5. Mechanical constraints on the functional morphology of the gibbon hind limb

    PubMed Central

    Channon, Anthony J; Günther, Michael M; Crompton, Robin H; Vereecke, Evie E

    2009-01-01

    Gibbons utilize a number of locomotor modes in the wild, including bipedalism, leaping and, most of all, brachiation. Each locomotor mode puts specific constraints on the morphology of the animal; in some cases these may be complementary, whereas in others they may conflict. Despite several studies of the locomotor biomechanics of gibbons, very little is known about the musculoskeletal architecture of the limbs. In this study, we present quantitative anatomical data of the hind limb for four species of gibbon (Hylobates lar, H. moloch, H. pileatus and Symphalangus syndactylus). Muscle mass and fascicle lengths were obtained from all of the major hind limb muscles and the physiological cross-sectional area was calculated and scaled to remove the effect of body size. The results clearly indicate that, for all of the species studied, the major hip, knee and ankle extensors are short-fascicled and pennate. The major hip and knee flexors, however, are long-fascicled, parallel muscles with relatively small physiological cross-sectional areas. We hypothesize that the short-fascicled muscles could be coupled with a power-amplifying mechanism and are predominantly useful in leaping. The long-fascicled knee and hip flexors are adapted for a wide range of joint postures and can play a role in flexing the legs during brachiation. PMID:19627388

  6. Mechanical constraints on the functional morphology of the gibbon hind limb.

    PubMed

    Channon, Anthony J; Günther, Michael M; Crompton, Robin H; Vereecke, Evie E

    2009-10-01

    Gibbons utilize a number of locomotor modes in the wild, including bipedalism, leaping and, most of all, brachiation. Each locomotor mode puts specific constraints on the morphology of the animal; in some cases these may be complementary, whereas in others they may conflict. Despite several studies of the locomotor biomechanics of gibbons, very little is known about the musculoskeletal architecture of the limbs. In this study, we present quantitative anatomical data of the hind limb for four species of gibbon (Hylobates lar, H. moloch, H. pileatus and Symphalangus syndactylus). Muscle mass and fascicle lengths were obtained from all of the major hind limb muscles and the physiological cross-sectional area was calculated and scaled to remove the effect of body size. The results clearly indicate that, for all of the species studied, the major hip, knee and ankle extensors are short-fascicled and pennate. The major hip and knee flexors, however, are long-fascicled, parallel muscles with relatively small physiological cross-sectional areas. We hypothesize that the short-fascicled muscles could be coupled with a power-amplifying mechanism and are predominantly useful in leaping. The long-fascicled knee and hip flexors are adapted for a wide range of joint postures and can play a role in flexing the legs during brachiation.

  7. COORDINATED, MULTI-JOINT, FATIGUE-RESISTANT FELINE STANCE PRODUCED WITH INTRAFASCICULAR HIND LIMB NERVE STIMULATION

    PubMed Central

    Normann, R A; Dowden, B R; Frankel, M A; Wilder, A M; Hiatt, S D; Ledbetter, N M; Warren, D A; Clark, G A

    2012-01-01

    The production of graceful skeletal movements requires coordinated activation of multiple muscles that produce torques around multiple joints. The work described herein is focused on one such movement, stance, that requires coordinated activation of extensor muscles acting around the hip, knee and ankle joints. The forces evoked in these muscles by external stimulation all have a complex dependence on muscle length and shortening velocities, and some of these muscles are bi-articular. In order to recreate sit-to-stand maneuvers in the anesthetized feline, we excited the hind limb musculature using intrafascicular multielectrode stimulation (IFMS) of the muscular branch of the sciatic nerve, the femoral nerve, and the main branch of the sciatic nerve. Stimulation was achieved with either acutely or chronically implanted Utah Slanted Electrode Arrays (USEAs) via subsets of electrodes 1) that activated motor units in the extensor muscles of the hip, knee, and ankle joints, 2) that were able to evoke large extension forces, and 3) that manifested minimal coactivation of the targeted motor units. Three hind limb force-generation strategies were investigated, including sequential activation of independent motor units to increase force, and interleaved or simultaneous IFMS of three sets of six or more USEA electrodes that excited the hip, knee, and ankle extensors. All force-generation strategies evoked stance, but the interleaved IFMS strategy also reduced muscle fatigue produced by repeated sit-to-stand maneuvers compared with fatigue produced by simultaneous activation of different motor neuron pools. These results demonstrate the use of interleaved IFMS as a means to recreate coordinated, fatigue-resistant multi-joint muscle forces in the unilateral hind limb. This muscle activation paradigm could provide a promising neuroprosthetic approach for the restoration of sit-to-stand transitions in individuals who are paralyzed by spinal cord injury, stroke, or disease. PMID

  8. Coordinated, multi-joint, fatigue-resistant feline stance produced with intrafascicular hind limb nerve stimulation

    NASA Astrophysics Data System (ADS)

    Normann, R. A.; Dowden, B. R.; Frankel, M. A.; Wilder, A. M.; Hiatt, S. D.; Ledbetter, N. M.; Warren, D. A.; Clark, G. A.

    2012-04-01

    The production of graceful skeletal movements requires coordinated activation of multiple muscles that produce torques around multiple joints. The work described herein is focused on one such movement, stance, that requires coordinated activation of extensor muscles acting around the hip, knee and ankle joints. The forces evoked in these muscles by external stimulation all have a complex dependence on muscle length and shortening velocities, and some of these muscles are biarticular. In order to recreate sit-to-stand maneuvers in the anesthetized feline, we excited the hind limb musculature using intrafascicular multielectrode stimulation (IFMS) of the muscular branch of the sciatic nerve, the femoral nerve and the main branch of the sciatic nerve. Stimulation was achieved with either acutely or chronically implanted Utah Slanted Electrode Arrays (USEAs) via subsets of electrodes (1) that activated motor units in the extensor muscles of the hip, knee and ankle joints, (2) that were able to evoke large extension forces and (3) that manifested minimal coactivation of the targeted motor units. Three hind limb force-generation strategies were investigated, including sequential activation of independent motor units to increase force, and interleaved or simultaneous IFMS of three sets of six or more USEA electrodes that excited the hip, knee and ankle extensors. All force-generation strategies evoked stance, but the interleaved IFMS strategy also reduced muscle fatigue produced by repeated sit-to-stand maneuvers compared with fatigue produced by simultaneous activation of different motor neuron pools. These results demonstrate the use of interleaved IFMS as a means to recreate coordinated, fatigue-resistant multi-joint muscle forces in the unilateral hind limb. This muscle activation paradigm could provide a promising neuroprosthetic approach for the restoration of sit-to-stand transitions in individuals who are paralyzed by spinal cord injury, stroke or disease.

  9. Muscular reconstruction and functional morphology of the hind limb of santacrucian (Early Miocene) sloths (Xenarthra, Folivora) of Patagonia.

    PubMed

    Toledo, Néstor; Bargo, M Susana; Vizcaíno, Sergio F

    2015-05-01

    This article presents a morphofunctional analysis of the hind limb of Santacrucian (Early Miocene) sloths from southernmost Patagonia (Argentina). These fossil sloths were mid sized to large animals, ranging from 40 to 120 kg, and their postcranial skeleton was markedly different in shape compared with that of extant tree sloths, which vary from 2 to 10 kg. The functional anatomy of the hind limb of Santacrucian sloths was compared with that of living xenarthrans (tree sloths, anteaters, and armadillos), which involved reconstruction of the hind limb musculature and comparative and qualitative morphofunctional analyses, and hypotheses on the biological role of the hind limb in terms of preferences in substrate, posture, and strategies of locomotion were formulated. The hind limb of Santacrucian sloths bears strong resemblances to that of living South American anteaters in stoutness of skeletal elements, form of the characteristics related to muscular and ligamentous attachments, and conservative, pentadactylous strong-clawed pes. The musculature was very well developed, allowing powerful forces, principally in entire limb adduction, crus flexion and extension, pes extension, and toe prehension. These functional features, together with those of the forelimb, are congruent with climbing behavior, and support the hypothesis that Santacrucian sloths were good but slow climbing mammals. However, their climbing strategies were limited, owing principally to their comparatively large body size, and they relied to a large extent on their powerful musculature and curved manual and pedal unguals for both moving and standing on the arboreal supports.

  10. The effect of baclofen on the hind limb flexor reflex of the spinal rat.

    PubMed

    Sypniewska, M

    1979-01-01

    The effect of baclofen on the hind limb flexor reflex of the spinal rat was studied. Baclofen inhibited the flexor reflex, this effect not being antagonized by picrotoxin and bicuculline. Baclofen reduced the stimulating action of quipazine and LSD, had no effect on the clonidine-induced reflex stimulation, but inhibited the flexor reflex stimulation induced by amphetamine and fenfluramine. The results obtained bring forth some doubts as to the GABA-mimetic action of baclofen. The action of baclofen on the spinal cord seems to be directed mainly to the presynaptic part of the noradrenergic and serotonergic systems.

  11. 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

  12. VEGF and IGF Delivered from Alginate Hydrogels Promote Stable Perfusion Recovery in Ischemic Hind Limbs of Aged Mice and Young Rabbits.

    PubMed

    Anderson, Erin M; Silva, Eduardo A; Hao, Yibai; Martinick, Kathleen D; Vermillion, Sarah A; Stafford, Alexander G; Doherty, Elisabeth G; Wang, Lin; Doherty, Edward J; Grossman, Paul M; Mooney, David J

    2017-09-21

    Biomaterial-based delivery of angiogenic growth factors restores perfusion more effectively than bolus delivery methods in rodent models of peripheral vascular disease, but the same success has not yet been demonstrated in clinically relevant studies of aged or large animals. These studies explore, in clinically relevant models, a therapeutic angiogenesis strategy for the treatment of peripheral vascular disease that overcomes the challenges encountered in previous clinical trials. Alginate hydrogels providing sustained release of vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF) were injected into ischemic hind limbs in middle-aged and old mice, and also in young rabbits, as a test of the scalability of this local growth factor treatment. Spontaneous perfusion recovery diminished with increasing age, and only the combination of VEGF and IGF delivery from gels significantly rescued perfusion in middle-aged (13 months) and old (20 months) mice. In rabbits, the delivery of VEGF alone or in combination with IGF from alginate hydrogels, at a dose 2 orders of magnitude lower than the typical doses used in past rabbit studies, enhanced perfusion recovery when given immediately after surgery, or as a treatment for chronic ischemia. Capillary density measurements and angiographic analysis demonstrated the benefit of gel delivery. These data together suggest that alginate hydrogels providing local delivery of low doses of VEGF and IGF constitute a safe and effective treatment for hind-limb ischemia in clinically relevant animal models, thereby supporting the potential clinical translation of this concept. © 2017 S. Karger AG, Basel.

  13. Combined effects of soy isoflavones and milk basic protein on bone mineral density in hind-limb unloaded mice

    PubMed Central

    Matsumoto, Yu; Tousen, Yuko; Nishide, Yoriko; Tadaishi, Miki; Kato, Ken; Ishimi, Yoshiko

    2016-01-01

    We examined whether the combination of isoflavone and milk basic protein both are reported to be effective for bone metabolism, prevents bone loss induced by skeletal hind-limb unloading in mice. Female ddY strain mice, aged 8 weeks, were divided into six groups (n = 6–8 each): (1) normally housed group, (2) loading group, (3) hind-limb unloading group fed a control diet, (4) hind-limb unloading group fed a 0.2% isoflavone conjugates diet, (5) hind-limb unloading group fed a 1.0% milk basic protein diet, and (6) hind-limb unloading group fed a 0.2% isoflavone conjugates and 1.0% milk basic protein diet. After 3 weeks, femoral bone mineral density was markedly reduced in unloading mice. The combination of isoflavone and milk basic protein showed cooperative effects in preventing bone loss and milk basic protein inhibited the increased expression of osteogenic genes in bone marrow cells in unloading mice. These results suggest that the combination of soy isoflavone and milk basic protein may be useful for bone health in subjects with disabling conditions as well as astronauts. PMID:27013781

  14. Treatment effect with anti-RAGE F(ab')2 antibody improves hind limb angiogenesis and blood flow in Type 1 diabetic mice with left femoral artery ligation.

    PubMed

    Tekabe, Yared; Anthony, Tamykah; Li, Qing; Ray, Rashmi; Rai, Vivek; Zhang, Geping; Schmidt, Ann Marie; Johnson, Lynne L

    2015-06-01

    We investigated treatment with a receptor for advanced glycation endproduct (RAGE) blocking antibody on angiogenic response to hind limb ischemia in diabetic mice. Streptozotocin treated C57BL/6 mice received either murine monoclonal anti-RAGE F(ab')2 intraperitoneally (n=10) or saline (n=9) for 9 weeks. Diabetic plus 10 non-diabetic C57BL/6 mice underwent left femoral artery ligation and 5 days later angiogenesis imaging with (99m)Tc-Arg-Gly-Asp (RGD) nanoSPECT/CT. Twenty-four days later, hind limb blood flow was measured with ultrasound, the mice were euthanized, and tissue was taken for immunohistochemistry. The angiogenic imaging signal in ischemic limbs was higher in RAGE-ab treated versus saline treated mice at day 5 (3.1±1.4 vs 1.68±0.35, p=0.02) and blood flow was higher at day 24 (1.49±0.5 vs 0.61±0.39, p=0.04). Immunohistochemistry of ischemic muscles showed greater capillary density in the RAGE-ab treated group versus the vehicle-treated group (p<0.001) (NS from non-diabetic mice). In conclusion, treatment with anti-RAGE F(ab')2 in diabetic mice improves neovascularization in the ischemic leg. © The Author(s) 2015.

  15. 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.

  16. Perivertebral B-cell lymphoma in a Queensland koala (Phascolarctos cinereus adustus) with paralytic symptoms in the hind limbs.

    PubMed

    Kido, Nobuhide; Edamura, Kazuya; Inoue, Naomi; Shibuya, Hisashi; Sato, Tsuneo; Kondo, Masako; Shindo, Izumi

    2012-08-01

    A male Queensland koala (Phascolarctos cinereus adustus) at Kanazawa Zoological Gardens (Kanagawa, Japan) exhibited paralytic symptoms in the hind limbs. Computed tomography and magnetic resonance imaging revealed a mass on the left ventral side of the 11th to 13th thoracic vertebrae, and the presence of myelitis or edema in the spinal cord. The koala was under anesthesia during the examination and suddenly developed ventricular fibrillation and died. Necropsy revealed a firm flat ovoid hemorrhagic mass on the vertebrae. Following a microscopic examination including immunohistochemistry, the perivertebral mass was diagnosed as B cell lymphoma. Therefore, neoplastic cell infiltration into the spinal cord may cause paralytic symptoms in the hind limbs.

  17. 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

  18. The development of functional innervation in the hind limb of the chick embryo.

    PubMed Central

    Landmesser, L; Morris, D G

    1975-01-01

    1. The development of functional motor innervation was studied in the hind limb of chick embryos from Stages 25 to 43 by observing contraction of individual muscles and by recording the resultant tension when individual spinal nerves were electrically stimulated. 2. At later developmental stages (35-43) a given muscle always received functional innervation from specific spinal nerves. This pattern, with respect to the craniocaudal position of motoneurones, was similar to those described for amphibians and mammals. 3. The observed pattern was similar throughout development from the time that movement could first be elicited at Stages 27-28. There was no indication that motoneurones form initial synapses with inappropriate muscles. 4. Recordings from muscle nerves during excitation of individual spinal nerves gave results similar to the tension recordings, showing that even at early developmental stages muscle nerves did not contain substantial numbers of inappropriate axons. 5. Most limb muscles or primitive muscle masses became functionally innervated at the same time with no clearly defined proximo-distal sequence of limb innervation. 6. It appears that chick motoneurones are initially specified with respect to their peripheral destination and grow out selectively to synapse with appropriate muscles from the outset. PMID:1177095

  19. FACS-based Satellite Cell Isolation From Mouse Hind Limb Muscles.

    PubMed

    Gromova, Anastasia; Tierney, Matthew T; Sacco, Alessandra

    2015-08-20

    Fluorescence Activated Cell Sorting (FACS) is a sensitive and accurate method for purifying satellite cells, or muscle stem cells, from adult mouse skeletal muscle (Liu et al., 2013; Sacco et al., 2008; Tierney et al., 2014). Mechanical and enzymatic digestion of hind limb muscles releases mononuclear muscle cells into suspension. This protocol employs fractionation strategies to deplete cells expressing the cell surface markers CD45, CD31, CD11b and Ly-6A/E-Sca1, both by magnetic separation and FACS-based exclusion, and positively select for cells expressing a7-integrin and CD34. This enables the researcher to successfully enrich satellite cells that uniformly express the paired-box transcription factor Pax7 and are capable of long-term self-renewal, skeletal muscle repair and muscle stem cell pool repopulation.

  20. Effect of demedullation on freezing injury in hind limbs of rats

    NASA Astrophysics Data System (ADS)

    Dhingra, Shashi; Bhatia, B.; Chhina, G. S.; Singh, Baldev

    1987-09-01

    Freezing incidence and tissue loss on exposure of hind limbs of female Wistar rats to freezing mixture was reduced by demedullation 6 days prior to cold exposure (p<0.01 and p<0.001 respectively); demedullation 1 h after freezing injury had no effect on tissue loss. Noradrenaline (1 mg/kg i.p.) 5 min before exposure increased the freezing incidence in intact (p<0.05) as well as in demedullated rats (p<0.01), with no effect on tissue loss. Adrenaline (500 mg/kg i.p.) had no effect on either. A sustained fall in plasma adrenaline after demedullation leading to reduced reactivity of the blood vessels to some vasoactive agents is postulated.

  1. Pancreatic Histology and Associated Biochemical Changes in Rats on Hind-Limb Suspension

    NASA Astrophysics Data System (ADS)

    Soulsby, Michael; Johnson, Emily; Akel, Nisreen; Agarwal, Rakhee; Gaddy, Dana; Dobretsov, Maxim; Chowdhury, Parimal

    2011-06-01

    The pancreas plays an important role in regulating many of the key endocrine hormones and digestive enzymes that are required for nutrition and survival of the organism. This study examines the pancreatic histology and associated biochemical changes in rats on hind limb suspension (HLS) after exposure to simulated microgravity. Results show that MDA and glutathione levels were significantly increased in the suspended (HLS) groups as compared to the control group. Plasma insulin levels averaged 2.43±0.32 ng/ml in the control animals and decreased significantly to 1.47±0.24 ng/ml in the suspended group. Histopathology revealed increased vacuolation, pyknosis, membrane thickening, increase of zymogen granules and increase in islets (both in size and number) in the suspended group as compared to the control group.

  2. 3D reconstruction of digitized histological sections for vasculature quantification in the mouse hind limb

    NASA Astrophysics Data System (ADS)

    Xu, Yiwen; Pickering, J. Geoffrey; Nong, Zengxuan; Gibson, Eli; Ward, Aaron D.

    2014-03-01

    In contrast to imaging modalities such as magnetic resonance imaging and micro computed tomography, digital histology reveals multiple stained tissue features at high resolution (0.25μm/pixel). However, the two-dimensional (2D) nature of histology challenges three-dimensional (3D) quantification and visualization of the different tissue components, cellular structures, and subcellular elements. This limitation is particularly relevant to the vasculature, which has a complex and variable structure within tissues. The objective of this study was to perform a fully automated 3D reconstruction of histology tissue in the mouse hind limb preserving the accurate systemic orientation of the tissues, stained with hematoxylin and immunostained for smooth muscle α actin. We performed a 3D reconstruction using pairwise rigid registrations of 5μm thick, paraffin-embedded serial sections, digitized at 0.25μm/pixel. Each registration was performed using the iterative closest points algorithm on blood vessel landmarks. Landmarks were vessel centroids, determined according to a signed distance map of each pixel to a decision boundary in hue-saturation-value color space; this decision boundary was determined based on manual annotation of a separate training set. Cell nuclei were then automatically extracted and corresponded to refine the vessel landmark registration. Homologous nucleus landmark pairs appearing on not more than two adjacent slides were chosen to avoid registrations which force curved or non-sectionorthogonal structures to be straight and section-orthogonal. The median accumulated target registration errors ± interquartile ranges for the vessel landmark registration, and the nucleus landmark refinement were 43.4+/-42.8μm and 2.9+/-1.7μm, respectively (p<0.0001). Fully automatic and accurate 3D rigid reconstruction of mouse hind limb histology imaging is feasible based on extracted vasculature and nuclei.

  3. Engendering Allograft Ignorance in a Mouse Model of Allogeneic Skin Transplantation to the Distal Hind Limb

    PubMed Central

    Agarwal, Shailesh; Loder, Shawn; Wood, Sherri; Cederna, Paul S.; Bishop, D. Keith; Wang, Stewart C.; Levi, Benjamin

    2015-01-01

    Objective The aim of this study was to demonstrate lymphatic isolation in a model of hind limb lymph node (LN) excision, consisting of ipsilateral popliteal and inguinal LN excision and to evaluate the immunologic response to allogeneic skin transplanted onto this region of lymphatic isolation. Methods To study lymphatic flow, C57BL/6 mice underwent lymphadenectomy (n = 5), sham lymphadenectomy (n = 5), or no intervention (n = 5), followed by methylene blue injection. Mice were dissected to determine whether methylene blue traveled to the iliac LN. To study host response to skin transplantation, C57BL/6 mice underwent allogeneic skin transplantation with LN excision (n = 6), allogeneic skin transplantation alone (n = 6), or syngeneic skin transplantation (n = 4). Skin grafts were placed distal to the popliteal fossa and mice were euthanized at day 10. Grafts were stained for endothelial cell and proliferation markers (CD31 and Ki67, respectively). Secondary lymphoid tissues (spleen, ipsilateral axillary LN, and contralateral inguinal LN) were removed and rechallenged with BALB/c alloantigen in vitro with subsequent assay of interferon-γ and interleukin 4 cell expression using ELISPOT technique. Results Mice that underwent LN excision had no evidence of methylene blue in the iliac nodes; mice without surgical intervention or with sham LN excision consistently had methylene blue visible in the ipsilateral iliac nodes. Mice treated with allogeneic skin transplantation and LN excision had lower expression of interferon-γ and interleukin 4 in the secondary lymphoid tissues. Conclusions Lymph node excision completely interrupts lymphatic flow of the hind limb. This model of lymphatic isolation impairs the ability of the transplant recipient to acutely mount a Th1 or Th2 response to allogeneic skin transplants. PMID:24509194

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2016-09-01

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

  7. The development of motor projection patterns in the chick hind limb.

    PubMed Central

    Landmesser, L

    1978-01-01

    1. Retrograde transport of horseradish peroxidase was used to map the initial projection patterns of lumbosacral motoneurones to the embryonic chick hind limb. 2. The stage 28 segmental projection pattern to each of the four primary muscle masses was characteristic and indistinguishable from the stage 36 projection pattern to the sum of the muscles derived from that mass. In addition, the adductor motoneurone pool was found to be similar in position (both rostro-caudal and mediolateral) at stages 29, 30, 32, 33 1/2 and 36. 3. Therefore axons from lumbosacral motoneurones project for the most part only to appropriate regions from early times shortly after they grow into the limb bud. Furthermore, the attainment of the segmental projection pattern occurs prior to the normal time of, and therefore without the aid of, cell death. This conclusion was supported by electrophysiological recordings made from muscle nerves. 4. A regionalization of the projection patterns within a single muscle mass could be shown both anatomically and physiologically prior to the cleavage of the mass into individual muscles and the projections were in a general way appropriate for the muscles derived from those regions. 5. Therefore the process of muscle cleavage does not in itself create the specific projection patterns observed, and motoneurone axons appear to grow to and to ramify and make synapses only within regions which correspond to their adult muscles. 6. Finally, the termination site of each motoneurone axon in the early limb was found to be tightly correlated in a somatotopic fashion with the position occupied by its soma in the cord. This suggests that some feature of the motoneurone related to its position may be of importance in achieving the specific projection patterns observed. Images Plate 1 PMID:731552

  8. A reproducible radiation delivery method for unanesthetized rodents during periods of hind limb unloading

    NASA Astrophysics Data System (ADS)

    Walb, M. C.; Black, P. J.; Payne, V. S.; Munley, M. T.; Willey, J. S.

    2015-07-01

    Exposure to the spaceflight environment has long been known to be a health challenge concerning many body systems. Both microgravity and/or ionizing radiation can cause acute and chronic effects in multiple body systems. The hind limb unloaded (HLU) rodent model is a ground-based analogue for microgravity that can be used to simulate and study the combined biologic effects of reduced loading with spaceflight radiation exposure. However, studies delivering radiation to rodents during periods of HLU are rare. Herein we report the development of an irradiation protocol using a clinical linear accelerator that can be used with hind limb unloaded, unanesthetized rodents that is capable of being performed at most academic medical centers. A 30.5 cm × 30.5 cm × 40.6 cm rectangular chamber was constructed out of polymethyl methacrylate (PMMA) sheets (0.64 cm thickness). Five centimeters of water-equivalent material were placed outside of two PMMA inserts on either side of the rodent that permitted the desired radiation dose buildup (electronic equilibrium) and helped to achieve a flatter dose profile. Perforated aluminum strips permitted the suspension dowel to be placed at varying heights depending on the rodent size. Radiation was delivered using a medical linear accelerator at an accelerating potential of 10 MV. A calibrated PTW Farmer ionization chamber, wrapped in appropriately thick tissue-equivalent bolus material to simulate the volume of the rodent, was used to verify a uniform dose distribution at various regions of the chamber. The dosimetry measurements confirmed variances typically within 3%, with maximum variance <10% indicated through optically stimulated luminescent dosimeter (OSLD) measurements, thus delivering reliable spaceflight-relevant total body doses and ensuring a uniform dose regardless of its location within the chamber. Due to the relative abundance of LINACs at academic medical centers and the reliability of their dosimetry properties, this

  9. A Reproducible Radiation Delivery Method for Unanesthetized Rodents during Periods of Hind Limb Unloading

    PubMed Central

    Walb, M.C.; Black, P.J.; Payne, V.S.; Munley, M.T.; Willey, J.S.

    2015-01-01

    Exposure to the spaceflight environment has long been known to be a health challenge concerning many body systems. Both microgravity and/or ionizing radiation can cause acute and chronic effects in multiple body systems. The hind limb unloaded (HLU) rodent model is a ground-based analogue for microgravity that can be used to simulate and study the combined biologic effects of reduced loading with spaceflight radiation exposure. However, studies delivering radiation to rodents during periods of HLU are rare. Herein we report the development of an irradiation protocol using a clinical linear accelerator that can be used with hind limb unloaded, unanesthetized rodents that is capable of being performed at most academic medical centers. A 30.5 cm × 30.5 cm × 40.6 cm rectangular chamber was constructed out of polymethyl methacrylate (PMMA) sheets (0.64 cm thickness). Five cm of water-equivalent material were placed outside of two PMMA inserts on either side of the rodent that permitted the desired radiation dose buildup (electronic equilibrium) and helped to achieve a flatter dose profile. Perforated aluminum strips permitted the suspension dowel to be placed at varying heights depending on the rodent size. Radiation was delivered using a medical linear accelerator at an accelerating potential of 10 MV. A calibrated PTW Farmer ionization chamber, wrapped in appropriately thick tissue-equivalent bolus material to simulate the volume of the rodent, was used to verify a uniform dose distribution at various regions of the chamber. The dosimetry measurements confirmed variances typically within 3%, with maximum variance <10% indicated through optically stimulated luminescent dosimeter (OSLD) measurements, thus delivering reliable spaceflight-relevant total body doses and ensuring a uniform dose regardless of its location within the chamber. Due to the relative abundance of LINAC’s at academic medical centers and the reliability of their dosimetry properties, this method

  10. A reproducible radiation delivery method for unanesthetized rodents during periods of hind limb unloading.

    PubMed

    Walb, M C; Black, P J; Payne, V S; Munley, M T; Willey, J S

    2015-07-01

    Exposure to the spaceflight environment has long been known to be a health challenge concerning many body systems. Both microgravity and/or ionizing radiation can cause acute and chronic effects in multiple body systems. The hind limb unloaded (HLU) rodent model is a ground-based analogue for microgravity that can be used to simulate and study the combined biologic effects of reduced loading with spaceflight radiation exposure. However, studies delivering radiation to rodents during periods of HLU are rare. Herein we report the development of an irradiation protocol using a clinical linear accelerator that can be used with hind limb unloaded, unanesthetized rodents that is capable of being performed at most academic medical centers. A 30.5 cm×30.5 cm×40.6 cm30.5 cm×30.5 cm×40.6 cm rectangular chamber was constructed out of polymethyl methacrylate (PMMA) sheets (0.64 cm thickness). Five centimeters of water-equivalent material were placed outside of two PMMA inserts on either side of the rodent that permitted the desired radiation dose buildup (electronic equilibrium) and helped to achieve a flatter dose profile. Perforated aluminum strips permitted the suspension dowel to be placed at varying heights depending on the rodent size. Radiation was delivered using a medical linear accelerator at an accelerating potential of 10 MV. A calibrated PTW Farmer ionization chamber, wrapped in appropriately thick tissue-equivalent bolus material to simulate the volume of the rodent, was used to verify a uniform dose distribution at various regions of the chamber. The dosimetry measurements confirmed variances typically within 3%, with maximum variance <10% indicated through optically stimulated luminescent dosimeter (OSLD) measurements, thus delivering reliable spaceflight-relevant total body doses and ensuring a uniform dose regardless of its location within the chamber. Due to the relative abundance of LINACs at academic medical centers and the reliability of their

  11. Effects of Hind Limb Unloading on Pharmacokinetics of Procainamide in Mice

    NASA Technical Reports Server (NTRS)

    Risin, Semyon A.; Dasgupta, Amitava; Ramesh, Govindarajan T.; Risin, Diana

    2007-01-01

    The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in space. It is prudent to expect that low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration. Among the medications of special interest are the cardiovascular drugs, especially the antiarrhythmic agents. In this study we used hind limb unloaded (HLU) mice as a model to investigate possible changes in the PK of a common antiarrhythmic drug procainamide (PA). Prior to drug administration the experimental animals were tail suspended for 24 hours and the control animals were kept free. PA (150-250 mg per kg) was given orally by a gavage procedure. After that the experimental mice were kept suspended for additional 1, 2, 3 and 6 hours. At these time points the serum concentration of PA and N-acetyl-procainamide (NAPA), an active metabolite which is formed by N-acetyltransferase in the liver, were measured by the fluorescence polarization immunoassay (FPIA) on the AxSYM autoanalyzer (Abbott Laboratories, Abbott Park, IL). The serum level of PA in HLU mice at 1 hour after administration was almost 40% lower than in controls. At 2-3 hours the difference still maintained, however, it was not statistically significant; at 6 hours no difference was detected. The level of NAPA in HLU mice was slightly lower at 1 and 2 hours but the difference did not reach statistical significance. The estimated PA half-life time in HLU mice was almost 55% longer than in control animals. These results confirm that hind limb unloading and related hemodynamic changes significantly alter the PK of PA. The effects are most likely primarily associated with a decrease in the drug absorption, especially within the first two hours after administration. At the same time prolongation of the PA half

  12. Effects of Hind Limb Unloading on Pharmacokinetics of Procainamide in Mice

    NASA Technical Reports Server (NTRS)

    Risin, Semyon A.; Dasgupta, Amitava; Ramesh, Govindarajan T.; Risin, Diana

    2007-01-01

    The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in space. It is prudent to expect that low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration. Among the medications of special interest are the cardiovascular drugs, especially the antiarrhythmic agents. In this study we used hind limb unloaded (HLU) mice as a model to investigate possible changes in the PK of a common antiarrhythmic drug procainamide (PA). Prior to drug administration the experimental animals were tail suspended for 24 hours and the control animals were kept free. PA (150-250 mg per kg) was given orally by a gavage procedure. After that the experimental mice were kept suspended for additional 1, 2, 3 and 6 hours. At these time points the serum concentration of PA and N-acetyl-procainamide (NAPA), an active metabolite which is formed by N-acetyltransferase in the liver, were measured by the fluorescence polarization immunoassay (FPIA) on the AxSYM autoanalyzer (Abbott Laboratories, Abbott Park, IL). The serum level of PA in HLU mice at 1 hour after administration was almost 40% lower than in controls. At 2-3 hours the difference still maintained, however, it was not statistically significant; at 6 hours no difference was detected. The level of NAPA in HLU mice was slightly lower at 1 and 2 hours but the difference did not reach statistical significance. The estimated PA half-life time in HLU mice was almost 55% longer than in control animals. These results confirm that hind limb unloading and related hemodynamic changes significantly alter the PK of PA. The effects are most likely primarily associated with a decrease in the drug absorption, especially within the first two hours after administration. At the same time prolongation of the PA half

  13. Effects of Cold Water Immersion on Edema Formation After Blunt Injury to the Hind Limbs of Rats

    PubMed Central

    Dolan, Michael G.; Thornton, Richard M.; Fish, Dale R.; Mendel, Frank C.

    1997-01-01

    Objective: Despite the long history of using cryotherapy to control edema, we found no randomized, controlled studies providing evidence to substantiate this common clinical practice. The purpose of this study was to determine whether cold water immersion affects edema formation following blunt injuries in rats. Design and Setting: The feet of 16 rats were traumatized after hind limb volumes were determined. Four 30-minute treatments of cold water immersion (12.8°C to 15.6°C, 55°F to 60°F), interspersed with four 30-minute rest periods, began immediately after trauma to one randomly selected hind limb of each rat. The limb remained in a dependent position during all treatments, rest periods, and volumetric measurements. Subjects: Sixteen anesthetized Zucker Lean rats were used in the study. Measurements: Limb volumes were measured after each treatment and rest period for a total of 4 hours. Results: The volume of treated limbs was significantly smaller (p < .05) than the volume of untreated limbs after the first treatment and remained smaller throughout the experiment. Conclusions: Immersing rat limbs in 12.8°C to 15.6°C (55°F to60°F) water immediately after blunt injury was effective in curbing edema formation. ImagesFig 1. PMID:16558455

  14. Three-dimensional kinematics of the pelvis and hind limbs in chimpanzee (Pan troglodytes) and human bipedal walking.

    PubMed

    O'Neill, Matthew C; Lee, Leng-Feng; Demes, Brigitte; Thompson, Nathan E; Larson, Susan G; Stern, Jack T; Umberger, Brian R

    2015-09-01

    The common chimpanzee (Pan troglodytes) is a facultative biped and our closest living relative. As such, the musculoskeletal anatomies of their pelvis and hind limbs have long provided a comparative context for studies of human and fossil hominin locomotion. Yet, how the chimpanzee pelvis and hind limb actually move during bipedal walking is still not well defined. Here, we describe the three-dimensional (3-D) kinematics of the pelvis, hip, knee and ankle during bipedal walking and compare those values to humans walking at the same dimensionless and dimensional velocities. The stride-to-stride and intraspecific variations in 3-D kinematics were calculated using the adjusted coefficient of multiple correlation. Our results indicate that humans walk with a more stable pelvis than chimpanzees, especially in tilt and rotation. Both species exhibit similar magnitudes of pelvis list, but with segment motion that is opposite in phasing. In the hind limb, chimpanzees walk with a more flexed and abducted limb posture, and substantially exceed humans in the magnitude of hip rotation during a stride. The average stride-to-stride variation in joint and segment motion was greater in chimpanzees than humans, while the intraspecific variation was similar on average. These results demonstrate substantial differences between human and chimpanzee bipedal walking, in both the sagittal and non-sagittal planes. These new 3-D kinematic data are fundamental to a comprehensive understanding of the mechanics, energetics and control of chimpanzee bipedalism. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Angiogenesis effect of therapeutic ultrasound on ischemic hind limb in mice

    PubMed Central

    Huang, Jing-Juan; Shi, Yi-Qin; Li, Rui-Lin; Hu, An; Zhou, Hong-Sheng; Cheng, Qian; Xu, Zheng; Yang, Zhi-Ming; Hao, Chang-Ning; Duan, Jun-Li

    2014-01-01

    Although significant progress in bypass surgery and catheter intervention against peripheral artery disease, the number of severe critical limb ischemia (CLI) patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. The purpose of this study was to determine the mechanism of therapeutic ultrasound (TUS) on ischemic angiogenesis using mouse model of hindlimb ischemia and the cellular/molecular mechanisms underlying TUS-related neovascularization. The hindlimb ischemic mice were exposed to extracorporeal TUS for 3, 6, 9 minute per day (1 MHz, 0.3 W/cm2) until day 14 after left femoral artery ligation. Increased blood perfusion and capillary density were determined following 9 min of TUS compared with ischemic group. Moreover, TUS treatment increased the protein levels of vascular endothelial growth factor (VEGF), hypoxic inducible factor-1α (HIF-1α), endothelial nitric oxide synthase (eNOS) and p-Akt in vivo. TUS promoted capillary-like tube formation, migration and motility of human umbilical venous endothelial cells (HUVECs). Furthermore, the protein expressions of VEGF, eNOS and p-Akt were increased after TUS treatment. In conclusion, TUS therapy promotes postnatal neovascularization through multiple angiogenic pathways in mice model of ischemic hindlimb. PMID:25628781

  16. Muscle moment arms of the gibbon hind limb: implications for hylobatid locomotion

    PubMed Central

    Channon, Anthony J; Crompton, Robin H; Günther, Michael M; Vereecke, Evie E

    2010-01-01

    Muscles facilitate skeletal movement via the production of a torque or moment about a joint. The magnitude of the moment produced depends on both the force of muscular contraction and the size of the moment arm used to rotate the joint. Hence, larger muscle moment arms generate larger joint torques and forces at the point of application. The moment arms of a number of gibbon hind limb muscles were measured on four cadaveric specimens (one Hylobates lar, one H. moloch and two H. syndactylus). The tendon travel technique was used, utilizing an electro-goniometer and a linear voltage displacement transducer. The data were analysed using a technique based on a differentiated cubic spline and normalized to remove the effect of body size. The data demonstrated a functional differentiation between voluminous muscles with short fascicles having small muscle moment arms and muscles with longer fascicles and comparatively smaller physiological cross-sectional area having longer muscle moment arms. The functional implications of these particular configurations were simulated using a simple geometric fascicle strain model that predicts that the rectus femoris and gastrocnemius muscles are more likely to act primarily at their distal joints (knee and ankle, respectively) because they have short fascicles. The data also show that the main hip and knee extensors maintain a very small moment arm throughout the range of joint angles seen in the locomotion of gibbons, which (coupled to voluminous, short-fascicled muscles) might help facilitate rapid joint rotation during powerful movements. PMID:20447251

  17. Local and distant trauma after hypervelocity ballistic impact to the pig hind limb.

    PubMed

    Chen, Jin; Zhang, Bo; Chen, Wei; Kang, Jian-Yi; Chen, Kui-Jun; Wang, Ai-Min; Wang, Jian-Min

    2016-01-01

    The development of high-energy weapons could increase the velocity of projectiles to well over 1000 m/s. The nature of the injuries caused by the ballistic impact of projectiles at velocities much faster than 1000 m/s is unclear. This study characterizes the mechanical and biochemical alterations caused by high-speed ballistic impact generated by spherical steel ball to the hind limbs of the pig. That the local and distal injuries caused by hypervelocity ballistic impact to the living body are also identified. It is showed that the severity of the injury was positively correlated with the velocity of the projectile. And 4000 m/s seems to be the critical velocity for the 5.6 mm spherical steel ball, which would cause severe damage to either local or distal organs, as below that speed the projectile penetrated the body while above that speed it caused severe damage to the body. In addition, vaporization prevented the projectile from penetrating the body and the consequent pressure wave seems to be the causal factor for the distant damage.

  18. Du-zhong (Eucommia ulmoides) prevents disuse-induced osteoporosis in hind limb suspension rats.

    PubMed

    Pan, Yalei; Niu, Yinbo; Li, Chenrui; Zhai, Yuankun; Zhang, Rong; Guo, Xin; Mei, Qibing

    2014-01-01

    Du-Zhong has a long history of being used in traditional Chinese formulas to treat bone related diseases. The objective of the present study is to systematically investigate the effects of Du-Zhong cortex extract (DZCE) on disuse-induced osteoporosis. Rats were randomly divided into four groups, and three groups were treated with hind limb suspension (HLS). Control and HLS group received deionized distilled water, while the other two groups received alendronate (2.0 mg/kg/day) and DZCE (300 mg/kg/day) respectively by intragastric gavage for six weeks (two weeks prior to and during the four weeks of HLS). Dual-energy X-ray absorptiometry, assay of biochemical markers, and three-point bending test were employed to determine the effect of various treatments on bone mass, turnover, and strength. The trabecular bone microarchitecture was assessed by microCT analysis. DZCE could effectively prevent the bone loss induced by HLS, which was indicated by decreased levels of bone turnover markers as well as the changes in urinary calcium and phosphorus. The DZCE treatment also enhanced the biomechanical strength of bone and prevented the deterioration of trabecular bone microarchitecture. DZCE administration was able to prevent disuse-induced osteoporosis by regulating the bone metabolism, suggesting that DZCE could be used as an alternative therapy for the prevention of disuse-induced osteoporosis.

  19. Influence of 14-day hind limb unloading on isolated muscle spindle activity in rats.

    PubMed

    Zhao, Xue Hong; Fan, Xiao Li; Song, Xin Ai; Wu, Su Di; Ren, Jun Chan; Chen, Ming Xia

    2010-09-01

    During hind limb unloading (HU), the soleus is often in a shortened position and the natural physiological stimulus of muscle spindles is altered, such that muscle spindle activity also changes. Using isolated spindle conditions, the present study investigates the electrophysiological activity and ultrastructure of muscle spindles following HU. Results show that muscle spindle discharges fall into either of two main patterns, single spikes or spike clusters in shortened positions, with a steady frequency of 18-38 spikes/s (mean 29.08 +/- 2.45) in an extended position. Following 14-day HU, afferent discharge activity was significantly altered in soleus muscle spindles. Duration of individual spikes was significantly prolonged, from 0.54 +/- 0.05 ms for control rats to 1.53 +/- 0.25 ms for rats in the HU group. In a shortened position, regular rhythm afferent discharges were obviously depressed, and the majority of muscle spindles became silent, while in an extended position, the discharges remained continuous but with decreased frequency. Results also show that the ultrastructure of muscle spindles experience degenerative changes during HU. Altered muscle spindle afference could possibly modify the activity of motor neurons and further affect the activity of extrafusal fibers.

  20. Mechanical Overloading Increases Maximal Force and Reduces Fragility in Hind Limb Skeletal Muscle from Mdx Mouse.

    PubMed

    Ferry, Arnaud; Parlakian, Ara; Joanne, Pierre; Fraysse, Bodvael; Mgrditchian, Takouhie; Roy, Pauline; Furling, Denis; Butler-Browne, Gillian; Agbulut, Onnik

    2015-07-01

    There is fear that mechanical overloading (OVL; ie, high-force contractions) accelerates Duchenne muscular dystrophy. Herein, we determined whether short-term OVL combined with wheel running, short-term OVL combined with irradiation, and long-term OVL are detrimental for hind limb mdx mouse muscle, a murine model of Duchene muscular dystrophy exhibiting milder dystrophic features. OVL was induced by the surgical ablation of the synergic muscles of the plantaris muscle, a fast muscle susceptible to contraction-induced muscle damage in mdx mice. We found that short-term OVL combined with wheel and long-term OVL did not worsen the deficit in specific maximal force (ie, absolute maximal force normalized to muscle size) and histological markers of muscle damage (percentage of regenerating fibers and fibrosis) in mdx mice. Moreover, long-term OVL did not increase the alteration in calcium homeostasis and did not deplete muscle cell progenitors expressing Pax 7 in mdx mice. Irradiation before short-term OVL, which is believed to inhibit muscle regeneration, was not more detrimental to mdx than control mice. Interestingly, short-term OVL combined with wheel and long-term OVL markedly improved the susceptibility to contraction-induced damage, increased absolute maximal force, induced hypertrophy, and promoted a slower, more oxidative phenotype. Together, these findings indicate that OVL is beneficial to mdx muscle, and muscle regeneration does not mask the potentially detrimental effect of OVL. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  1. Morphological changes in hind limb muscles elicited by adjuvant-induced arthritis of the rat knee.

    PubMed

    Ozawa, J; Kurose, T; Kawamata, S; Yamaoka, K

    2010-02-01

    We investigated qualitative and quantitative changes in rat hind limb muscles caused by complete Freund's adjuvant (CFA)-induced knee joint pain. One week after CFA injection, muscle atrophy was induced only on the CFA-injected side. Wet weight of the rectus femoris (RF) and soleus (SOL) muscles were significantly decreased by 20% and 19%, respectively. The reduction in cross-sectional areas by CFA was similar for fast and slow muscle fibers in the RF (10% vs 15%, respectively) and SOL muscles (16% vs 16%, respectively). At the light microscopic level, pathological changes were not found in the RF muscles on both sides, although the infiltration of mononuclear cells and muscle regeneration were found in the SOL muscles on CFA-injected and contralateral control sides. On the other hand, electron microscopy revealed degenerative changes in the RF and SOL muscles on the CFA-injected side. Interestingly, sarcomere hypercontraction, indicating overexercise, was observed to a limited extent in the SOL muscles on the control side. In conclusions, knee joint pain can trigger the rapid development of muscle atrophy with degenerative changes not only in thigh but also calf muscles. This indicates that early interventions to inhibit joint pain or inflammation may prevent muscle atrophy.

  2. Muscle moment arms of the gibbon hind limb: implications for hylobatid locomotion.

    PubMed

    Channon, Anthony J; Crompton, Robin H; Günther, Michael M; Vereecke, Evie E

    2010-04-01

    Muscles facilitate skeletal movement via the production of a torque or moment about a joint. The magnitude of the moment produced depends on both the force of muscular contraction and the size of the moment arm used to rotate the joint. Hence, larger muscle moment arms generate larger joint torques and forces at the point of application. The moment arms of a number of gibbon hind limb muscles were measured on four cadaveric specimens (one Hylobates lar, one H. moloch and two H. syndactylus). The tendon travel technique was used, utilizing an electro-goniometer and a linear voltage displacement transducer. The data were analysed using a technique based on a differentiated cubic spline and normalized to remove the effect of body size. The data demonstrated a functional differentiation between voluminous muscles with short fascicles having small muscle moment arms and muscles with longer fascicles and comparatively smaller physiological cross-sectional area having longer muscle moment arms. The functional implications of these particular configurations were simulated using a simple geometric fascicle strain model that predicts that the rectus femoris and gastrocnemius muscles are more likely to act primarily at their distal joints (knee and ankle, respectively) because they have short fascicles. The data also show that the main hip and knee extensors maintain a very small moment arm throughout the range of joint angles seen in the locomotion of gibbons, which (coupled to voluminous, short-fascicled muscles) might help facilitate rapid joint rotation during powerful movements.

  3. Segmentation of digitized histological sections for quantification of the muscularized vasculature in the mouse hind limb.

    PubMed

    Xu, Yiwen; Pickering, J Geoffrey; Nong, Zengxuan; Ward, Aaron D

    2017-04-01

    Immunohistochemical tissue staining enhances microvasculature characteristics, including the smooth muscle in the medial layer of the vessel walls that is responsible for regulation of blood flow. The vasculature can be imaged in a comprehensive fashion using whole-slide scanning. However, since each such image potentially contains hundreds of small vessels, manual vessel delineation and quantification is not practically feasible. In this work, we present a fully automatic segmentation and vasculature quantification algorithm for whole-slide images. We evaluated its performance on tissue samples drawn from the hind limbs of wild-type mice, stained for smooth muscle using 3,3'-Diaminobenzidine (DAB) immunostain. The algorithm was designed to be robust to vessel fragmentation due to staining irregularity, and artefactual staining of nonvessel objects. Colour deconvolution was used to isolate the DAB stain for detection of vessel wall fragments. Complete vessels were reconstructed from the fragments by joining endpoints of topological skeletons. Automatic measures of vessel density, perimeter, wall area and local wall thickness were taken. The segmentation algorithm was validated against manual measures, resulting in a Dice similarity coefficient of 89%. The relationships observed between these measures were as expected from a biological standpoint, providing further reinforcement of the accuracy of this system. This system provides a fully automated and accurate means of measuring the arteriolar and venular morphology of vascular smooth muscle.

  4. 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

  5. Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration.

    PubMed

    Rinkevich, Yuval; Montoro, Daniel T; Muhonen, Ethan; Walmsley, Graham G; Lo, David; Hasegawa, Masakazu; Januszyk, Michael; Connolly, Andrew J; Weissman, Irving L; Longaker, Michael T

    2014-07-08

    The requirement and influence of the peripheral nervous system on tissue replacement in mammalian appendages remain largely undefined. To explore this question, we have performed genetic lineage tracing and clonal analysis of individual cells of mouse hind limb tissues devoid of nerve supply during regeneration of the digit tip, normal maintenance, and cutaneous wound healing. We show that cellular turnover, replacement, and cellular differentiation from presumed tissue stem/progenitor cells within hind limb tissues remain largely intact independent of nerve and nerve-derived factors. However, regenerated digit tips in the absence of nerves displayed patterning defects in bone and nail matrix. These nerve-dependent phenotypes mimic clinical observations of patients with nerve damage resulting from spinal cord injury and are of significant interest for translational medicine aimed at understanding the effects of nerves on etiologies of human injury.

  6. Clonal analysis reveals nerve-dependent and independent roles on mammalian hind limb tissue maintenance and regeneration

    PubMed Central

    Rinkevich, Yuval; Montoro, Daniel T.; Muhonen, Ethan; Walmsley, Graham G.; Lo, David; Hasegawa, Masakazu; Januszyk, Michael; Connolly, Andrew J.; Weissman, Irving L.; Longaker, Michael T.

    2014-01-01

    The requirement and influence of the peripheral nervous system on tissue replacement in mammalian appendages remain largely undefined. To explore this question, we have performed genetic lineage tracing and clonal analysis of individual cells of mouse hind limb tissues devoid of nerve supply during regeneration of the digit tip, normal maintenance, and cutaneous wound healing. We show that cellular turnover, replacement, and cellular differentiation from presumed tissue stem/progenitor cells within hind limb tissues remain largely intact independent of nerve and nerve-derived factors. However, regenerated digit tips in the absence of nerves displayed patterning defects in bone and nail matrix. These nerve-dependent phenotypes mimic clinical observations of patients with nerve damage resulting from spinal cord injury and are of significant interest for translational medicine aimed at understanding the effects of nerves on etiologies of human injury. PMID:24958860

  7. Stem cell use in critical limb ischemia.

    PubMed

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

    2007-02-01

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

  8. Impact of neonatal asphyxia and hind limb immobilization on musculoskeletal tissues and S1 map organization: implications for cerebral palsy.

    PubMed

    Coq, Jacques-Olivier; Strata, Fabrizio; Russier, Michaël; Safadi, Fayez F; Merzenich, Michael M; Byl, Nancy N; Barbe, Mary F

    2008-03-01

    Cerebral palsy (CP) is a complex disorder of locomotion, posture and movements resulting from pre-, peri- or postnatal damage to the developing brain. In a previous study (Strata, F., Coq, J.O., Byl, N.N., Merzenich, M.M., 2004. Comparison between sensorimotor restriction and anoxia on gait and motor cortex organization: implications for a rodent model of cerebral palsy. Neuroscience 129, 141-156.), CP-like movement disorders were more reliably reproduced in rats by hind limb sensorimotor restriction (disuse) during development rather than perinatal asphyxia (PA). To gain new insights into the underpinning mechanisms of CP symptoms we investigated the long-term effects of PA and disuse on the hind limb musculoskeletal histology and topographical organization in the primary somatosensory cortex (S1) of adult rats. Developmental disuse (i.e. hind limb immobilization) associated with PA induced muscle fiber atrophy, extracellular matrix changes in the muscle, and mild to moderate ankle and knee joint degeneration at levels greater than disuse alone. Sensorimotor restricted rats with or without PA exhibited a topographical disorganization of the S1 cortical hind limb representation with abnormally large, multiple and overlapping receptive fields. This disorganization was enhanced when disuse and PA were associated. Altered cortical neuronal properties included increased cortical responsiveness and a decrease in neuronal selectivity to afferent inputs. These data support previous observations that asphyxia per se can generate the substrate for peripheral tissue and brain damage, which are worsened by aberrant sensorimotor experience during maturation, and could explain the disabling movement disorders observed in children with CP.

  9. A three-dimensional analysis of the morphological evolution and locomotor behaviour of the carnivoran hind limb

    PubMed Central

    2014-01-01

    Background The shape of the appendicular bones in mammals usually reflects adaptations towards different locomotor abilities. However, other aspects such as body size and phylogeny also play an important role in shaping bone design. We used 3D landmark-based geometric morphometrics to analyse the shape of the hind limb bones (i.e., femur, tibia, and pelvic girdle bones) of living and extinct terrestrial carnivorans (Mammalia, Carnivora) to quantitatively investigate the influence of body size, phylogeny, and locomotor behaviour in shaping the morphology of these bones. We also investigated the main patterns of morphological variation within a phylogenetic context. Results Size and phylogeny strongly influence the shape of the hind limb bones. In contrast, adaptations towards different modes of locomotion seem to have little influence. Principal Components Analysis and the study of phylomorphospaces suggest that the main source of variation in bone shape is a gradient of slenderness-robustness. Conclusion The shape of the hind limb bones is strongly influenced by body size and phylogeny, but not to a similar degree by locomotor behaviour. The slender-robust “morphological bipolarity” found in bone shape variability is probably related to a trade-off between maintaining energetic efficiency and withstanding resistance to stresses. The balance involved in this trade-off impedes the evolution of high phenotypic variability. In fact, both morphological extremes (slender/robust) are adaptive in different selective contexts and lead to a convergence in shape among taxa with extremely different ecologies but with similar biomechanical demands. Strikingly, this “one-to-many mapping” pattern of evolution between morphology and ecology in hind limb bones is in complete contrast to the “many-to-one mapping” pattern found in the evolution of carnivoran skull shape. The results suggest that there are more constraints in the evolution of the shape of the appendicular

  10. A three-dimensional analysis of the morphological evolution and locomotor behaviour of the carnivoran hind limb.

    PubMed

    Martín-Serra, Alberto; Figueirido, Borja; Palmqvist, Paul

    2014-06-14

    The shape of the appendicular bones in mammals usually reflects adaptations towards different locomotor abilities. However, other aspects such as body size and phylogeny also play an important role in shaping bone design.We used 3D landmark-based geometric morphometrics to analyse the shape of the hind limb bones (i.e., femur, tibia, and pelvic girdle bones) of living and extinct terrestrial carnivorans (Mammalia, Carnivora) to quantitatively investigate the influence of body size, phylogeny, and locomotor behaviour in shaping the morphology of these bones. We also investigated the main patterns of morphological variation within a phylogenetic context. Size and phylogeny strongly influence the shape of the hind limb bones. In contrast, adaptations towards different modes of locomotion seem to have little influence. Principal Components Analysis and the study of phylomorphospaces suggest that the main source of variation in bone shape is a gradient of slenderness-robustness. The shape of the hind limb bones is strongly influenced by body size and phylogeny, but not to a similar degree by locomotor behaviour. The slender-robust "morphological bipolarity" found in bone shape variability is probably related to a trade-off between maintaining energetic efficiency and withstanding resistance to stresses. The balance involved in this trade-off impedes the evolution of high phenotypic variability. In fact, both morphological extremes (slender/robust) are adaptive in different selective contexts and lead to a convergence in shape among taxa with extremely different ecologies but with similar biomechanical demands. Strikingly, this "one-to-many mapping" pattern of evolution between morphology and ecology in hind limb bones is in complete contrast to the "many-to-one mapping" pattern found in the evolution of carnivoran skull shape. The results suggest that there are more constraints in the evolution of the shape of the appendicular skeleton than in that of skull shape

  11. Kinetic, kinematic, magnetic resonance and owner evaluation of dogs before and after the amputation of a hind limb.

    PubMed

    Galindo-Zamora, Vladimir; von Babo, Verena; Eberle, Nina; Betz, Daniela; Nolte, Ingo; Wefstaedt, Patrick

    2016-01-25

    The amputation of a limb is a surgical procedure that is regularly performed in small animal practice. In spite of several clinical reports indicating high owner satisfaction after limb amputation in dogs, an amputation is still very critically seen by the owners, and even by some veterinarians, due to the lack of accurate information about the recovery of amputee patients. Thus, the objective of this study was to prospectively evaluate, both objectively and subjectively, the recovery outcome of dogs undergoing a hind limb amputation. Twelve patients in which a hind limb amputation was scheduled were studied. Kinetic and kinematic gait analyses were performed before the amputation, and 10, 30, 90 and 120 days after surgery. Magnetic resonance (MR) examination of the contralateral stifle joint was performed before and 120 days after amputation. The subjective impressions of the owners were gathered at the same examination times of the gait analyses. Kinetic data showed a redistribution of the load to all remaining limbs after the amputation; ten days after the procedure patients had already established their new locomotory pattern. Kinematic data showed significant differences between sessions in the mean angle progression curves of almost all analyzed joints; however, the ranges of motion were very similar before and after the amputation, and remained constant in the subsequent sessions after the amputation. No changes in the signal intensity of the soft tissues evaluated, and no evidence of cartilage damage or osteoarthritis was seen on the MR examination of the contralateral stifle. Owners evaluated the results of the amputation very positively, both during and at the end of the study. Dogs had a quick adaptation after a hind limb amputation, and the adaptation process began before the amputation was performed. This happened without evidence of morphologic changes in the contralateral stifle joint, and with a very positive evaluation from the owner.

  12. Osteology and radiographic anatomy of the pelvis and hind limb of healthy ring-tailed lemurs (Lemur catta).

    PubMed

    Makungu, M; Groenewald, H B; du Plessis, W M; Barrows, M; Koeppel, K N

    2014-06-01

    In family Lemuridae, anatomical variations exist. Considering its conservation status (near threatened) and presence of similarities between strepsirrhines and primitive animals, it was thought to be beneficial to describe the gross osteology and radiographic anatomy of the pelvis and hind limb of ring-tailed lemurs (Lemur catta) as a reference for clinical use and species identification. Radiography was performed in 14 captive adult ring-tailed lemurs. The radiographic findings were correlated with bone specimens from two adult animals. Additionally, computed tomography of the hind limbs was performed in one animal. The pelvic bone has a well-developed caudal ventral iliac spine. The patella has a prominent tuberosity on the cranial surface. The first metatarsal bone and digit 1 are markedly stouter than the other metatarsal bones and digits with medial divergence from the rest of the metatarsal bones and digits. Ossicles were seen in the lateral meniscus, inter-phalangeal joint of digit 1 and in the infrapatellar fat pad. Areas of mineral opacity were seen within the external genitalia, which are believed to be the os penis and os clitoris. Variations exist in the normal osteology and radiographic appearance of the pelvis and hind limb of different animal species. The use of only atlases from domestic cats and dogs for interpretative purposes may be misleading. © 2013 Blackwell Verlag GmbH.

  13. [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.

  14. 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

  15. 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

  16. 2013 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report.

    PubMed

    2016-01-01

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

  17. 2014 JAPAN Critical Limb Ischemia Database (JCLIMB) Annual Report.

    PubMed

    2016-01-01

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

  18. 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

  19. Effect of recovery mode following hind-limb suspension on soleus muscle composition in the rat

    NASA Technical Reports Server (NTRS)

    McNulty, A. L.; Otto, A. J.; Kasper, C. E.; Thomas, D. P.

    1992-01-01

    The purpose of this study was to compare the effects of two different recovery modes from hind-limb suspension-induced hypodynamia on whole body and muscle (soleus) growth as well as soleus composition and size changes of different fiber types within this same muscle. Following 28 days of tail-suspension, rats were returned to their cages and sedentarily recovered (HS), or were exercised by running on a treadmill 5 days/wk, at progressively increasing workloads (HR) for one month. Sedentary and running control groups of animals (CS, CR) were also evaluated for comparative purposes. The exercise program, which was identical for CR and HR groups, had no effect on body wt., soleus wt., soleus muscle composition or fiber size in CR rats. Atrophied soleus muscle and reduced soleus wt./body wt. ratio (both 60% of control) had returned to control values by day 7 of recovery in both suspended groups despite the fact that whole body wt. gain was significantly reduced (p less than 0.05) in HR as compared to HS rats. Atrophied soleus Type I fiber mean cross-sectional area in both HR and HS groups demonstrated similar and significant (p less than 0.01) increases during recovery. Increases in Type IIa and IIc fiber area during this same period were significant only in the HR group. While the percentage area of muscle composed of Type I fibers increased in both hypodynamic groups during recovery, the reduction in area percentage of muscle made up of Type IIa fibers was again only significant in the HR group.(ABSTRACT TRUNCATED AT 250 WORDS).

  20. Muscle growth and fiber type composition in hind limb muscles during postnatal development in pigs.

    PubMed

    Wank, Veit; Fischer, Martin S; Walter, Bernd; Bauer, Reinhard

    2006-01-01

    Rapid postnatal development in pigs is reflected by differentiation in skeletal muscle. This process depends on muscle function and demands, but a comprehensive overview of individual developmental characteristics of quickly growing leg muscles in pigs is still missing. This study focused on the development of 10 hind limb muscles in pigs. To determine these changes in mass, fiber type patterns and fiber diameters were analyzed 0, 2, 4, 7, 14, 28, 42, 56 and 400 days after birth. Generally, the proportion of slow fibers increased from birth to 8 weeks. Thereafter, only minor changes in muscle fiber type composition were observed. The majority of the muscles contained less then 10% slow-twitch fibers at birth, increasing to between 12 (Musculus vastus lateralis) and 38% (M. gastrocnemius medialis) in adult pigs. By contrast, postural muscles already had 20-30% slow fibers at birth, and this contribution increased up to 65% in adults (i.e. M. vastus intermedius). From birth to the 2nd week, only in slow fibers could activity of oxidative enzymes be detected. A differentiation of fast-twitch fibers into subtypes with high (comparable to type IIA) and low oxidative metabolism (equivalent to type IIB) occurred between the 2nd and 4th week of life. The ratio between type II fibers with high and low oxidative enzyme activity did not change markedly through development in any muscle, although there was a trend towards an increasing proportion of type IIA fibers in the soleus. In the majority of the muscles investigated, the fast-twitch fibers with low oxidative metabolism (IIB) obtained the largest cross-sectional area. In contrast, at birth no remarkable differences in the diameter of fast and slow fibers were found. The rapid increase in muscle mass compared to body mass reflects the high performance in meat production of the cross pig investigated.

  1. A three-dimensional musculoskeletal model of the chimpanzee (Pan troglodytes) pelvis and hind limb.

    PubMed

    O'Neill, Matthew C; Lee, Leng-Feng; Larson, Susan G; Demes, Brigitte; Stern, Jack T; Umberger, Brian R

    2013-10-01

    Musculoskeletal models have become important tools for studying a range of muscle-driven movements. However, most work has been in modern humans, with few applications in other species. Chimpanzees are facultative bipeds and our closest living relatives, and have provided numerous important insights into our own evolution. A chimpanzee musculoskeletal model would allow integration across a wide range of laboratory-based experimental data, providing new insights into the determinants of their locomotor performance capabilities, as well as the origins and evolution of human bipedalism. Here, we described a detailed three-dimensional (3D) musculoskeletal model of the chimpanzee pelvis and hind limb. The model includes geometric representations of bones and joints, as well as 35 muscle-tendon units that were represented using 44 Hill-type muscle models. Muscle architecture data, such as muscle masses, fascicle lengths and pennation angles, were drawn from literature sources. The model permits calculation of 3D muscle moment arms, muscle-tendon lengths and isometric muscle forces over a wide range of joint positions. Muscle-tendon moment arms predicted by the model were generally in good agreement with tendon-excursion estimates from cadaveric specimens. Sensitivity analyses provided information on the parameters that model predictions are most and least sensitive to, which offers important context for interpreting future results obtained with the model. Comparisons with a similar human musculoskeletal model indicate that chimpanzees are better suited for force production over a larger range of joint positions than humans. This study represents an important step in understanding the integrated function of the neuromusculoskeletal systems in chimpanzee locomotion.

  2. Effect of thermal injury on the kinin system in rabbit hind limb lymph

    PubMed Central

    Lewis, G. P.; Wawretschek, W. A.

    1971-01-01

    1. The kinin-forming activity of hind limb lymph and of plasma has been examined in rabbits before and after thermal injury. 2. Neither plasma nor lymph contained much active kallikrein activity but the enzyme was evident in samples treated with glass or with acid. 3. There was little or no increase in the activity of enzyme activated by glass after thermal injury, but an increase in the activity of enzyme activated by acid regularly occurred. 4. There were two increases in the activity of enzyme activated by acid—one about 2 h and the other 4-6 h after thermal injury. They corresponded to increases in vascular permeability as indicated by increases in the concentration of lymph protein. 5. There was considerably more kininogen in the lymph and plasma than was used in the assays of kallikrein activity, showing that the increased kinin-forming activity in lymph was not the result of the passage of kininogen from the plasma. 6. The increase in activity in lymph was not usually accompanied by a similar increase in the plasma. However, an increase in the activity of enzyme activated by acid sometimes occurred in the plasma simply as a result of prolonged anaesthesia. 7. It is suggested that whereas the enzyme activated by glass is a measure of prekallikrein, the acid activatable enzyme appears as a result of the dissociation of a kallikrein-inhibitor complex. An increase in the concentration of this complex is therefore an indication of the preceding activation of kallikrein. PMID:5136453

  3. Dynamics of goat distal hind limb muscle–tendon function in response to locomotor grade

    PubMed Central

    McGuigan, M. Polly; Yoo, Edwin; Lee, David V.; Biewener, Andrew A.

    2009-01-01

    Summary The functional roles of the lateral gastrocnemius (LG), medial gastrocnemius (MG) and superficial digital flexor (SDF) muscle–tendon units (MTUs) in domestic goats (N=6) were studied as a function of locomotor grade, testing the hypothesis that changes in distal limb muscle work would reflect changes in mechanical work requirements while goats walked or trotted on the level, 15 deg. decline and 15 deg. incline. As steep terrain-adapted animals, changes in muscle work output are expected to be particularly important for goats. In vivo muscle–tendon forces, fascicle length changes and muscle activation were recorded via tendon force buckles, sonomicrometry and electromyography to evaluate the work performance and elastic energy recovery of the three distal MTUs. These recordings confirmed that fascicle strain and force within goat distal hind limb muscles are adjusted in response to changes in mechanical work demand associated with locomotor grade. In general, muscle work was modulated most consistently by changes in fascicle strain, with increased net shortening (P<0.001) observed as goats switched from decline to level to incline locomotion. Peak muscle stresses increased as goats increased speed from a walk to a trot within each grade condition (P<0.05), and also increased significantly with grade (P<0.05 to P<0.01). Due to the increase in net fascicle shortening and muscle force, net muscle work per cycle also increased significantly (P<0.05 to P<0.005) as goats switched from decline to level to incline conditions (LG work: 20 mJ to 56 mJ to 209 mJ; MG work: –7 mJ to 34 mJ to 179 mJ; SDF work: –42 mJ to 14 mJ to 71 mJ, at a 2.5 ms–1 trot). Although muscle work was modulated in response to changes in grade, the amount of work produced by these three distal pennate muscles was small (being <3%) in comparison with the change in mechanical energy required of the limb as a whole. Elastic energy recovery in the SDF and gastrocnemius (GA) tendons was

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

    PubMed

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

    2009-05-01

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

  5. The response of the hind-limb vascular bed of the rabbit to sympathetic stimulation and its modification by pregnancy.

    PubMed Central

    Humphreys, P W; Joels, N

    1982-01-01

    1. Pressure-flow relationships in the hind limb, perfused with blood at a series of constant flows, have been compared in primigravid and virgin rabbits following section of the lumbar sympathetic chain. 2. In the absence of sympathetic stimulation perfusion pressure was lower (P less than 0.05) in the pregnant rabbits at all levels of flow to the leg. 3. It is concluded that pregnancy leads to a reduction in the vascular resistance of the acutely sympathectomized hind limb. 4. The pressure-flow curves of hind limbs from pregnant and non-pregnant rabbits in which the cutaneous circulation had been excluded by skinning the leg and ligating the ankle were also compared. Again, perfusion pressure at each flow level was lower in the limbs from the pregnant animals (P less than 0.05). 5. The sympathetic supply was stimulated at frequencies of 0.3, 1, 3, 7, 15 and 30 Hz. Irrespective of whether the cutaneous circulation was excluded, the pressure-flow curves for the hind limbs of pregnant and non-pregnant rabbits were different at the lower frequencies. As stimulus frequency rose this difference became smaller, and at a stimulus frequency of 7-15 Hz or more there was little difference in the position of the curves in pregnant and non-pregnant rabbits. 6. Examination of the pressure-flow curves suggests that when, as in these experiments, flow is held constant, the ability of sympathetic stimulation to increase the resistance to blood flow is reduced in pregnancy. However, if these pressure-flow curves are used to predict the change of flow that would occur at a constant perfusion pressure, the response to sympathetic stimulation appears to be greater in pregnancy. 7. Further analysis of the findings, based on certain assumptions, suggests that differences between the pressure-flow curves of pregnant and non-pregnant animals during sympathetic stimulation are due in the main to either a differing size of the unstimulated vascular beds or a differing compliance of their

  6. 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.

  7. 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

  8. Increased androgenic sensitivity in the hind limb muscular system marks the evolution of a derived gestural display

    PubMed Central

    Mangiamele, Lisa A.; Fuxjager, Matthew J.; Schuppe, Eric R.; Taylor, Rebecca S.; Hödl, Walter; Preininger, Doris

    2016-01-01

    Physical gestures are prominent features of many species’ multimodal displays, yet how evolution incorporates body and leg movements into animal signaling repertoires is unclear. Androgenic hormones modulate the production of reproductive signals and sexual motor skills in many vertebrates; therefore, one possibility is that selection for physical signals drives the evolution of androgenic sensitivity in select neuromotor pathways. We examined this issue in the Bornean rock frog (Staurois parvus, family: Ranidae). Males court females and compete with rivals by performing both vocalizations and hind limb gestural signals, called “foot flags.” Foot flagging is a derived display that emerged in the ranids after vocal signaling. Here, we show that administration of testosterone (T) increases foot flagging behavior under seminatural conditions. Moreover, using quantitative PCR, we also find that adult male S. parvus maintain a unique androgenic phenotype, in which androgen receptor (AR) in the hind limb musculature is expressed at levels ∼10× greater than in two other anuran species, which do not produce foot flags (Rana pipiens and Xenopus laevis). Finally, because males of all three of these species solicit mates with calls, we accordingly detect no differences in AR expression in the vocal apparatus (larynx) among taxa. The results show that foot flagging is an androgen-dependent gestural signal, and its emergence is associated with increased androgenic sensitivity within the hind limb musculature. Selection for this novel gestural signal may therefore drive the evolution of increased AR expression in key muscles that control signal production to support adaptive motor performance. PMID:27143723

  9. Activation patterns of embryonic chick hind limb muscles recorded in ovo and in an isolated spinal cord preparation.

    PubMed

    Landmesser, L T; O'Donovan, M J

    1984-02-01

    Muscle activation patterns of embryonic chick hind limb muscles were determined from electromyographic (e.m.g.) recordings in an isolated spinal cord/hind limb preparation of stage 34-36 embryos, and were compared with in ovo e.m.g. activity from similarly staged embryos. Muscle activity in ovo consisted of periodically recurring sequences of bursts during which antagonistic muscles often alternated and synergistic muscles were co-active, as compatible with their mature function. However, more variable behaviour was also observed. Burst sequences in ovo were often initiated by a short-duration, high-amplitude discharge that occurred synchronously in all muscles studied, and which was followed by a period of electrical silence that was longest in the flexor muscles. This type of activity has not been described previously in mature animals. In ovo movement sequences were generally initiated by extensor activity which progressively declined in duration and intensity throughout the sequence, while flexor activity progressively intensified. The onset of activity in extensor muscles was accompanied by an abrupt decrease in flexor activity, whereas the converse was not observed. Spontaneous movement sequences also occurred when the spinal cord and hind limb were isolated and maintained in oxygenated Tyrode solution for several hours. Deafferentation experiments indicated that the motor pattern in this preparation was generated centrally by circuits within the spinal cord. Activity from the isolated cord was less variable than that occurring in ovo, consisting of sequences of highly regular recurring bursts. Each burst began with a brief high-amplitude discharge that occurred synchronously in all muscles and which was similar to that observed in ovo. This was followed by a silent period, which was longest in the flexors, and then by a more prolonged burst. Although its behaviour differs from that in ovo in some respects, it is concluded that the isolated cord maintained in

  10. Activation patterns of embryonic chick hind limb muscles recorded in ovo and in an isolated spinal cord preparation.

    PubMed Central

    Landmesser, L T; O'Donovan, M J

    1984-01-01

    Muscle activation patterns of embryonic chick hind limb muscles were determined from electromyographic (e.m.g.) recordings in an isolated spinal cord/hind limb preparation of stage 34-36 embryos, and were compared with in ovo e.m.g. activity from similarly staged embryos. Muscle activity in ovo consisted of periodically recurring sequences of bursts during which antagonistic muscles often alternated and synergistic muscles were co-active, as compatible with their mature function. However, more variable behaviour was also observed. Burst sequences in ovo were often initiated by a short-duration, high-amplitude discharge that occurred synchronously in all muscles studied, and which was followed by a period of electrical silence that was longest in the flexor muscles. This type of activity has not been described previously in mature animals. In ovo movement sequences were generally initiated by extensor activity which progressively declined in duration and intensity throughout the sequence, while flexor activity progressively intensified. The onset of activity in extensor muscles was accompanied by an abrupt decrease in flexor activity, whereas the converse was not observed. Spontaneous movement sequences also occurred when the spinal cord and hind limb were isolated and maintained in oxygenated Tyrode solution for several hours. Deafferentation experiments indicated that the motor pattern in this preparation was generated centrally by circuits within the spinal cord. Activity from the isolated cord was less variable than that occurring in ovo, consisting of sequences of highly regular recurring bursts. Each burst began with a brief high-amplitude discharge that occurred synchronously in all muscles and which was similar to that observed in ovo. This was followed by a silent period, which was longest in the flexors, and then by a more prolonged burst. Although its behaviour differs from that in ovo in some respects, it is concluded that the isolated cord maintained in

  11. Morphology of the pelvis and hind limb of the red panda (Ailurus fulgens) evidenced by gross osteology, radiography and computed tomography.

    PubMed

    Makungu, M; du Plessis, W M; Groenewald, H B; Barrows, M; Koeppel, K N

    2015-12-01

    The red panda (Ailurus fulgens) is a quadrupedal arboreal animal primarily distributed in the Himalayas and southern China. It is a species commonly kept in zoological collections. This study was carried out to describe the morphology of the pelvis and hind limb of the red panda evidenced by gross osteology, radiography and computed tomography as a reference for clinical use and identification of skeletons. Radiography of the pelvis and right hind limb was performed in nine and seven animals, respectively. Radiographic findings were correlated with bone specimens from three adult animals. Computed tomography of the torso and hind limb was performed in one animal. The pelvic bone had a wide ventromedial surface of the ilium. The trochlea of the femur was wide and shallow. The patella was similar to that seen in feline species. The medial fabella was not seen radiographically in any animal. The cochlea grooves of the tibia were shallow with a poorly defined intermediate ridge. The trochlea of the talus was shallow and presented with an almost flattened medial ridge. The tarsal sesamoid bone was always present. The lateral process of the base of the fifth metatarsal (MT) bone was directed laterally. The MT bones were widely spaced. The morphology of the pelvis and hind limb of the red panda indicated flexibility of the pelvis and hind limb joints as an adaptation to an arboreal quadrupedal lifestyle.

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

    PubMed

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

    2016-04-01

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

  13. Hind limb scaling of kangaroos and wallabies (superfamily Macropodoidea): implications for hopping performance, safety factor and elastic savings

    PubMed Central

    McGowan, C P; Skinner, J; Biewener, A A

    2008-01-01

    The aim of this study was to examine hind limb scaling of the musculoskeletal system in the Macropodoidea, the superfamily containing wallabies and kangaroos, to re-examine the effect of size on the locomotor mechanics and physiology of marsupial hopping. Morphometric musculoskeletal analyses were conducted of 15 species and skeletal specimens of 21 species spanning a size range from 0.8 to 80 kg that included representatives of 12 of the 16 extant genera of macropodoids. We found that unlike other groups, macropodoids are able to match force demands associated with increasing body size primarily through a combination of positive allometry in muscle area and muscle moment arms. Isometric scaling of primary hind limb bones suggests, however, that larger species experience relatively greater bone stresses. Muscle to tendon area ratios of the ankle extensors scale with strong positive allometry, indicating that peak tendon stresses also increase with increasing body size but to a lesser degree than previously reported. Consistent with previous morphological and experimental studies, large macropodoids are therefore better suited for elastic strain energy recovery but operate at lower safety factors, which likely poses an upper limit to body size. Scaling patterns for extant macropodoids suggest that extinct giant kangaroos (∼250 kg) were likely limited in locomotor capacity. PMID:18086129

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

    PubMed

    Ren, C; Gao, X; Steinberg, G K; Zhao, H

    2008-02-19

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

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2017-03-01

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

  17. AB296. SPR-23 Aberrant bladder reflexes can drive hind limb locomotor activity following complete suprasacral spinal cord injury

    PubMed Central

    Inouye, Brian M.; Brooks, Jillene M.; Degoski, Danielle J.; Hughes, Francis M.; Purves, J. Todd; Fraser, Matthew O.

    2016-01-01

    Objective Many rats with chronic suprasacral spinal cord injury (SCI) demonstrate hind limb locomotor activity (HLLA) in response to external crede or high pressure contractions during cystometry. We propose that this aberrant, pressure-driven bladder reflex pathway may be harnessed to facilitate walking in SCI patients. As a first step in exploring this possibility, we examined the relationship between intravesical pressure (IVP) and HLLA in chronic suprasacral SCI rats. Methods Female rats (4 weeks post-SCI at T9-10, n=16) were anesthetized with isoflurane and fitted with transvesical catheters and right quadriceps EMG electrodes to monitor bladder and hind limb locomotor activities, respectively. The animals were mounted in Ballman restraint cages to which they had been previously acclimated. The catheter was connected to a pressure transducer, an infusion pump, and a saline-filled reservoir mounted on a metered vertical pole (pressure clamp). After 30 min of recovery from anesthesia, the bladder was filled at 0.1 mL/min with saline to verify bladder-to-bladder reflex activity for 30 min. IVP was then increased in an interrupted stepwise fashion from 0–120 cmH2O at 10 cmH2O increments. Each step consisted of five minutes: 3 minutes at the new pressure followed by 2 minutes at 0 cmH2O. IVP and the number of HLLA events (as defined by rhythmic EMG discharges of 3–10 cycles/event) were recorded for each pressure step. This process was repeated for two more trials for each rat to assess the durability of the reflex. Data were analyzed using ANOVA with repeated measures both within and across pressure escalation trials. P<0.05 was considered significant. Results ANOVA revealed that locomotor events increased with increasing IVP and decreased with the number of escalation trials (P<0.0001 for both effects). The increase in the number of locomotor events with increasing IVP appeared to plateau at ~50–60 cmH2O (P<0.05 for all). The average of the maximal number of

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

    PubMed

    Wayne Causey, Marlin; Eichler, Charles

    2014-03-01

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

  19. Accuracy and precision of hind limb foot contact timings of horses determined using a pelvis-mounted inertial measurement unit.

    PubMed

    Starke, Sandra D; Witte, Thomas H; May, Stephen A; Pfau, Thilo

    2012-05-11

    Gait analysis using small sensor units is becoming increasingly popular in the clinical context. In order to segment continuous movement from a defined point of the stride cycle, knowledge about footfall timings is essential. We evaluated the accuracy and precision of foot contact timings of a defined limb determined using an inertial sensor mounted on the pelvis of ten horses during walk and trot at different speeds and in different directions. Foot contact was estimated from vertical velocity events occurring before maximum sensor roll towards the contralateral limb. Foot contact timings matched data from a synchronised hoof mounted accelerometer well when velocity minimum was used for walk (mean (SD) difference of 15 (18)ms across horses) and velocity zero-crossing for trot (mean (SD) difference from -4 (14) to 12 (7)ms depending on the condition). The stride segmentation method also remained robust when applied to movement data of hind limb lame horses. In future, this method may find application in segmenting overground sensor data of various species. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Niacin promotes revascularization and recovery of limb function in diet-induced obese mice with peripheral ischemia.

    PubMed

    Pang, Dominic K T; Nong, Zengxuan; Sutherland, Brian G; Sawyez, Cynthia G; Robson, Debra L; Toma, Jelena; Pickering, J Geoffrey; Borradaile, Nica M

    2016-06-01

    Niacin can reduce vascular disease risk in individuals with metabolic syndrome, but in light of recent large randomized controlled trials outcomes, its biological actions and clinical utility remain controversial. Niacin can improve endothelial function, vascular inflammation, and vascular regeneration, independent of correcting dyslipidemia, in various lean rodent models of vascular injury. Here, we tested whether niacin could directly improve endothelial cell angiogenic function during combined exposure to excess fatty acids and hypoxia, and whether intervention with niacin during continued feeding of western diet could improve revascularization and functional recovery in obese, hyperlipidemic mice with peripheral ischemia. Treatment with niacin (10 μmol/L) increased human microvascular endothelial cell angiogenic function during exposure to high fatty acids and hypoxia (2% oxygen), as determined by tube formation on Matrigel. To assess revascularization in vivo, we used western diet-induced obese mice with unilateral hind limb femoral artery ligation and excision. Treatment for 14 days postinjury with once daily i.p. injections of a low dose of niacin (50 mg/kg) improved recovery of hind limb use, in association with enhanced revascularization and decreased inflammation of the tibialis anterior muscle. These effects were concomitant with decreased plasma triglycerides, but not increased plasma apoAI. Thus, niacin improves endothelial tube formation under lipotoxic and hypoxic conditions, and moreover, promotes revascularization and functional hind limb recovery following ischemic injury in diet-induced obese mice with hyperlipidemia. These data may have implications for niacin therapy in the treatment of peripheral ischemic vascular disease associated with metabolic syndrome.

  1. Vasomotor responses in the hind limbs of foetal and new-born lambs to asphyxia and aortic chemoreceptor stimulation.

    PubMed

    Dawes, G S; Lewis, B V; Milligan, J E; Roach, M R; Talner, N S

    1968-03-01

    1. Hind limb blood flow was measured in lambs of from 91 days gestation (delivered by Caesarean section) to 1 month after birth (term is about 147 days), under chloralose anaesthesia. Vascular resistance/100 g wet wt. increased progressively with age. There was reflex femoral vascular tone from the earliest age studied, as shown by vasodilatation on cutting the sciatic nerve.2. On asphyxia by cord occlusion reflex femoral vasoconstriction began earlier and was somewhat greater in older foetal lambs. At all ages, and after denervation of the hind limb, there was vasodilatation after local ischaemia, and a vasoconstriction of delayed onset during asphyxia attributed to release of noradrenaline into the circulation. The vasoconstrictor effect of noradrenaline in immature lambs was at least as great as at term or in the new-born.3. Injections of minimal effective doses of cyanide were used to localize possible chemoreceptor sites in foetal lambs. Injection into the left atrium caused a rise of arterial pressure, femoral vasoconstriction and a complex change in heart rate (usually bradycardia) but rarely any respiratory movement. After atropine, cyanide caused a large tachycardia. All responses were much reduced or abolished by cervical vagotomy.4. Injection of the same doses of cyanide into a jugular vein, the right ventricle, pulmonary or common carotid arteries of foetal lambs caused negligible cardiovascular or respiratory effects, whereas injection into the carotids of new-born lambs caused a profound hyperpnoea.5. It is concluded that the aortic chemoreceptors are active in the foetus, are supplied from the left heart, and that they probably represent the primary defence in blood gas homeostasis by their effects on the circulation.

  2. Vasomotor responses in the hind limbs of foetal and new-born lambs to asphyxia and aortic chemoreceptor stimulation

    PubMed Central

    Dawes, G. S.; Lewis, B. V.; Milligan, J. E.; Roach, Margot R.; Talner, N. S.

    1968-01-01

    1. Hind limb blood flow was measured in lambs of from 91 days gestation (delivered by Caesarean section) to 1 month after birth (term is about 147 days), under chloralose anaesthesia. Vascular resistance/100 g wet wt. increased progressively with age. There was reflex femoral vascular tone from the earliest age studied, as shown by vasodilatation on cutting the sciatic nerve. 2. On asphyxia by cord occlusion reflex femoral vasoconstriction began earlier and was somewhat greater in older foetal lambs. At all ages, and after denervation of the hind limb, there was vasodilatation after local ischaemia, and a vasoconstriction of delayed onset during asphyxia attributed to release of noradrenaline into the circulation. The vasoconstrictor effect of noradrenaline in immature lambs was at least as great as at term or in the new-born. 3. Injections of minimal effective doses of cyanide were used to localize possible chemoreceptor sites in foetal lambs. Injection into the left atrium caused a rise of arterial pressure, femoral vasoconstriction and a complex change in heart rate (usually bradycardia) but rarely any respiratory movement. After atropine, cyanide caused a large tachycardia. All responses were much reduced or abolished by cervical vagotomy. 4. Injection of the same doses of cyanide into a jugular vein, the right ventricle, pulmonary or common carotid arteries of foetal lambs caused negligible cardiovascular or respiratory effects, whereas injection into the carotids of new-born lambs caused a profound hyperpnoea. 5. It is concluded that the aortic chemoreceptors are active in the foetus, are supplied from the left heart, and that they probably represent the primary defence in blood gas homeostasis by their effects on the circulation. PMID:4295757

  3. Arboreal Day Geckos (Phelsuma madagascariensis) Differentially Modulate Fore- and Hind Limb Kinematics in Response to Changes in Habitat Structure

    PubMed Central

    Zhuang, Mingna V.; Higham, Timothy E.

    2016-01-01

    By using adhesion, geckos can move through incredibly challenging habitats. However, continually changing terrain may necessitate modulation of the adhesive apparatus in order to maximize its effectiveness over a range of challenges. Behaviorally modulating how the adhesive system is applied can occur by altering the alignment of the foot relative to the long axis of the body and/or the angles between the digits (interdigital angle). Given the directionality of the adhesive system, geckos likely vary the application of the system via these mechanisms as they run. We quantified 3D movements (using high-speed video) of the day gecko, Phelsuma madagascariensis, running on a range of ecologically relevant inclines (0°, 45°, 90°) and perch diameters (1.5 cm, 10 cm and broad). We measured the instantaneous sum of interdigital angles and foot alignment relative to the body, as well as other kinematic variables, throughout each stride and across treatments. Modulation of foot alignment at 45° and 90° was similar between the forelimb and hind limb, but differed at 0°, suggesting that P. madagascariensis is able to exert an adhesive force using multiple strategies. Both the sum of interdigital angles and alignment in the fore- and hind foot were modulated. Differences in modulation between the limbs are likely related to the underlying morphology. The modulation of interdigital angle and foot alignment suggests that aspects other than the mechanism of adhesion, such as joint morphology, are important for arboreal movement in geckos. Our study of foot usage in arboreal locomotion reveals patterns that may be widespread across pad-bearing lizards. In addition to understanding the constraints exerted by the adhesive apparatus, we highlight how biomechanical traits may respond to the evolution of novel adaptations and morphologies. PMID:27145027

  4. Leukotrienes but not complement mediate limb ischemia-induced lung injury.

    PubMed Central

    Klausner, J M; Paterson, I S; Kobzik, L; Valeri, C R; Shepro, D; Hechtman, H B

    1989-01-01

    Reperfusion after limb ischemia leads to sequestration of polymorphonuclear leukocytes (PMN) in the lungs and to leukocyte- (WBC) and thromboxane- (Tx) dependent respiratory dysfunction. This study examines the intermediary role of the chemoattractants leukotriene (LT)B4 and complement (C) fragments. Anesthetized sheep with chronic lung lymph fistulae underwent 2 hours of tourniquet ischemia of both hind limbs. In untreated controls (n = 7), 1 minute after tourniquet release, mean pulmonary artery pressure (MPAP) rose from 13 to 38 mmHg (p less than 0.05) and returned to baseline within 30 minutes. Pulmonary artery wedge pressure was unchanged from 3.6 mmHg. There were increases in plasma LTB4 levels from 2.46 to 9.34 ng/ml (p less than 0.01), plasma TxB2 levels from 211 to 735 pg/ml (p less than 0.05), and lung lymph TxB2 from 400 to 1005 pg/ml (p less than 0.05). C3 levels were 96% of baseline values. Thirty minutes after reperfusion, lung lymph flow (QL) increased from 4.3 to 8.3 ml/30 minutes (p less than 0.05), lymph/plasma protein ratio was unchanged from 0.6, and the lymph protein clearance increased from 2.6 to 4.6 ml/30 minutes (p less than 0.05), data consistent with increased microvascular permeability. WBC count fell within the first hour from 6853 to 3793/mm3 (p less than 0.01). Lung histology showed leukosequestration, 62 PMN/10 high-power fields (HPF) and proteinaceous exudates. In contrast to this untreated ischemic group, animals treated with the lypoxygenase inhibitor diethylcarbamazine (n = 5) demonstrated a blunted reperfusion-induced rise in MPAP to 17 mmHg (p less than 0.05). There were no increases in LTB4, TxB2, QL or lymph protein clearance (p less than 0.05). WBC count was unchanged and lung leukosequestration was reduced to 40 PMN/10 HPF (p less than 0.05). Decomplementation with cobra venom factor (n = 4) resulted in plasma C3 levels, 10% of baseline, but tourniquet release still led to pulmonary hypertension, elevated LTB4, TxB2 levels

  5. 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

  6. 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.

  7. A system identification analysis of neural adaptation dynamics and nonlinear responses in the local reflex control of locust hind limbs.

    PubMed

    Dewhirst, Oliver P; Angarita-Jaimes, Natalia; Simpson, David M; Allen, Robert; Newland, Philip L

    2013-02-01

    Nonlinear type system identification models coupled with white noise stimulation provide an experimentally convenient and quick way to investigate the often complex and nonlinear interactions between the mechanical and neural elements of reflex limb control systems. Previous steady state analysis has allowed the neurons in such systems to be categorised by their sensitivity to position, velocity or acceleration (dynamics) and has improved our understanding of network function. These neurons, however, are known to adapt their output amplitude or spike firing rate during repetitive stimulation and this transient response may be more important than the steady state response for reflex control. In the current study previously used system identification methods are developed and applied to investigate both steady state and transient dynamic and nonlinear changes in the neural circuit responsible for controlling reflex movements of the locust hind limbs. Through the use of a parsimonious model structure and Monte Carlo simulations we conclude that key system dynamics remain relatively unchanged during repetitive stimulation while output amplitude adaptation is occurring. Whilst some evidence of a significant change was found in parts of the systems nonlinear response, the effect was small and probably of little physiological relevance. Analysis using biologically more realistic stimulation reinforces this conclusion.

  8. 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

  9. [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.

  10. Association of abnormal hind-limb postures and back arch with gait abnormality in dairy cattle.

    PubMed

    Hoffman, A C; Moore, D A; Vanegas, J; Wenz, J R

    2014-01-01

    Detection of lameness in individual cows is important for the prompt treatment of this painful and production-limiting disease. Current methods for lameness detection involve watching cows walk for several strides. If clinical signs predictive of lameness could be observed more conveniently, as cows are undergoing regularly scheduled examinations while standing, detection levels could increase. The objective of this study was to assess the association between postures observed while cows are standing in stanchions and clinical lameness evaluated by locomotion scoring, and to evaluate the observation of these postures as a test for lameness. The study included 1,243 cows from 4 farms. Cows were observed while standing in stanchions for regularly scheduled management procedures and the presence of arched back and cow-hocked, wide-stance, and favored-limb postures were recorded. The same cows were locomotion-scored as they exited the milking parlor. The proportion of cows observed with arched back and cow-hocked and favored-limb postures increased with increasing severity of lameness (higher locomotion score) but did not increase for the wide-stance posture. For the presence of these postures as a test for lameness (locomotion score ≥3), sensitivity and specificity were 0.63 and 0.64 for back arch, 0.54 and 0.57 for cow hocks, and 0.05 and 0.98 for favored limb. Back-arched, cow-hocked, and favored limb postures were associated with lameness but were not highly sensitive or specific as diagnostic tests. However, observation of back arch may be useful to identify cows needing further examination.

  11. Response of lymphatics of canine hind limb to sympathetic nerve stimulation.

    PubMed

    Browse, N L

    1968-07-01

    1. The changes in lymphatic pressure in a limb whose circulation was temporarily arrested with a pneumatic cuff have been studied.2. Stimulation of the lumbar sympathetic chain caused an increase in lymphatic pressure. It has been shown that this is a primary not a secondary phenomenon, due to an active lymphomotor mechanism.3. The increase of lymphatic tone is proportional to the rate of stimulation; peak values are reached between 5 and 9 impulses/sec.

  12. 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.

  13. 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.

  14. Effects of stretching and disuse on amino acids in muscles of rat hind limbs

    NASA Technical Reports Server (NTRS)

    Jaspers, Stephen R.; Henriksen, Erik J.; Satarug, Soisungwan; Tischler, Marc E.

    1989-01-01

    The effects of disuse and passive stretch on the concentrations of amino acids and ammonia in the unloaded soleus muscle was investigated in hindquarter-suspended (for six days by casting one foot in dorsiflexion) tail-casted rats. For a comparison with the condition of unloading, amino acids and ammonia were also measured in shortened extensor digitorum longus in the same casted limb and in denervated leg muscles. The results obtained suggest that passive stretch diminishes some of the characteristic alterations of amino acid concentrations due to unloading. This effect of stretch is considered to be due to the maintenance of muscle tension.

  15. Study of Hind Limb Tissue Gas Phase Formation in Response to Suspended Adynamia and Hypokinesia

    NASA Technical Reports Server (NTRS)

    Butler, Bruce D.

    1996-01-01

    The purpose of this study was to investigate the hypothesis that reduced joint/muscle activity (hypo kinesia) as well as reduced or null loading of limbs (adynamia) in gravity would result in reduced decompression-induced gas phase and symptoms of decompression sickness (DCS). Finding a correlation between the two phenomena would correspond to the proposed reduction in tissue gas phase formation in astronauts undergoing decompression during extravehicular activity (EVA) in microgravity. The observation may further explain the reported low incidence of DCS in space.

  16. Effects of stretching and disuse on amino acids in muscles of rat hind limbs

    NASA Technical Reports Server (NTRS)

    Jaspers, Stephen R.; Henriksen, Erik J.; Satarug, Soisungwan; Tischler, Marc E.

    1989-01-01

    The effects of disuse and passive stretch on the concentrations of amino acids and ammonia in the unloaded soleus muscle was investigated in hindquarter-suspended (for six days by casting one foot in dorsiflexion) tail-casted rats. For a comparison with the condition of unloading, amino acids and ammonia were also measured in shortened extensor digitorum longus in the same casted limb and in denervated leg muscles. The results obtained suggest that passive stretch diminishes some of the characteristic alterations of amino acid concentrations due to unloading. This effect of stretch is considered to be due to the maintenance of muscle tension.

  17. 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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2017-07-21

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

  20. Mitochondrial-Targeted Antioxidant Maintains Blood Flow, Mitochondrial Function, and Redox Balance in Old Mice Following Prolonged Limb Ischemia.

    PubMed

    Miura, Shunsuke; Saitoh, Shu-Ichi; Kokubun, Tomoki; Owada, Takashi; Yamauchi, Hiroyuki; Machii, Hirofumi; Takeishi, Yasuchika

    2017-09-04

    Aging is a major factor in the decline of limb blood flow with ischemia. However, the underlying mechanism remains unclear. We investigated the role of mitochondrial reactive oxygen species (ROS) with regard to limb perfusion recovery in aging during ischemia. We performed femoral artery ligation in young and old mice with or without treatment with a scavenger of mitochondrial superoxide, MitoTEMPO (180 μg/kg/day, from pre-operative day 7 to post-operative day (POD) 21) infusion using an implanted mini-pump. The recoveries of cutaneous blood flow in the ischemic hind limb were lower in old mice than in young mice but were improved in MitoTEMPO-treated old mice. Mitochondrial DNA damage appeared in ischemic aged muscles but was eliminated by MitoTEMPO treatment. For POD 2, MitoTEMPO treatment suppressed the expression of p53 and the ratio of Bax/Bcl2 and upregulated the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in ischemic aged skeletal muscles. For POD 21, MitoTEMPO treatment preserved the expression of PGC-1α in ischemic aged skeletal muscle. The ischemic soleus of old mice showed a lower mitochondrial respiratory control ratio in POD 21 compared to young mice, which was recovered in MitoTEMPO-treated old mice. Scavenging of mitochondrial superoxide attenuated mitochondrial DNA damage and preserved the mitochondrial respiration, in addition to suppression of the expression of p53 and preservation of the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in ischemic skeletal muscles with aging. Resolution of excessive mitochondrial superoxide could be an effective therapy to recover blood flow of skeletal muscle during ischemia in senescence.

  1. Young's modulus and SEM analysis of leg bones exposed to simulated microgravity by hind limb suspension (HLS)

    SciTech Connect

    Patel, Niravkumar D.; Mehta, Rahul; Ali, Nawab; Soulsby, Michael; Chowdhury, Parimal

    2013-04-19

    The aim of this study was to determine composition of the leg bone tissue of rats that were exposed to simulated microgravity by Hind-Limb Suspension (HLS) by tail for one week. The leg bones were cross sectioned, cleaned of soft tissues, dried and sputter coated, and then placed horizontally on the stage of a Scanning Electron Microscope (SEM) for analysis. Interaction of a 17.5 keV electron beam, incident from the vertical direction on the sample, generated images using two detectors. X-rays emitted from the sample during electron bombardment were measured with an Energy Dispersive Spectroscopy (EDS) feature of SEM using a liquid-nitrogen cooled Si(Li) detector with a resolution of 144 eV at 5.9 keV ({sub 25}Mn K{sub {alpha}} x-ray). K{sub {alpha}}- x-rays from carbon, oxygen, phosphorus and calcium formed the major peaks in the spectrum. Relative percentages of these elements were determined using a software that could also correct for ZAF factors namely Z(atomic number), A(X-ray absorption) and F(characteristic fluorescence). The x-rays from the control groups and from the experimental (HLS) groups were analyzed on well-defined parts (femur, tibia and knee) of the leg bone. The SEM analysis shows that there are definite changes in the hydroxyl or phosphate group of the main component of the bone structure, hydroxyapatite [Ca{sub 10}(PO{sub 4}){sub 6}(OH){sub 2}], due to hind limb suspension. In a separate experiment, entire leg bones (both from HLS and control rats) were subjected to mechanical stress by mean of a variable force. The stress vs. strain graph was fitted with linear and polynomial function, and the parameters reflecting the mechanical strength of the bone, under increasing stress, were calculated. From the slope of the linear part of the graph the Young's modulus for HLS bones were calculated and found to be 2.49 times smaller than those for control bones.

  2. Actions on gamma-motoneurones elicited by electrical stimulation of cutaneous afferent fibres in the hind limb of the cat.

    PubMed

    Johansson, H; Sojka, P

    1985-09-01

    The reflex actions elicited by graded electrical stimulation of hind-limb cutaneous (sural, superficial peroneal and tibial) nerves were investigated with intra- and extracellular micro-electrode recordings in gamma-motoneurones projecting to hind-limb muscles in twenty-four cats anaesthetized with alpha-chloralose. In total, reflex responses of 100 gamma-motoneurones were analysed. 82 of the gamma-cells were classified as dynamic (43) or static (39) using the method of mesencephalic stimulation (Appelberg, Hulliger, Johansson & Sojka, 1982). The general responsiveness (i.e. number of input nerves with effect/number of input nerves tested) of the whole sample of gamma-cells to stimulation of skin nerves was extremely high (94.8%). All negative observations were encountered among static and non-classified gamma-cells. Generally, the stimulation strengths needed for evoking effects in the gamma-cells were very low. A majority of the excitatory effects in the dynamic cells appeared with stimulation intensities below 1.5 threshold (T), while most static cells were excited with stimulation strengths between 1.5 and 2 T. Also a statistical comparison of the populations of stimulation strength thresholds for the excitatory effects revealed a significant difference (P less than 0.0009) between dynamic and static gamma-cells. By contrast, the thresholds for inhibitory effects in dynamic cells were slightly higher than for excitatory effects (P less than 0.0009). As regards excitation of static cells, inhibition of dynamic cells and inhibition of static cells, no statistically significant threshold differences were found. A strong dominance of excitation over inhibition was found in both dynamic and static flexor (posterior biceps and semitendinosus) gamma-motoneurones from all input nerves. In comparison to flexor gamma-motoneurones, there was a much higher incidence of inhibitory and mixed (excitatory and inhibitory) responses in extensor (triceps) gamma-motoneurones, from

  3. Quantitative evaluation of bone development of the distal phalanx of the cow hind limb using computed tomography.

    PubMed

    Tsuka, T; Ooshita, K; Sugiyama, A; Osaki, T; Okamoto, Y; Minami, S; Imagawa, T

    2012-01-01

    Computed tomography (CT) was performed on 400 claws (200 inner and 200 outer claws) of 100 pairs of bovine hind limbs to investigate the etiological theory that an exacerbating factor for ulceration is exostosis of the tuberculum flexorium within the distal phalanx. A variety of morphological changes of the tuberculum flexorium of bovine hind limb claws was visualized by 3-dimensional CT, and the geometry of these claws suggested a growth pattern of bone development with respect to the assumed daily loading patterns. This growth occurs initially at the abaxial caudal aspect of the distal phalanx and is followed by horizontal progression toward the axial aspect. The length of downward bone development on the solar face of the distal phalanx was 2.73±1.32 mm in the outer claws, significantly greater than in the inner claws (2.38±0.96 mm). Ratios of downward (vertical) bone development to the thickness of the subcutis and the corium (VerBD ratios) did not differ between the outer and inner claws (36.7 vs. 38.3%, respectively). Ratios of horizontal bone development to the axial-to-abaxial line of the tuberculum flexorium (HorBD ratios) were approximately 60% for both outer and inner claws. These quantitative measures regarding horizontal and vertical bone development within the distal phalanx were positively correlated with age and VerBD ratios (r=0.53 and r=0.36 for the inner and outer claws, respectively). Correlations between claw width of the outer claw and length of vertical bone development (r=0.43), the HorBD ratio (r=0.51), and the VerBD ratio (r=0.42) suggested that the relative size difference between the inner and outer claws enhances bone development in the outer claw. Correlation coefficients between VerBD and HorBD ratios (r=0.52 and 0.63 for the inner and outer claws, respectively) suggested that horizontal and vertical bone development occurs as a synchronized process within the tuberculum flexorium. This age-related progress of bone development

  4. Young's modulus and SEM analysis of leg bones exposed to simulated microgravity by hind limb suspension (HLS)

    NASA Astrophysics Data System (ADS)

    Patel, Niravkumar D.; Mehta, Rahul; Ali, Nawab; Soulsby, Michael; Chowdhury, Parimal

    2013-04-01

    The aim of this study was to determine composition of the leg bone tissue of rats that were exposed to simulated microgravity by Hind-Limb Suspension (HLS) by tail for one week. The leg bones were cross sectioned, cleaned of soft tissues, dried and sputter coated, and then placed horizontally on the stage of a Scanning Electron Microscope (SEM) for analysis. Interaction of a 17.5 keV electron beam, incident from the vertical direction on the sample, generated images using two detectors. X-rays emitted from the sample during electron bombardment were measured with an Energy Dispersive Spectroscopy (EDS) feature of SEM using a liquid-nitrogen cooled Si(Li) detector with a resolution of 144 eV at 5.9 keV (25Mn Kα x-ray). Kα- x-rays from carbon, oxygen, phosphorus and calcium formed the major peaks in the spectrum. Relative percentages of these elements were determined using a software that could also correct for ZAF factors namely Z(atomic number), A(X-ray absorption) and F(characteristic fluorescence). The x-rays from the control groups and from the experimental (HLS) groups were analyzed on well-defined parts (femur, tibia and knee) of the leg bone. The SEM analysis shows that there are definite changes in the hydroxyl or phosphate group of the main component of the bone structure, hydroxyapatite [Ca10(PO4)6(OH)2], due to hind limb suspension. In a separate experiment, entire leg bones (both from HLS and control rats) were subjected to mechanical stress by mean of a variable force. The stress vs. strain graph was fitted with linear and polynomial function, and the parameters reflecting the mechanical strength of the bone, under increasing stress, were calculated. From the slope of the linear part of the graph the Young's modulus for HLS bones were calculated and found to be 2.49 times smaller than those for control bones.

  5. 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.

  6. Real-time control of hind limb functional electrical stimulation using feedback from dorsal root ganglia recordings

    NASA Astrophysics Data System (ADS)

    Bruns, Tim M.; Wagenaar, Joost B.; Bauman, Matthew J.; Gaunt, Robert A.; Weber, Douglas J.

    2013-04-01

    Objective. Functional electrical stimulation (FES) approaches often utilize an open-loop controller to drive state transitions. The addition of sensory feedback may allow for closed-loop control that can respond effectively to perturbations and muscle fatigue. Approach. We evaluated the use of natural sensory nerve signals obtained with penetrating microelectrode arrays in lumbar dorsal root ganglia (DRG) as real-time feedback for closed-loop control of FES-generated hind limb stepping in anesthetized cats. Main results. Leg position feedback was obtained in near real-time at 50 ms intervals by decoding the firing rates of more than 120 DRG neurons recorded simultaneously. Over 5 m of effective linear distance was traversed during closed-loop stepping trials in each of two cats. The controller compensated effectively for perturbations in the stepping path when DRG sensory feedback was provided. The presence of stimulation artifacts and the quality of DRG unit sorting did not significantly affect the accuracy of leg position feedback obtained from the linear decoding model as long as at least 20 DRG units were included in the model. Significance. This work demonstrates the feasibility and utility of closed-loop FES control based on natural neural sensors. Further work is needed to improve the controller and electrode technologies and to evaluate long-term viability.

  7. RIP2-mediated LKB1 deletion causes axon degeneration in the spinal cord and hind-limb paralysis.

    PubMed

    Sun, Gao; Reynolds, Richard; Leclerc, Isabelle; Rutter, Guy A

    2011-03-01

    Axon degeneration is observed in neurodegenerative diseases and neuroinflammatory disorders, such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. The molecular basis of this process remains largely unknown. Here, we show that mice deleted for the tumour suppressor LKB1 (also called STK11) in the spinal cord, some parts of the brain and in the endocrine pancreas (βLKB1KO mice) develop hind-limb dysfunction and axon degeneration at about 7 weeks. Demyelination and macrophage infiltration are observed in the white matter of these mice, predominantly in the bilateral and anterior funiculi of the thoracic segment of the spinal cord, suggesting damage to the ascending sensory signalling pathway owing to LKB1 deletion in the brain. Microtubule structures were also affected in the degenerated foci, with diminished neurofilament and tubulin expression. Deletion of both PRKAA1 genes, whose products AMPKα1 and AMPKα2 are also downstream targets of LKB1, with the same strategy was without effect. We thus define LKB1 as an intrinsic suppressor of axon degeneration and a possible target for strategies that can reverse this process.

  8. Countercurrent compartmental models describe hind limb skeletal muscle helium kinetics at resting and low blood flows in sheep.

    PubMed

    Doolette, D J; Upton, R N; Grant, C

    2005-10-01

    This study evaluated the relative importance of perfusion and diffusion mechanisms in compartmental models of blood : tissue helium exchange in a predominantly skeletal muscle tissue bed in the sheep hind limb. Helium has different physiochemical properties from previously studied gases and is a common diluent gas in underwater diving where decompression schedules are based on theoretical models of inert gas kinetics. Helium kinetics across skeletal muscle were determined during and after 20 min of helium inhalation, at separate resting and low steady-states of femoral vein blood flow in six sheep under isoflurane anaesthesia. Helium concentrations in arterial and femoral vein blood were determined using gas chromatographic analysis and femoral vein blood flow was monitored continuously. Parameters and model selection criteria of various perfusion-limited or perfusion-diffusion compartmental models of skeletal muscle were estimated by simultaneous fitting of the models to the femoral vein helium concentrations for both blood flow states. A model comprising two parallel perfusion-limited compartment models fitted the data well but required a 51-fold difference in relative compartment perfusion that did not seem physiologically plausible. Models that allowed a countercurrent diffusion exchange of helium between arterial and venous vessels outside of the tissue compartments provided better overall fit of the data and credible parameter estimates. These results suggest a role of arterial-venous diffusion in blood : tissue helium equilibration in skeletal muscle.

  9. Segment and joint angles of hind limb during bipedal and quadrupedal walking of the bonobo (Pan paniscus).

    PubMed

    D'Août, Kristiaan; Aerts, Peter; De Clercq, Dirk; De Meester, Koen; Van Elsacker, Linda

    2002-09-01

    We describe segment angles (trunk, thigh, shank, and foot) and joint angles (hip, knee, and ankle) for the hind limbs of bonobos walking bipedally ("bent-hip bent-knee walking," 17 sequences) and quadrupedally (33 sequences). Data were based on video recordings (50 Hz) of nine subjects in a lateral view, walking at voluntary speed. The major differences between bipedal and quadrupedal walking are found in the trunk, thigh, and hip angles. During bipedal walking, the trunk is approximately 33-41 degrees more erect than during quadrupedal locomotion, although it is considerably more bent forward than in normal human locomotion. Moreover, during bipedal walking, the hip has a smaller range of motion (by 12 degrees ) and is more extended (by 20-35 degrees ) than during quadrupedal walking. In general, angle profiles in bonobos are much more variable than in humans. Intralimb phase relationships of subsequent joint angles show that hip-knee coordination is similar for bipedal and quadrupedal walking, and resembles the human pattern. The coordination between knee and ankle differs much more from the human pattern. Based on joint angles observed throughout stance phase and on the estimation of functional leg length, an efficient inverted pendulum mechanism is not expected in bonobos.

  10. Expression of nestin, desmin and vimentin in intact and regenerating muscle spindles of rat hind limb skeletal muscles.

    PubMed

    Cízková, Dana; Soukup, Tomás; Mokrý, Jaroslav

    2009-02-01

    We describe the expression and distribution patterns of nestin, desmin and vimentin in intact and regenerating muscle spindles of the rat hind limb skeletal muscles. Regeneration was induced by intramuscular isotransplantation of extensor digitorum longus (EDL) or soleus muscles from 15-day-old rats into the EDL muscle of adult female inbred Lewis rats. The host muscles with grafts were excised after 7-, 16-, 21- and 29-day survival and immunohistochemically stained. Nestin expression in intact spindles in host muscles was restricted to Schwann cells of sensory and motor nerves. In transplanted muscles, however, nestin expression was also found in regenerating "spindle fibers", 7 and 16 days after grafting. From the 21st day onwards, the regenerated spindle fibers were devoid of nestin immunoreactivity. Desmin was detected in spindle fibers at all developmental stages in regenerating as well as in intact spindles. Vimentin was expressed in cells of the outer and inner capsules of all muscle spindles and in newly formed myoblasts and myotubes of regenerating spindles 7 days after grafting. Our results show that the expression pattern of these intermediate filaments in regenerating spindle fibers corresponds to that found in regenerating extrafusal fibers, which supports our earlier suggestion that they resemble small-diameter extrafusal fibers.

  11. Real-time control of hind limb functional electrical stimulation using feedback from dorsal root ganglia recordings

    PubMed Central

    Bruns, Tim M; Wagenaar, Joost B; Bauman, Matthew J; Gaunt, Robert A; Weber, Douglas J

    2013-01-01

    Objective Functional electrical stimulation (FES) approaches often utilize an open-loop controller to drive state transitions. The addition of sensory feedback may allow for closed-loop control that can respond effectively to perturbations and muscle fatigue. Approach We evaluated the use of natural sensory nerve signals obtained with penetrating microelectrode arrays in lumbar dorsal root ganglia (DRG) as real-time feedback for closed-loop control of FES-generated hind limb stepping in anesthetized cats. Main results Leg position feedback was obtained in near real-time at 50 ms intervals by decoding the firing rates of more than 120 DRG neurons recorded simultaneously. Over 5 m of effective linear distance was traversed during closed-loop stepping trials in each of two cats. The controller compensated effectively for perturbations in the stepping path when DRG sensory feedback was provided. The presence of stimulation artifacts and the quality of DRG unit sorting did not significantly affect the accuracy of leg position feedback obtained from the linear decoding model as long as at least 20 DRG units were included in the model. Significance This work demonstrates the feasibility and utility of closed-loop FES control based on natural neural sensors. Further work is needed to improve the controller and electrode technologies and to evaluate long-term viability. PMID:23503062

  12. Implanting iodine-125 seeds into rat dorsal root ganglion for neuropathic pain: neuronal microdamage without impacting hind limb motion.

    PubMed

    Jiao, Ling; Zhang, Tengda; Wang, Huixing; Zhang, Wenyi; Fan, Saijun; Huo, Xiaodong; Zheng, Baosen; Ma, Wenting

    2014-06-15

    The use of iodine-125 ((125)I) in cancer treatment has been shown to relieve patients' pain. Considering dorsal root ganglia are critical for neural transmission between the peripheral and central nervous systems, we assumed that (125)I could be implanted into rat dorsal root ganglia to provide relief for neuropathic pain. (125)I seeds with different radioactivity (0, 14.8, 29.6 MBq) were implanted separately through L4-5 and L5-6 intervertebral foramen into the vicinity of the L5 dorsal root ganglion. von Frey hair results demonstrated the mechanical pain threshold was elevated after implanting (125)I seeds from the high radioactivity group. Transmission electron microscopy revealed that nuclear membrane shrinkage, nucleolar margination, widespread mitochondrial swelling, partial vacuolization, lysosome increase, and partial endoplasmic reticulum dilation were visible at 1,440 hours in the low radioactivity group and at 336 hours in the high radioactivity group. Abundant nuclear membrane shrinkage, partial fuzzy nuclear membrane and endoplasmic reticulum necrosis were observed at 1,440 hours in the high radioactivity group. No significant difference in combined behavioral scores was detected between preoperation and postoperation in the low and high radioactivity groups. These results suggested that the mechanical pain threshold was elevated after implanting (125)I seeds without influencing motor functions of the hind limb, although cell injury was present.

  13. IL-20 is an arteriogenic cytokine that remodels collateral networks and improves functions of ischemic hind limbs

    PubMed Central

    Tritsaris, Katerina; Myren, Maja; Ditlev, Sisse B.; Hübschmann, Martin V.; van der Blom, Ida; Hansen, Anker Jon; Olsen, Uffe B.; Cao, Renhai; Zhang, Junhang; Jia, Tanghong; Wahlberg, Eric; Dissing, Steen; Cao, Yihai

    2007-01-01

    Successful therapeutic angiogenesis for the treatment of ischemic disorders relies on selection of optimal proangiogenic or arteriogenic agents that are able to promote establishment of functional collateral networks. Here, we show that IL-20, a pleiotropic inflammatory cytokine, displays an imperative effect on vascular remodeling. Stimulation of both large and microvascular endothelial cells with IL-20 leads to activation of receptor-dependent multiple intracellular signaling components, including increased phosphorylation levels of JAK2/STAT5, Erk1/2, and Akt; activation of small GTP-binding proteins Rac and Rho; and intracellular release of calcium. Surprisingly, IL-20 significantly promotes endothelial cell tube formation without affecting their proliferation and motility. These findings suggest that the vascular function of IL-20 involves endothelial cell organization, vessel maturation, and remodeling. Consistent with this notion, delivery of IL-20 to the ischemic muscle tissue significantly improves arteriogenesis and blood perfusion in a rat hind-limb model. Our findings provide mechanistic insights on vascular functions of IL-20 and define therapeutic implication of this cytokine for the treatment of ischemic disorders. PMID:17878297

  14. Medical and endovascular management of critical limb ischemia.

    PubMed

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

    2009-04-01

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

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

    PubMed

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

    1993-10-01

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

  16. Fasting increases palmitic acid incorporation into rat hind-limb intramuscular acylglycerols while short-term cold exposure has no effect.

    PubMed

    Synak, M; Zarzeczny, R; Górecka, M; Langfort, J; Kaciuba-Uściłko, H; Zernicka, Ewa

    2011-09-01

    The aim of the study was to investigate the palmitic acid incorporation into intramuscular acylglycerols in perfused hind-limb skeletal muscles of different fibre types in rats either fasted for 48 h or exposed to cold (6 °C) for 12 h. Hind-limb preparations of fasted and cold exposed rats were perfused with buffers containing tritium labelled and cold palmitic acid. Palmitic acid incorporation into intracellular lipid pools in the soleus, plantaris, red and white gastrocnemius and red and white quadriceps was measured. It was found that fasting increased approximately 2-fold palmitic acid incorporation in all muscles examined regardless of the fibre type composition of the muscle. On the other hand, exposure to cold had no effect on the palmitic acid incorporation into intramuscular acylglycerols regardless the muscle fibre type. The increased incorporation of palmitic acid into acylglycerols in fasted animals is in line with data showing that 48 h fasting stimulates the expression of plasma membrane proteins putatively facilitating fatty acid uptake. It appears that although 12 h cold exposure increases the use of fatty acids as energy substrates it does not alter the incorporation of palmitic acid into intramuscular acylglycerols in the perfused rat hind-limb.

  17. Longitudinal evaluation of mouse hind limb bone loss after spinal cord injury using novel, in vivo, methodology.

    PubMed

    McManus, Madonna M; Grill, Raymond J

    2011-12-07

    Spinal cord injury (SCI) is often accompanied by osteoporosis in the sublesional regions of the pelvis and lower extremities, leading to a higher frequency of fractures. As these fractures often occur in regions that have lost normal sensory function, the patient is at a greater risk of fracture-dependent pathologies, including death. SCI-dependent loss in both bone mineral density (BMD, grams/cm2) and bone mineral content (BMC, grams) has been attributed to mechanical disuse, aberrant neuronal signaling and hormonal changes. The use of rodent models of SCI-induced osteoporosis can provide invaluable information regarding the mechanisms underlying the development of osteoporosis following SCI as well as a test environment for the generation of new therapies. Mouse models of SCI are of great interest as they permit a reductionist approach to mechanism-based assessment through the use of null and transgenic mice. While such models have provided important data, there is still a need for minimally-invasive, reliable, reproducible, and quantifiable methods in determining the extent of bone loss following SCI, particularly over time and within the same cohort of experimental animals, to improve diagnosis, treatment methods, and/or prevention of SCI-induced osteoporosis. An ideal method for measuring bone density in rodents would allow multiple, sequential (over time) exposures to low-levels of X-ray radiation. This study describes the use of a new whole-animal scanner, the IVIS Lumina XR (Caliper Instruments) that can be used to provide low-energy (1-3 milligray (mGy)) high-resolution, high-magnification X-ray images of mouse hind limb bones over time following SCI. Significant bone density loss was seen in the tibiae of mice by 10 days post-spinal transection when compared to uninjured, age-matched control (naïve) mice (13% decrease, p < 0.0005). Loss of bone density in the distal femur was also detectable by day 10 post-SCI, while a loss of density in the proximal

  18. MRI-Based Computational Model of Heterogeneous Tracer Transport following Local Infusion into a Mouse Hind Limb Tumor

    PubMed Central

    Magdoom, Kulam Najmudeen; Pishko, Gregory L.; Rice, Lori; Pampo, Chris; Siemann, Dietmar W.; Sarntinoranont, Malisa

    2014-01-01

    Systemic drug delivery to solid tumors involving macromolecular therapeutic agents is challenging for many reasons. Amongst them is their chaotic microvasculature which often leads to inadequate and uneven uptake of the drug. Localized drug delivery can circumvent such obstacles and convection-enhanced delivery (CED) - controlled infusion of the drug directly into the tissue - has emerged as a promising delivery method for distributing macromolecules over larger tissue volumes. In this study, a three-dimensional MR image-based computational porous media transport model accounting for realistic anatomical geometry and tumor leakiness was developed for predicting the interstitial flow field and distribution of albumin tracer following CED into the hind-limb tumor (KHT sarcoma) in a mouse. Sensitivity of the model to changes in infusion flow rate, catheter placement and tissue hydraulic conductivity were investigated. The model predictions suggest that 1) tracer distribution is asymmetric due to heterogeneous porosity; 2) tracer distribution volume varies linearly with infusion volume within the whole leg, and exponentially within the tumor reaching a maximum steady-state value; 3) infusion at the center of the tumor with high flow rates leads to maximum tracer coverage in the tumor with minimal leakage outside; and 4) increasing the tissue hydraulic conductivity lowers the tumor interstitial fluid pressure and decreases the tracer distribution volume within the whole leg and tumor. The model thus predicts that the interstitial fluid flow and drug transport is sensitive to porosity and changes in extracellular space. This image-based model thus serves as a potential tool for exploring the effects of transport heterogeneity in tumors. PMID:24619021

  19. Scaling factor relating conduction velocity and diameter for myelinated afferent nerve fibres in the cat hind limb.

    PubMed Central

    Boyd, I A; Kalu, K U

    1979-01-01

    1. Compound action potentials were recorded from certain muscle and cutaneous nerves in normal and chronically de-efferentated hind limbs of cats during stimulation of the appropriate dorsal spinal roots, 2. The peaks for groups I, II and III in the compound action potential were correlated with the corresponding peaks in the fibre-diameter histograms of the same de-efferentated nerve after processing it for light microscopy. 3. The scaling factor (ratio of conduction velocity in m/sec to total diameter in micrometer) was not constant for all sizes of fibre nor did it increase progressively with fibre size. Evidence is presented that a logarithmic relation between conduction velocity and fibre diameter is not appropriate. 4. In muscle nerves the scaling factor for fibres fixed by glutaraldehyde perfusion and embedded in Epon was 5.7 for group I afferent fibres and 4.6 for myelinated fibres in both group II and group III. 5. In cutaneous nerves the scaling factor was 5.6 for large fibres (group I or Abeta) and 4.6 for small fibres (group III or Adelta). 6. The scaling factor for group I fibres is the same as was found previously for alpha-efferent fibres, and that for groups II and III is the same as for gamma-efferent fibres (Boyd & Davey, 1968). 7. The possibility that there is a clear discontinuity in scaling factor between fibres in groups I and alpha, and those in other functional groups, is discussed. 8. It is concluded that there must be some structural feature of alpha and group I fibres which differs from that of smaller myelinated fibres. It is likely that a difference in the relative thickness of the myelin sheath is involved and possibly also in the conductances responsible for generating the action potential. Images Plate 1 PMID:458657

  20. MRI-based computational model of heterogeneous tracer transport following local infusion into a mouse hind limb tumor.

    PubMed

    Magdoom, Kulam Najmudeen; Pishko, Gregory L; Rice, Lori; Pampo, Chris; Siemann, Dietmar W; Sarntinoranont, Malisa

    2014-01-01

    Systemic drug delivery to solid tumors involving macromolecular therapeutic agents is challenging for many reasons. Amongst them is their chaotic microvasculature which often leads to inadequate and uneven uptake of the drug. Localized drug delivery can circumvent such obstacles and convection-enhanced delivery (CED)--controlled infusion of the drug directly into the tissue--has emerged as a promising delivery method for distributing macromolecules over larger tissue volumes. In this study, a three-dimensional MR image-based computational porous media transport model accounting for realistic anatomical geometry and tumor leakiness was developed for predicting the interstitial flow field and distribution of albumin tracer following CED into the hind-limb tumor (KHT sarcoma) in a mouse. Sensitivity of the model to changes in infusion flow rate, catheter placement and tissue hydraulic conductivity were investigated. The model predictions suggest that 1) tracer distribution is asymmetric due to heterogeneous porosity; 2) tracer distribution volume varies linearly with infusion volume within the whole leg, and exponentially within the tumor reaching a maximum steady-state value; 3) infusion at the center of the tumor with high flow rates leads to maximum tracer coverage in the tumor with minimal leakage outside; and 4) increasing the tissue hydraulic conductivity lowers the tumor interstitial fluid pressure and decreases the tracer distribution volume within the whole leg and tumor. The model thus predicts that the interstitial fluid flow and drug transport is sensitive to porosity and changes in extracellular space. This image-based model thus serves as a potential tool for exploring the effects of transport heterogeneity in tumors.

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

    PubMed

    Conde, Ian Del; Erwin, Phillip A

    2014-09-01

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

  2. 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.

  3. 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.

  4. 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

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

    PubMed

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

    2017-03-01

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

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

    PubMed

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

    2014-04-01

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

  7. Sources of Delay in the Acute Limb Ischemia Patient Pathway.

    PubMed

    Normahani, Pasha; Standfield, Nigel J; Jaffer, Usman

    2017-01-01

    Acute limb ischemia (ALI) continues to pose a significant challenge to clinicians and is associated with an unacceptably high rate of morbidity and mortality. Despite its time critical nature, little is known regarding the delays encountered during the patient pathway. The aim of this study was to identify sources of delay in the patient pathway at our institution. Sixty-seven cases of ALI of the lower extremities from 66 patients, who had presented to our center between May 2003 and April 2014, were identified for retrospective analysis. Data were retrieved from the patient records, discharge summaries and hospital laboratory, emergency department and radiology databases. Median time from onset of symptom to arrival at our institution was 11.35 hr (interquartile range [IQR] 6.27-72). Median cumulative time taken from arrival to vascular team review was 40 min (22.5-120), to imaging being performed was 4.75 hr (2.42-17.25), and to intervention being performed was 10.2 hr (4-31). There were significantly longer delays to presentation in those transferred from inpatient beds as compared with those transferred from the emergency department of other hospitals (66 hr [10.3-98] vs. 8 hr [5.6-14.9], P = 0.007). In total, 84.6% of patients underwent preoperative arterial imaging. Time taken from arrival to diagnostic arterial imaging was significantly longer in patients presenting out-of-ours (15 hr [6.5-20.75]) as compared with patients presenting in-hours (3.5 hr [2-6.5], P = 0.014) or during the weekend (2 hr [2-3], P = 0.022). Time from presentation to intervention was significantly shorter in patients presenting over the weekend (3.9 hr [2.6-5.1]) as compared with those presenting in-hours (14.2 hr [6.2-29], P = 0.006) and out-of-hours (16 hr [10-33], P = 0.021). Out-of-hours, a significant portion of the delay, was attributable to imaging (median time to imaging 15 hr). This study demonstrates the systematic nature of delays in the patient

  8. A flexible electrode array for muscle impedance measurements in the mouse hind limb: A tool to speed research in neuromuscular disease

    NASA Astrophysics Data System (ADS)

    Li, J.; Rutkove, S. B.

    2013-04-01

    Electrical impedance myography (EIM) is a bioelectrical impedance technique focused on the assessment of neuromuscular diseases using tetrapolar surface arrays. Recently, we have shown that reproducible and sensitive EIM measurements can be made on the gastrocnemius muscle of the mouse hind limb and that these are sensitive to disease alterations. A dedicated array would help speed data acquisition and provide additional sensitivity to disease-induced alterations. A flexible electrode array was developed with electrode sizes of 1mm × 1mm by Parlex, Inc. Tetrapolar electrode sets were arranged both parallel to (longitudinal) and orthogonally to (transverse) the major muscle fiber direction of the gastrocnemius muscle. Measurements were made with a dedicated EIM system. A total of 11 healthy animals and 7 animals with spinal muscular atrophy (a form of motor neuron disease) were evaluated after the fur was completely removed with a depilatory agent from the hind limb. Standard electrophysiologic testing (compound motor action potential amplitude and motor unit number estimation) was also performed. The flexible electrode array demonstrated high repeatability in both the longitudinal and transverse directions in the healthy and diseased animals (with intraclass correlation coefficients of 0.94 and 0.89, respectively, for phase angle measured transversely). In addition, differences between healthy and diseased animals were identifiable. For example, the 50 kHz transverse phase angle was higher in the healthy as compared to the SMA animals (16.8° ± 0.5 vs. 14.3° ± 0.7, respectively) at 21 weeks of age (p = 0.01). Differences in anisotropy were also identifiable. Correlations to several standard neurophysiologic parameters also appeared promising. This novel flexible tetrapolar electrode array can be used on the mouse hind limb and provides multidirectional data that can be used to assess muscle health. This technique has the potential of finding widespread use in

  9. Type B Dissection Resulting in Acute Limb Ischemia in a Patient With a History of EVAR.

    PubMed

    Jayakumar, Lalithapriya; Lombardi, Joseph V; Caputo, Francis J

    2017-02-01

    Type B aortic dissection (TBAD) can be complicated due to visceral and limb malperfusion. We present the case of a patient with a TBAD 5 months after endovascular aneurysm repair (EVAR) for an infrarenal aortic aneurysm, which resulted in a right leg acute limb ischemia due to impingement of the EVAR from to the dissection. In the following discussion, we will review the literature and describe our technique for the treatment of this infrequent problem.

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

    PubMed Central

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

    2009-01-01

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

  11. Epidural electrical stimulation in severe limb ischemia. Pain relief, increased blood flow, and a possible limb-saving effect.

    PubMed Central

    Augustinsson, L E; Carlsson, C A; Holm, J; Jivegård, L

    1985-01-01

    Peripheral vascular disease of the extremities causes ischemic pain and, at times, skin ulcerations and gangrene. It has been suggested that epidural spinal electrical stimulation (ESES) could improve peripheral circulation. Since 1978 we have used ESES in 34 patients with severe limb ischemia; all had resting pain and most had ischemic ulcers. Arterial surgery was technically impossible. Twenty-six patients had arteriosclerotic disease, one had Buerger's disease, and seven had severe vasospastic disorders. Ninety-four per cent of the patients experienced pain relief. ESES healed ulcers in 50% of those with preoperative nonhealing skin ulcerations. Seventy per cent of the patients showed improved skin temperature recordings. Only 38% of the stimulated arteriosclerotic patients underwent amputations during a mean followup period of 16 months, as compared to 90% of a comparable group of unstimulated patients. ESES is very promising in severe limb ischemia where reconstructive surgery is impossible or has failed. PMID:3874610

  12. 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.

  13. 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

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

    PubMed Central

    Gardner, Andrew W.; Montgomery, Polly S.

    2010-01-01

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

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

    NASA Astrophysics Data System (ADS)

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

    2017-04-01

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

  16. 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.

  17. Coadministration of adipose-derived stem cells and control-released basic fibroblast growth factor facilitates angiogenesis in a murine ischemic hind limb model.

    PubMed

    Horikoshi-Ishihara, Hisako; Tobita, Morikuni; Tajima, Satoshi; Tanaka, Rica; Oshita, Takashi; Tabata, Yasuhiko; Mizuno, Hiroshi

    2016-12-01

    Adipose-derived stem cells (ASCs) have angiogenic potential owing to their differentiation into endothelial cells and their release of angiogenic growth factors to elicit paracrine effects. In addition, control-released basic fibroblast growth factor (bFGF) sustained with a gelatin hydrogel also supports effective angiogenesis. We sought to determine if coadministration of ASCs and control-released bFGF into murine ischemic limbs facilitates angiogenesis. Levels of growth factors in the conditioned media of ASCs cultured with or without control-released bFGF were measured by enzyme-linked immunosorbent assays. A murine ischemic hind limb model was generated and intramuscularly injected with the following: gelatin hydrogel (group 1), a high number of ASCs (group 2), control-released bFGF (group 3), a small number of ASCs and control-released bFGF (group 4), and a high number of ASCs and control-released bFGF (group 5). Macroscopic and microscopic vascular changes were evaluated until day 7 by laser Doppler perfusion imaging and histologic analyses, respectively. Secretion of hepatocyte growth factor, vascular endothelial growth factor, and transforming growth factor-β1 was enhanced by control-released bFGF. Vascular improvement was achieved in groups 4 and 5 according to laser Doppler perfusion imaging. Hematoxylin and eosin staining and CD31 immunohistochemical staining demonstrated an increase in the vascular density, vessel diameter, and thickness of vessel walls in groups 4 and 5. Cells positively stained for CD146, α-smooth muscle actin, and transforming growth factor-β1 were observed around vessel walls in groups 4 and 5. These findings suggest that coadministration of ASCs and control-released bFGF facilitates angiogenesis in terms of vessel maturation in a murine ischemic hind limb model. Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

  18. Inhalation anesthesia of rats: influence of the fraction of inspired oxygen on limb ischemia/reperfusion injury.

    PubMed

    Zhang, S; Duehrkop, C; Plock, J A; Rieben, R

    2016-06-01

    Inhalation anesthesia with isoflurane is a well-established and safe method used in small laboratory animals. In most cases oxygen is used as a carrier gas for isoflurane, but room air or mixtures of oxygen with air or nitrous oxide are also being used. Anesthesia is therefore administered using different fractions of inspired oxygen (FiO2), and this may have consequences for the outcome of experiments. The aim of the present study was to investigate the influence of FiO2 on rat hind limb ischemia/reperfusion injury and to refine the used inhalation anesthesia. Male Wistar rats were subjected to 3.5 h of ischemia and 2 h of reperfusion, and divided into three groups according to FiO2 in the O2/air/isoflurane anesthesia gas mixture: 40%, 60%, and 100% O2 Normal, healthy rats were used as controls. Muscle edema and creatine kinase MM, a marker for myocyte necrosis, were significantly increased with 40% FiO2 as compared with 100% FiO2 (P < 0.05). Partial pressure of oxygen, oxygen saturation, and oxyhemoglobin were significantly higher in the 100% O2 group as compared with 40% O2 No significant differences were detected for other parameters, such as the oxidative stress markers malondialdehyde and superoxide dismutase. We conclude that a refined inhalation anesthesia setting using 40% FiO2, reflecting more or less the clinical situation, leads to a more severe and more physiologically relevant reperfusion injury than higher FiO2. Oxidative stress did not correlate with FiO2 and seemed to have no influence on reperfusion injury.

  19. The Effects of Inclination (Up and Down) of the Treadmill on the Electromyogram Activities of the Forelimb and Hind limb Muscles at a Walk and a Trot in Thoroughbred Horses

    PubMed Central

    TAKAHASHI, Toshiyuki; MATSUI, Akira; MUKAI, Kazutaka; OHMURA, Hajime; HIRAGA, Atsushi; AIDA, Hiroko

    2014-01-01

    ABSTRACT It is important to know the effects of the inclination of a slope on the activity of each muscle, because training by running on a sloped track is commonly used for Thoroughbred racehorses. The effects of incline (from −6 to +6%) on the forelimbs and hind limbs during walking and trotting on a treadmill were evaluated by an integrated electromyogram (iEMG). The muscle activities in the forelimbs (5 horses) and hind limbs (4 horses) were measured separately. Two stainless steel wires were inserted into each of the brachiocephalicus (Bc), biceps brachii (BB), splenius (Sp), and pectoralis descendens (PD) in the forelimb experiment and into the longissimus dorsi (LD), vastus lateralis (VL), gluteus medius (GM), and biceps femoris (BF) in the hind limb experiment. The EMG recordings were taken at a sampling rate of 1,000 Hz. At a walk, the iEMG values for the forelimb were not significantly different under any of the inclinations. In the hind limb, the iEMG values for the GM and BF significantly decreased as the inclination decreased. At a trot, the iEMG values for the Bc in the forelimb significantly decreased as the inclination of the treadmill decreased. In the hind limb, the iEMG values for the LD, GM, and BF significantly decreased as the inclination decreased. Uphill exercise increased the iEMG values for the Bc, LD, GM, and BF, while downhill exercise resulted in little increase in the iEMG values. It was concluded that the effects of inclination on the muscle activities were larger for the uphill exercises, and for the hind limb muscles compared with the forelimb muscles. PMID:25558180

  20. The Effects of Inclination (Up and Down) of the Treadmill on the Electromyogram Activities of the Forelimb and Hind limb Muscles at a Walk and a Trot in Thoroughbred Horses.

    PubMed

    Takahashi, Toshiyuki; Matsui, Akira; Mukai, Kazutaka; Ohmura, Hajime; Hiraga, Atsushi; Aida, Hiroko

    2014-01-01

    It is important to know the effects of the inclination of a slope on the activity of each muscle, because training by running on a sloped track is commonly used for Thoroughbred racehorses. The effects of incline (from -6 to +6%) on the forelimbs and hind limbs during walking and trotting on a treadmill were evaluated by an integrated electromyogram (iEMG). The muscle activities in the forelimbs (5 horses) and hind limbs (4 horses) were measured separately. Two stainless steel wires were inserted into each of the brachiocephalicus (Bc), biceps brachii (BB), splenius (Sp), and pectoralis descendens (PD) in the forelimb experiment and into the longissimus dorsi (LD), vastus lateralis (VL), gluteus medius (GM), and biceps femoris (BF) in the hind limb experiment. The EMG recordings were taken at a sampling rate of 1,000 Hz. At a walk, the iEMG values for the forelimb were not significantly different under any of the inclinations. In the hind limb, the iEMG values for the GM and BF significantly decreased as the inclination decreased. At a trot, the iEMG values for the Bc in the forelimb significantly decreased as the inclination of the treadmill decreased. In the hind limb, the iEMG values for the LD, GM, and BF significantly decreased as the inclination decreased. Uphill exercise increased the iEMG values for the Bc, LD, GM, and BF, while downhill exercise resulted in little increase in the iEMG values. It was concluded that the effects of inclination on the muscle activities were larger for the uphill exercises, and for the hind limb muscles compared with the forelimb muscles.

  1. Connexions from large, ipsilateral hind limb muscle and skin afferents to the rostral main cuneate nucleus and to the nucleus X region in the cat.

    PubMed Central

    Johansson, H; Silfvenius, H

    1977-01-01

    1. Evidence is presented for an input from ipsilateral hind limb group I muscle afferents and low threshold cutaneous afferents, to cells in the rostral division of the main cuneate nucleus (rMCN) and in the region of the descending vestibular nucleus and the nucleus X of Brodal & Pompeiano (1957a), the (DV-X). 2. Thirteen group I-rMCN cells were recorded from. The functional properties of these cells were similar to those of nueleus Z (Landgren & Silfvenius, 1971; Johansson & Silfvenius, 1977a, b). The cells were monosynaptically linked to spinal dorsolateral fascicle (DLF) fibres. Nine cells projected to the contralateral thalamus, i.e. a second group I hind limb bulbothalamic tract is described. Ten cells were synaptically activated from the ipsilateral cerebellum from the anterior projection zone of the dorsal spinocerebellar tract (DSCT). Axon-collateral activation by DSCT fibres was established for two of these cells. They were both bulbothalamic relay cells. For the remaining eight cells, activated from the cerebellum, this was not proven. These cells could, however, either be linked to DSCT fibres or to short axon-collaterals of a cell body of unknown location. A projection from the rMCN to the cerebellum is described and agrees with recent anatomical findings. Two cells were not excited from the cerebellum. 3. Four rMCN cells were activated by cutaneous afferents with their secondary axons in the DLF. Suggestive evidence for a bulbothalamic cutaneous hind limb path via the rMCN is presented. Two cells were activated from the cerebellum, presumably via axon-collaterals of nonsegmental cells. 4. Eight group I-DV-X cells were recorded from. They were monosynaptically linked to spinal DLF fibres and resembled functionally the nucleus Z and rMCN cells when stimulated from the periphery. Two cells projected to the contralateral thalamus, and two others were synaptically excited. Seven cells were activated from the ipsilateral cerebellum. Two of them projected to

  2. Surgical treatment of lower limb ischemia in diabetic patients – long-term results

    PubMed Central

    Inan, Bekir; Ugurlucan, Murat; Aydin, Cemalettin; Teker, Melike Elif

    2013-01-01

    Introduction Lower limb ischemia may cause nonhealing ulcers, infection, amputation and even mortality in diabetic patients. In this study, we review our data of ischemic lower limb revascularization procedures in diabetic patients and present the early, mid- and long-term results. Material and methods From March 2004 to September 2008, 83 patients with lower limb ischemia in Fontaine class III and IV underwent distal arterial bypass procedures. Saphenous vein grafts were used for below-knee arterial bypasses in all patients. In 16 (19%) patients femoropopliteal bypasses were performed with PTFE grafts. Short-term and long-term surgical results were evaluated. Results Ulcer recovery was determined in 36% of patients. Graft patency was 95% and 1 death (1%) occurred in short-term follow-up. In long-term follow-up the total effectiveness rate was 74%. Graft patency was 79% and 6 deaths (7%) occurred during the follow-up. Conclusions Lower limb ischemia is a serious event in patients with diabetes mellitus. The consequences may include increased mortality and morbidity in this particular patient population. However, distal arterial revascularizations are considerably effective procedures to avoid amputation, to eliminate symptoms, to promote ulcer recovery and to help the patient participate in social life with acceptable short, mid- and long-term follow-up results. PMID:24482653

  3. Comparative Anatomy of the Hind Limb Vessels of the Bearded Capuchins (Sapajus libidinosus) with Apes, Baboons, and Cebus capucinus: With Comments on the Vessels' Role in Bipedalism

    PubMed Central

    Aversi-Ferreira, Roqueline A. G. M. F.; de Abreu, Tainá; Pfrimer, Gabriel A.; Silva, Sylla F.; Ziermann, Janine M.; Carneiro-e-Silva, Frederico O.; Tomaz, Carlos; Tavares, Maria Clotilde H.; Maior, Rafael S.; Aversi-Ferreira, Tales A.

    2013-01-01

    Capuchin monkeys are known to exhibit sporadic bipedalism while performing specific tasks, such as cracking nuts. The bipedal posture and locomotion cause an increase in the metabolic cost and therefore increased blood supply to lower limbs is necessary. Here, we present a detailed anatomical description of the capuchin arteries and veins of the pelvic limb of Sapajus libidinosus in comparison with other primates. The arterial pattern of the bearded capuchin hind limb is more similar to other quadrupedal Cebus species. Similarities were also found to the pattern observed in the quadruped Papio, which is probably due to a comparable pelvis and the presence of the tail. Sapajus' traits show fewer similarities when compared to great apes and modern humans. Moreover, the bearded capuchin showed unique patterns for the femoral and the short saphenous veins. Although this species switches easily from quadrupedal to bipedal postures, our results indicate that the bearded capuchin has no specific or differential features that support extended bipedal posture and locomotion. Thus, the explanation for the behavioral differences found among capuchin genera probably includes other aspects of their physiology. PMID:24396829

  4. 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

  5. Exploring the putative role of TRPV1 -dependent CGRP release in remote hind preconditioning-induced cardioprotection.

    PubMed

    Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh

    2017-10-01

    Remote ischemic preconditioning (RIPC) is a phenomenon whereby transient nonlethal ischemia and reperfusion episodes confer protection against prolonged ischemia reperfusion-induced injury. However, the underlying intracellular signaling has not been extensively explored. This study aimed to inspect the putative involvement of TRPV1 -dependent CGRP release in mediating remote hind limb preconditioning-induced cardioprotection. In this study, remote hind limb preconditioning stimulus was delivered (four consecutive episodes of 5 minutes of ischemia reperfusion) using a blood pressure cuff tied at the inguinal level of the rat. The isolated rat hearts were perfused on the Langendorff's system and were subjected to 30-minutes global ischemia and 120-minutes reperfusion. Prolonged ischemia and subsequent reperfusion led to myocardial injury that was evaluated in terms of infarct size, LDH release, CK release, LVDP, +dp/dtmax , -dp/dtmin , and coronary flow rate. The pharmacological agents used in this study included capsaicin as TRPV1 channel activator, sumatriptan and CGRP8-37 as CGRP blockers. Remote hind limb and capsaicin preconditioning (10 mg/kg(-1) ) significantly reduced the infarct size, LDH release, CK release and significantly improved LVDP, +dp/dtmax , -dp/dtmin , and coronary flow rate. However, remote hind limb and capsaicin preconditioning-induced cardioprotective effects were remarkably reduced in the presence of sumatriptan (8 mg/kg(-1) ) and CGRP8-37 (1 mg/kg(-1) ). This indicates that remote hind limb preconditioning stimulus probably activates TRPV1 channels which subsequently induces CGRP release to produce cardioprotective effects. © 2017 John Wiley & Sons Ltd.

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

    PubMed

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

    2016-10-01

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

  7. 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

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

    PubMed

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

    2016-10-25

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

  9. Development of a twenty-one-component finite element distal hind limb model: stress and strain in bovine digit structures as a result of loading on different floorings.

    PubMed

    Hinterhofer, C; Haider, H; Apprich, V; Ferguson, J C; Collins, S N; Stanek, C

    2009-03-01

    Finite element modeling is a unique way of introducing technical and material research into medical science. A bovine distal hind limb was scanned using computed tomography for geometric image capture and the data were subsequently divided (segmented) into 4 tissue types: bone, bone marrow, soft tissue, and the horn capsule. Material data from previous studies were integrated into the model. Flexor tendons were assembled as longitudinal structures starting at their cross-sectional areas at the height of the metatarsophalangeal joint, proceeding in the plantaro-distal direction and meeting the distal phalanx at the tuberculum flexorium. Three different flooring situations (full support floor, bearing weight in the abaxial half of the lateral claw and in the dorsal halves of both claws, respectively) were created to evaluate the effects of loading. Full support resulted in von Mises stress levels between 3.5 and 1.5 MPa for the osseous structures and some regions of the segmented soft tissue; stress patterns in the bulb and sole of the claw capsule (1.5 MPa) and in the floor (0.5 MPa) were similar to pressure plate data in vivo and in vitro, with corresponding strain values of 2.4%. Reduced support resulted in higher stresses (up to approximately 8 MPa) in bones, claw capsules, and tendons; high strains ( approximately 11%) were found in the soft tissue, depending on how the floor was constructed. Although the models may still be anatomically improved, stress and strain calculations are possible with results comparable to related research, and the model shows interaction between the 2 digits. This possibly will help with further understanding of the biomechanical function of this 2-digit structure. With respect to clinical interpretation, reduced support to the bovine hind limb increases focal stress peaks in the different tissues, which may indicate a location of potential injury.

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

    PubMed

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

    2013-06-01

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

  11. Proteomic analysis of fibroblastema formation in regenerating hind limbs of Xenopus laevis froglets and comparison to axolotl

    PubMed Central

    2014-01-01

    Background To gain insight into what differences might restrict the capacity for limb regeneration in Xenopus froglets, we used High Performance Liquid Chromatography (HPLC)/double mass spectrometry to characterize protein expression during fibroblastema formation in the amputated froglet hindlimb, and compared the results to those obtained previously for blastema formation in the axolotl limb. Results Comparison of the Xenopus fibroblastema and axolotl blastema revealed several similarities and significant differences in proteomic profiles. The most significant similarity was the strong parallel down regulation of muscle proteins and enzymes involved in carbohydrate metabolism. Regenerating Xenopus limbs differed significantly from axolotl regenerating limbs in several ways: deficiency in the inositol phosphate/diacylglycerol signaling pathway, down regulation of Wnt signaling, up regulation of extracellular matrix (ECM) proteins and proteins involved in chondrocyte differentiation, lack of expression of a key cell cycle protein, ecotropic viral integration site 5 (EVI5), that blocks mitosis in the axolotl, and the expression of several patterning proteins not seen in the axolotl that may dorsalize the fibroblastema. Conclusions We have characterized global protein expression during fibroblastema formation after amputation of the Xenopus froglet hindlimb and identified several differences that lead to signaling deficiency, failure to retard mitosis, premature chondrocyte differentiation, and failure of dorsoventral axial asymmetry. These differences point to possible interventions to improve blastema formation and pattern formation in the froglet limb. PMID:25063185

  12. The analysis of limbs acute ischemia during seasons on the territory of South Serbia.

    PubMed

    Damnjanović, Zoran; Jovanović, Milan; Janković, Irena; Cvetanović, Vladan; Smiljković, Igor; Janković, Dimitrije

    2013-02-01

    The aim of this study was to examine the seasons variations in incidence of limbs acute ischemia (LAI) as well as the connection between seasons with location of LAI, old age and gender. During the three year period between January 2009 and December 2011, at the Clinic for Vascular Surgery, Clinical Center of Nis, Serbia, 167 patients were hospitalized diagnosed with limbs acute ischemia. There was no statistically significant difference in patients distribution with LAI compared with seasons (p=0.726) and months of the year (p=0.0741). There was no statistically significant difference in patients age (p=0.066), sex (p=0.923) and LAI localization (p=0.219 ) in different seasons. The absence of seasonal and monthly patterns for the AIE creation as well as its localization is followed by the absence of a connection between the age and the sex..

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

    PubMed

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

    2016-01-01

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

  15. The pros and cons of endovascular and open surgical treatments for patients with acute limb ischemia.

    PubMed

    Branco, B C; Montero-Baker, M F; Mills, J L

    2015-06-01

    The present review addresses the pros and cons of the current, wide variety of therapeutic options available for the treatment of acute limb ischemia (ALI). Despite five prospective randomized controlled trials comparing catheter directed thrombolysis and open surgical revascularization, no single treatment strategy can yet be considered optimal for patients with ALI. This report includes 20 years of published data to evaluate the efficacy and safety profile of thrombolytic agents and adjunctive endovascular techniques when compared to open surgical revascularization.

  16. 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

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2007-04-21

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

  19. Effect of prolonged ischaemic time on muscular atrophy and regenerating nerve fibres in transplantation of the rat hind limb.

    PubMed

    Tsuji, Naoko; Yamashita, Shuji; Sugawara, Yasushi; Kobayashi, Eiji

    2012-09-01

    Our aim was to test the influence of cold ischaemia on replanted limbs, focusing on muscular atrophy and neurological recovery. Inbred wild-type and green fluorescent protein (GFP) transgenic (Tg) Lewis rats aged 8-10 weeks were used. The amputated limbs were transplanted at several cold ischaemic times (0, 1, 8, 12, 24, 48, and 72 hours). An arterial ischaemic model and a denervation model were used as controls. To study nerve regeneration, a GFP limb was transplanted on to the syngenic wild Lewis rat. These animals were evaluated histologically, electrophysiologically, and immunohistochemically. The longer the ischaemic time, the more evident was atrophy of the muscles. Electrophysiological investigation showed that the latency at 3 weeks was longer in the transplantation models than in the normal controls, particularly in the longer ischaemia group. Larger numbers of migrating Schwann cells were seen in the group with no delay than in the group that had been preserved for 12 hours. Ischaemia after amputation of a limb causes muscle cells to necrose and atrophy, and these changes worsen in proportion to the ischaemic preservation time. A delay in nerve regeneration and incomplete paralysis caused by malregeneration also affect muscular atrophy.

  20. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats

    PubMed Central

    Chou, Wei-Chi; Kao, Ming-Chang; Yue, Chung-Tai; Tsai, Pei-Shan; Huang, Chun-Jen

    2015-01-01

    Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR) of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group), sham-operation (Sham), or sham plus caffeine (n = 12 in each group). To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection) was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P < 0.001 and P = 0.008, resp.). Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2) and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P < 0.05). These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs. PMID:26648663

  1. Caffeine Mitigates Lung Inflammation Induced by Ischemia-Reperfusion of Lower Limbs in Rats.

    PubMed

    Chou, Wei-Chi; Kao, Ming-Chang; Yue, Chung-Tai; Tsai, Pei-Shan; Huang, Chun-Jen

    2015-01-01

    Reperfusion of ischemic limbs can induce inflammation and subsequently cause acute lung injury. Caffeine, a widely used psychostimulant, possesses potent anti-inflammatory capacity. We elucidated whether caffeine can mitigate lung inflammation caused by ischemia-reperfusion (IR) of the lower limbs. Adult male Sprague-Dawley rats were randomly allocated to receive IR, IR plus caffeine (IR + Caf group), sham-operation (Sham), or sham plus caffeine (n = 12 in each group). To induce IR, lower limbs were bilaterally tied by rubber bands high around each thigh for 3 hours followed by reperfusion for 3 hours. Caffeine (50 mg/kg, intraperitoneal injection) was administered immediately after reperfusion. Our histological assay data revealed characteristics of severe lung inflammation in the IR group and mild to moderate characteristic of lung inflammation in the IR + Caf group. Total cells number and protein concentration in bronchoalveolar lavage fluid of the IR group were significantly higher than those of the IR + Caf group (P < 0.001 and P = 0.008, resp.). Similarly, pulmonary concentrations of inflammatory mediators (tumor necrosis factor-α, interleukin-1β, and macrophage inflammatory protein-2) and pulmonary myeloperoxidase activity of the IR group were significantly higher than those of the IR + Caf group (all P < 0.05). These data clearly demonstrate that caffeine could mitigate lung inflammation induced by ischemia-reperfusion of the lower limbs.

  2. 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.

  3. 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.

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

    PubMed

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

    2017-09-21

    The Wound, Ischemia, and foot Infection (WIfI) classification system was created to encompass demographic changes and expanding techniques of revascularization to perform meaningful analyses of outcomes in the treatment of the threatened limb. The WIfI index is intended to be analogous to the TNM staging system for cancer, with restaging to be done after control of infection and after revascularization. Our goal was to evaluate the effectiveness of WIfI restaging after therapy in the prediction of limb outcomes. Preoperative WIfI scoring was performed prospectively for all critical limb ischemia patients who underwent revascularization from January 2014 to June 2015. WIfI restaging and assessment of outcomes were performed retrospectively through August 2016. WIfI classification was determined at the following intervals: preoperatively, immediately postoperatively, and 1 month and 6 months after intervention. Amputation-free survival (AFS) was the primary end point. Kaplan-Meier plot analysis and comparisons of preoperative grades with respective postoperative grades were performed using paired t-test, χ(2) test, and correlation analyses. A total of 180 limbs and 172 critical limb ischemia patients underwent revascularization, of which 29 limbs had major amputations (16%). Wound grades generally improved after surgery across the entire cohort. Major amputation was associated with preoperative wound grade and remained associated with wound grade at postoperative restaging at 1 month and beyond on the basis of amputation frequency analysis (preoperatively, 1 month, and 6 months, P = .03, < .001, and < .001, respectively). Wound grade was significantly associated with AFS at 1 month and 6 months after intervention (log-rank, P < .001 for restaging intervals). Ischemia grades improved initially with a slight decline across the cohort at 6 months. Ischemia grade at 1 month postoperatively was associated with AFS (log-rank, P = .03). Foot infection

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

    PubMed

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

    2012-12-01

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

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

    PubMed

    Beard, Jonathan D

    2008-12-01

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

  7. Data set incongruence and correlated character evolution: An example of functional convergence in the hind-limbs of stifftail diving ducks

    USGS Publications Warehouse

    McCracken, K.G.; Harshman, J.; Mcclellan, D.A.; Afton, A.D.

    1999-01-01

    The unwitting inclusion of convergent characters in phylogenetic estimates poses a serious problem for efforts to recover phylogeny. Convergence is not inscrutable, however, particularly when one group of characters tracks phylogeny and another set tracks adaptive history. In such cases, convergent characters may be correlated with one or a few functional anatomical units and readily identifiable by using comparative methods. Stifftail ducks (Oxyurinae) offer one such opportunity to study correlated character evolution and function in the context of phylogenetic reconstruction. Morphological analyses place stifftail ducks as part of a large clade of diving ducks that includes the sea ducks (Mergini), Hymenolaimus, Merganetta, and Tachyeres, and possibly the pochards (Aythyini). Molecular analyses, on the other hand, place stifftails far from other diving ducks and suggest, moreover, that stifftails are polyphyletic. Mitochondrial cytochrome b gene sequences of eight stifftail species traditionally supposed to form a clade were compared with each other and with sequences from 50 other anseriform and galliform species. Stifftail ducks are not the sister group of sea ducks but lie outside the typical ducks (Anatinae). Of the four traditional stifftail genera, monophyly of Oxyura and its sister group relationship with Nomonyx are strongly supported. Heteronetta probably is the sister group of that clade, but support is weak. Biziura is not a true stifftail. Within Oxyura, Old World species (O. australis, O. leucocephala, O. mnccoa) appear to form a clade, with New World species (O. jamaicensis, O. vittata) branching basally. Incongruence between molecules and morphology is interpreted to be the result of adaptive specialization and functional convergence in the hind limbs of Biziura and true stifftails. When morphological characters are divided into classes, only hind-limb characters are significantly in conflict with the molecular tree. Likewise, null models of

  8. Data set incongruence and correlated character evolution: an example of functional convergence in the hind-limbs of stifftail diving ducks.

    PubMed

    McCracken, K G; Harshman, J; McClellan, D A; Afton, A D

    1999-12-01

    The unwitting inclusion of convergent characters in phylogenetic estimates poses a serious problem for efforts to recover phylogeny. Convergence is not inscrutable, however, particularly when one group of characters tracks phylogeny and another set tracks adaptive history. In such cases, convergent characters may be correlated with one or a few functional anatomical units and readily identifiable by using comparative methods. Stifftail ducks (Oxyurinae) offer one such opportunity to study correlated character evolution and function in the context of phylogenetic reconstruction. Morphological analyses place stifftail ducks as part of a large clade of diving ducks that includes the sea ducks (Mergini), Hymenolaimus, Merganetta, and Tachyeres, and possibly the pochards (Aythyini). Molecular analyses, on the other hand, place stifftails far from other diving ducks and suggest, moreover, that stifftails are polyphyletic. Mitochondrial cytochrome b gene sequences of eight stifftail species traditionally supposed to form a clade were compared with each other and with sequences from 50 other anseriform and galliform species. Stifftail ducks are not the sister group of sea ducks but lie outside the typical ducks (Anatinae). Of the four traditional stifftail genera, monophyly of Oxyura and its sister group relationship with Nomonyx are strongly supported. Heteronetta probably is the sister group of that clade, but support is weak. Biziura is not a true stifftail. Within Oxyura, Old World species (O. australis, O. leucocephala, O. maccoa) appear to form a clade, with New World species (O. jamaicensis, O. vittata) branching basally. Incongruence between molecules and morphology is interpreted to be the result of adaptive specialization and functional convergence in the hind limbs of Biziura and true stifftails. When morphological characters are divided into classes, only hind-limb characters are significantly in conflict with the molecular tree. Likewise, null models of

  9. Contribution of hind limb flexor muscle afferents to the timing of phase transitions in the cat step cycle.

    PubMed

    Hiebert, G W; Whelan, P J; Prochazka, A; Pearson, K G

    1996-03-01

    1. In this investigation, we tested the hypothesis that muscle spindle afferents signaling the length of hind-leg flexor muscles are involved in terminating extensor activity and initiating flexion during walking. The hip flexor muscle iliopsoas (IP) and the ankle flexors tibialis anterior (TA) and extensor digitorum longus (EDL) were stretched or vibrated at various phases of the step cycle in spontaneously walking decerebrate cats. Changes in electromyogram amplitude, duration, and timing were then examined. The effects of electrically stimulating group I and II afferents in the nerves to TA and EDL also were examined. 2. Stretch of the individual flexor muscles (IP, TA, or EDL) during the stance phase reduced the duration of extensor activity and promoted the onset of flexor burst activity. The contralateral step cycle also was affected by the stretch, the duration of flexor activity being shortened and extensor activity occurring earlier. Therefore, stretch of the flexor muscles during the stance phase reset the locomotor rhythm to flexion ipsilaterally and extension contralaterally. 3. Results of electrically stimulating the afferents from the TA and EDL muscles suggested that different groups of afferents were responsible for the resetting of the step cycle. Stimulation of the TA nerve reset the locomotor step cycle when the stimulus intensity was in the group II range (2-5 xT). By contrast, stimulation of the EDL nerve generated strong resetting of the step cycle in the range of 1.2-1.4 xT, where primarily the group Ia afferents from the muscle spindles would be activated. 4. Vibration of IP or EDL during stance reduced the duration of the extensor activity by similar amounts to that produced by muscle stretch or by electrical stimulation of EDL at group Ia strengths. This suggests that the group Ia afferents from IP and EDL are capable of resetting the locomotor pattern generator. Vibration of TA did not affect the locomotor rhythm. 5. Stretch of IP or

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

    PubMed

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

    2006-05-01

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

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

    PubMed

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

    2017-08-01

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

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

    PubMed Central

    2012-01-01

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

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

    PubMed

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

    2016-08-17

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

  14. Arterial protocol including prophylactic distal perfusion catheter decreases limb ischemia complications in patients undergoing extracorporeal membrane oxygenation.

    PubMed

    Lamb, Kathleen M; DiMuzio, Paul J; Johnson, Adam; Batista, Philip; Moudgill, Neil; McCullough, Megan; Eisenberg, Joshua A; Hirose, Hitoshi; Cavarocchi, Nicholas C

    2017-04-01

    Venoarterial extracorporeal membrane oxygenation (ECMO) is a salvage therapy in patients with severe cardiopulmonary failure. Owing to the large size of the cannulas inserted via the femoral vessels (≤24-F) required for adequate oxygenation, this procedure could result in significant limb ischemic complications (10%-70%). This study evaluates the results of a distal limb perfusion arterial protocol designed to reduce associated complications. We conducted a retrospective institutional review board-approved review of consecutive patients requiring ECMO via femoral cannulation (July 2010-January 2015). To prevent arterial ischemia, a distal perfusion catheter (DPC) was placed antegrade into the superficial femoral artery and connected to the ECMO circuit. Limb perfusion was monitored via near-infrared spectroscopy (NIRS) placed on both calves. Decannulation involved open repair, patch angioplasty, and femoral thrombectomy as needed. A total of 91 patients were placed on ECMO via femoral arterial cannula (16-F to 24-F) for a mean duration of 9 days (range, 1-40 days). A percutaneous DPC was inserted prophylactically at the time of cannulation in 55 of 91 patients, without subsequent ischemia. Of the remaining 36 patients without initial DPC placement, 12 (33% without DPC) developed ipsilateral limb ischemia related to arterial insufficiency, as detected by NIRS and clinical findings. In these patients, the placement of a DPC (n = 7) with or without a fasciotomy, or with a fasciotomy alone (n = 4), resulted in limb salvage; only one patient required subsequent amputation. After decannulation (n = 7), no patients had further evidence of limb ischemia. Risk factors for the development of limb ischemia identified by categorical analysis included lack of DPC at time of cannulation and ECMO cannula size of less than 20-Fr. There was a trend toward younger patient age. Overall ECMO survival rate was 42%, whereas survival in patients with limb ischemia was only 25

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

    PubMed

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

    2008-11-01

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

  16. Involvement of spinal α2 -adrenoceptors in prolonged modulation of hind limb withdrawal reflexes following acute noxious stimulation in the anaesthetized rabbit.

    PubMed

    Harris, John

    2016-03-01

    The role of spinal α2 -adrenoceptors in mediating long-lasting modulation of hind limb withdrawal reflexes following acute noxious chemical stimulation of distant heterotopic and local homotopic locations has been investigated in pentobarbitone-anaesthetized rabbits. Reflexes evoked in the ankle extensor muscle medial gastrocnemius (MG) by electrical stimulation of the ipsilateral heel, and reflexes elicited in the ankle flexor tibialis anterior and the knee flexor semitendinosus by stimulation at the base of the ipsilateral toes, could be inhibited for over 1 h after mustard oil (20%) was applied to either the snout or into the contralateral MG. The heel-MG response was also inhibited after applying mustard oil across the plantar metatarsophalangeal joints of the ipsilateral foot, whereas this homotopic stimulus facilitated both flexor responses. Mustard oil also caused a significant pressor effect when applied to any of the three test sites. The selective α2 -adrenoceptor antagonist, RX 821002 (100-300 μg, intrathecally), had no effect on reflexes per se, but did cause a decrease in mean arterial blood pressure. In the presence of the α2 -blocker, inhibitory and facilitatory effects of mustard oil on reflexes were completely abolished. These data imply that long-lasting inhibition of spinal reflexes following acute noxious stimulation of distant locations involves activation of supraspinal noradrenergic pathways, the effects of which are dependent on an intact α2 -adrenoceptor system at the spinal level. These pathways and receptors also appear to be involved in facilitation (sensitization) as well as inhibition of reflexes following a noxious stimulus applied to the same limb.

  17. Combination of anti-ICAM-1 and anti-LFA-1 monoclonal antibody therapy prolongs allograft survival in rat hind-limb transplants.

    PubMed

    Ozer, K; Siemionow, M

    2001-10-01

    Immunosuppressive effects of monoclonal antibodies against adhesion molecules were validated in solid organ transplants. There have been only a few reports on the effect of these antibodies on limb transplantation. In this study, the authors investigated the effects of anti-ICAM-1 and anti-LFA-1 therapy in the rat hind-limb-cremaster transplantation model. Twenty transplantations were performed across a major histocompatibility barrier between Lewis Brown Norway (LBN, RT-1(l+n)) and Lewis (LEW, RT-1(l)) rats in four experimental groups of five animals each. Group 1 animals received only vehicle solution; Groups 2 and 3 received monoclonal antibodies against ICAM-1 and LFA-1, respectively; Group 4 received a combination dose. Treatments were continued for 7 days. Clinical signs of rejection were noted daily, and correlated with in vivo microcirculatory measurements. The activation of adhering leukocytes was significantly lower in rats treated with anti-ICAM-1, anti-LFA-1, and combination than in controls (p < 0.05). Transmigrating leukocytes were also reduced in antibody-treated groups, when compared to the control group (p < 0.05). The mean number of rolling lymphocytes was significantly reduced only in the combination group (p < 0.05). Endothelial edema index, a measure of endothelial swelling, was lowest in the combination group (p < 0.05). The first clinical signs of rejection were noted between the 5(th) and 9(th) days in the control group, on the 9(th) day in the anti-ICAM-1 or anti-LFA-1 groups, and on the 13(th) day with combination therapy. Monoclonal antibodies against LFA-1 or ICAM-1 alone inhibit the activation of leukocytes at the microcirculatory level but do not prolong graft survival. However, the combination of anti-ICAM-1 and anti-LFA-1 monoclonal antibodies significantly prolonged allograft survival in this composite tissue transplantation model.

  18. 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

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

    PubMed Central

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

    2013-01-01

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

  20. Vascular growth factor expression in a rat model of severe limb ischemia.

    PubMed

    Luo, Fuwen; Wariaro, David; Lundberg, Göran; Blegen, Harald; Wahlberg, Eric

    2002-12-01

    In ischemic tissue hypoxia induces production of vascular growth factors, especially VEGF, which initiate local angiogenesis. Collateralization-or arteriogenesis-occurs at a distance from the ischemic tissue and depends on different growth factors such as FGF-2. A spatial discrepancy in endogenous growth factor production in limb ischemia may have implications for therapeutic angiogenesis. The present study elucidates if such spatial and temporal variation occurs. A two-staged procedure was performed to generate severe long-lasting limb ischemia in 60 rats. At 1, 7, 28, and 56 days, subgroups were subjected to perfusion assessment with laser Doppler imaging and angiography. Muscle samples and foot skin were gathered to measure growth factor expression and signs of angiogenesis using immunohistochemistry. There was an early twofold increase (P < 0.05) in both VEGF and FGF-2 levels in distal muscle from the ischemic leg, but no significant rise in the thigh. The concentrations decreased over time with an exception for VEGF in soleus and FGF-2 in anterior tibial muscle, which remained high. An increased capillarity was noted (P < 0.05) in soleus after 28 days, and the number of BrdU-positive ECs was elevated in all ischemic samples at 56 days. Collateral arteries were observed on the angiograms after 7 days. The results suggest that in limb ischemia any major increase in vascular growth factor production is limited to ischemic tissue. The spatial and temporal distribution patterns of growth factor production are complex and to a great extent influenced by inflammation.

  1. Acute Limb Ischemia and Coronary Artery Disease in a Case of Kimura’s Disease

    PubMed Central

    Heo, Woon; Jun, Hee Jae; Kang, Do Kyun; Min, Ho-Ki; Hwang, Youn-Ho; Kim, Ji Yong; Nam, Kyung Han

    2017-01-01

    Kimura disease (KD) is an immune-mediated chronic inflammatory disease of unknown etiology. KD has many complications associated with hypereosinophilia, including various forms of allergic reactions and eosinophilic lung disease. Additionally, hypereosinophilia is associated with hypercoagulability, which may lead to thromboembolic events. A 36-year-old man with KD presented with acute limb ischemia and coronary artery occlusion. He underwent thrombectomy, partial endarterectomy of both popliteal arteries, and coronary artery stent insertion. KD is a systemic disease that affects many organs and presents with thromboembolism and vasculitis. In a patient with KD, physicians should evaluate the vascular system, including the coronary arteries. PMID:28382271

  2. 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.

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

    PubMed

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

    2017-05-01

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

  4. 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

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

    PubMed

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

    2012-12-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

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

    2015-10-01

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

  8. Reliability of preoperative duplex scanning in designing a therapeutic strategy for chronic lower limb ischemia.

    PubMed

    Fontcuberta, Juan; Flores, Angel; Orgaz, Antonio; Doblas, Manuel; Gil, Jose; Leal, Ignacio; Rodriguez, Ruben; Benito, Jose Maria; Bermúdez, Maria Dolores

    2009-01-01

    The objective of this study was to compare the treatment plan designed on the basis of preoperative duplex scanning evaluation of the critical limb ischemia with the treatment plan finally carried out, after assessing the findings obtained during surgical or endovascular treatment. Over a period of 51 months a preoperative duplex scanning study was carried out in 335 consecutive patients with chronic critical ischemia, to design the best therapeutic strategy. Agreement between both plans were as follows: 80%, 82,7% and 59% in the examinations of the iliac arteries, femoropopliteal or tibial arteries respectively. The operation plan was more frequently modified due to a duplex scanning failure in procedures involving the the distal vessels(10 of 44 [22.7%], p < 0.01). In conclusion, duplex scanning evaluation of patients with occlusive arterial disease of the lower limbs permits the design of both a medical and a surgical or endovascular treatment plan with a high level of agreement with the findings obtained during the revascularization procedure.

  9. The CD133+ cell as advanced medicinal product for myocardial and limb ischemia.

    PubMed

    Bongiovanni, Dario; Bassetti, Beatrice; Gambini, Elisa; Gaipa, Giuseppe; Frati, Giacomo; Achilli, Felice; Scacciatella, Paolo; Carbucicchio, Corrado; Pompilio, Giulio

    2014-10-15

    Ischemic diseases are the major cause of death and morbidity in Western countries. In the last decade, cell therapy has been suggested to be a promising treatment both in acute/chronic myocardial and peripheral ischemia. Different cell lineages have been tested, including endothelial progenitor cells. A subpopulation of bone marrow-derived immature ECPs, expressing the highly conserved stem cell glycoprotein antigen prominin-1 or CD133 marker, was shown to possess pro-angiogenic and antiapoptotic effects on ischemic tissues. The mechanisms implicated in CD133+ cells ability to contribute to neovascularization processes have been attributed to their ability to directly differentiate into newly forming vessels and to indirectly activate pro-angiogenic signaling by paracrine mechanisms. A large body of in vivo experimental evidences has demonstrated the potential of CD133+ cells to reverse ischemia. Moreover, several clinical trials have reported promising beneficial effects after infusion of autologous CD133+ into ischemic heart and limbs exploiting various delivery strategies. These trials have contributed to characterize the CD133+ manufacturing process as an advanced cell product (AMP). The aim of this review is to summarize available experimental and clinical data on CD133+ cells in the context of myocardial and peripheral ischemia, and to focus on the development of the CD133+ cell as an anti-ischemic AMP.

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

    PubMed Central

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

    2015-01-01

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

  11. Clinical staging of acute limb ischemia as the basis for choice of revascularization method: when and how to intervene.

    PubMed

    Rutherford, Robert B

    2009-03-01

    In acute lower limb ischemia, there are basically three management options: (1) clot removal by catheter-directed thrombolysis with or without percutaneous mechanical thrombectomy, (2) surgical thromboembolectomy followed by correction of underlying arterial lesions, and (3) anticoagulation with continued observation. Arterial embolic occlusion presents more abruptly and with more severe ischemia than arterial thrombosis, which occurs in narrowed arterial segments that have generally developed some degree of collateral circulation. The appropriate choice of treatment for acute limb ischemia depends to a great extent on the severity of the ischemia. Level of ischemia is readily determined by examining for sensory loss or motor deficit and interrogating the distal arteries and veins for audible flow signals with a handheld Doppler velocity detector. After clot removal, appropriate management of the responsible underlying lesion depends on its characteristics, best determined by vascular imaging. Staging the severity of ischemia according to clinical classification levels in the current reporting standards for lower extremity ischemia continues to serve as the basis for logical management decisions. This approach is outlined in algorithmic form and alternative pathways are discussed in this article.

  12. Noninvasive limb remote ischemic preconditioning contributes neuroprotective effects via activation of adenosine A1 receptor and redox status after transient focal cerebral ischemia in rats.

    PubMed

    Hu, Sheng; Dong, Hailong; Zhang, Haopeng; Wang, Shiquan; Hou, Lichao; Chen, Shaoyang; Zhang, Jinsong; Xiong, Lize

    2012-06-12

    To investigate whether activation of adenosine A1 receptor (A1R) through limb remote ischemic preconditioning (RIPC) by a noninvasive tourniquet contribute neuroprotective effects against rat focal cerebral ischemic injury induced by transient middle cerebral artery occlusion (MCAO). One hundred twenty-eight Sprague-Dawley (SD) rats were randomly assigned into eight groups (n=16 each): MCAO, Control, 8-cyclopentyl-1,3-dipropulxanthine (DPCPX, Adenosine A1 receptor antagonist), RIPC, DPCPX+RIPC, Vehicle+RIPC, 2-chloro-N(6)-cyclopentyladenosine (CCPA, Adenosine A1 receptor agonist) and CCPA+DPCPX groups. All animals underwent right middle cerebral artery occlusion (MCAO) for 2 h. Limb RIPC consisted of three cycles of 5-minute ischemia followed by 5-minute reperfusion in right hind-limb by tourniquet application. Neurological deficit scores were evaluated 24 h after reperfusion, and then the infarct volume was assessed with diffusion weighted imaging (DWI) and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. Inflammation was assessed by serum tumor necrosis factor α (TNF(α)) and NO; oxidative stress was estimated by malondialdehyde (MDA) and 4-hydroxyalkenals (4-HAD), superoxide dismutase (SOD) activity and GSH. Animals in the RIPC, Vehicle+RIPC and CCPA groups developed lower neurological deficit scores and smaller brain infarct volumes than the Control group (P<0.01). Animals in the DPCPX, DPCPX+RIPC and CCPA+DPCPX groups developed higher neurological deficit scores and larger brain infarct volumes than the RIPC, Vehicle+RIPC and CCPA groups (P<0.01). DPCPX abolished the protective effects of RIPC and CCPA. RIPC or CCPA induced a significant increase in brain MnSOD (manganese SOD) activity and NO generation, and this activity was abolished by DPCPX pretreatment. RIPC or CCPA induced a significant reduction (P<0.05) in the GSH and MDA+4HDA concentration and an accumulation in the GSSG concentration in both compartments (serum and tissue) as compared with the

  13. 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

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

    PubMed

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

    2014-01-01

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

  15. 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

  16. 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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2017-01-01

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

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

    PubMed

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

    2017-02-01

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

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

    PubMed

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

    2013-01-01

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

  1. 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

  2. Protective effect of focal adhesion kinase against skeletal muscle reperfusion injury after acute limb ischemia.

    PubMed

    Flück, M; von Allmen, R S; Ferrié, C; Tevaearai, H; Dick, F

    2015-03-01

    In cardiac muscle, ischemia reperfusion (IR) injury is attenuated by mitochondrial function, which may be upregulated by focal adhesion kinase (FAK). The aim of this study was to determine whether increased FAK levels reduced rhabdomyolysis in skeletal muscle too. In a translational in vivo experiment, rat lower limbs were subjected to 4 hours of ischemia followed by 24 or 72 hours of reperfusion. FAK expression was stimulated 7 days before (via somatic transfection with pCMV-driven FAK expression plasmid) and outcomes were measured against non-transfected and empty transfected controls. Slow oxidative (i.e., mitochondria-rich) and fast glycolytic (i.e., mitochondria-poor) type muscles were analyzed separately regarding rhabdomyolysis, apoptosis, and inflammation. Severity of IR injury was assessed using paired non-ischemic controls. After 24 hours of reperfusion, marked rhabdomyolysis was found in non-transfected and empty plasmid-transfected fast-type glycolytic muscle, tibialis anterior. Prior transfection enhanced FAK concentration significantly (p = 0.01). Concomitantly, levels of BAX, promoting mitochondrial transition pores, were reduced sixfold (p = 0.02) together with a blunted inflammation (p = 0.01) and reduced rhabdomyolysis (p = 0.003). Slow oxidative muscle, m. soleus, reacted differently: although apoptosis was detectable after IR, rhabdomyolysis did not appear before 72 hours of reperfusion; and FAK levels were not enhanced in ischemic muscle despite transfection (p = 0.66). IR-induced skeletal muscle rhabdomyolysis is a fiber type-specific phenomenon that appears to be modulated by mitochondria reserves. Stimulation of FAK may exploit these reserves constituting a potential therapeutic approach to reduce tissue loss following acute limb IR in fast-type muscle. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. 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.

  4. 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

  5. Pharmacokinetics of Acetaminophen in Hind Limbs Unloaded Mice: A Model System Simulating the Effects of Low Gravity on Astronauts in Space

    NASA Technical Reports Server (NTRS)

    Peterson, Amanda; Risin, Semyon A.; Ramesh, Govindarajan T.; Dasgupta, Amitava; Risin, Diana

    2008-01-01

    The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in Space. Low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration in astronauts. Acquiring of such knowledge has inherent difficulties due to limited opportunities for experimenting in Space. One of the approaches is to use model systems that simulate some of the Space conditions on Earth. In this study we used hind limbs unloaded mice (HLU) to investigate the possible changes in PK of acetaminophen, a widely used analgesic with high probability of use by astronauts. The HLU is recognized as an appropriate model for simulating the effects of low gravity on hemodynamic parameters. Mice were tail suspended (n = 24) for 24-96 hours prior to introduction of acetaminophen (150 - 300 mg/kg). The drug (in aqueous solution containing 10% ethyl alcohol by volume) was given orally by a gavage procedure and after the administration of acetaminophen mice were additionally suspended for 30 min, 1 and 2 hours. Control mice (n = 24) received the same dose of acetaminophen and were kept freely all the time. Blood specimens were obtained either from retroorbital venous sinuses or from heart. Acetaminophen concentration was measured in plasma by the fluorescent polarization immunoassay and the AxSYM analyzer (Abbott Laboratories). In control mice peak acetaminophen concentration was achieved at 30 min. By 1 hour the concentration decreased to less than 50% of the peak level and at 2 hours the drug was almost undetectable in the serum. HLU for 24 hours significantly altered the acetaminophen pharmacokinetic: at 30 min the acetaminophen concentrations were significantly (both statistically and medically significant) lower than in control mice. The concentrations also reduced less

  6. Pharmacokinetics of Acetaminophen in Hind Limbs Unloaded Mice: A Model System Simulating the Effects of Low Gravity on Astronauts in Space

    NASA Technical Reports Server (NTRS)

    Peterson, Amanda; Risin, Semyon A.; Ramesh, Govindarajan T.; Dasgupta, Amitava; Risin, Diana

    2008-01-01

    The pharmacokinetics (PK) of medications administered to astronauts could be altered by the conditions in Space. Low gravity and free floating (and associated hemodynamic changes) could affect the absorption, distribution, metabolism and excretion of the drugs. Knowledge of these alterations is essential for adjusting the dosage and the regimen of drug administration in astronauts. Acquiring of such knowledge has inherent difficulties due to limited opportunities for experimenting in Space. One of the approaches is to use model systems that simulate some of the Space conditions on Earth. In this study we used hind limbs unloaded mice (HLU) to investigate the possible changes in PK of acetaminophen, a widely used analgesic with high probability of use by astronauts. The HLU is recognized as an appropriate model for simulating the effects of low gravity on hemodynamic parameters. Mice were tail suspended (n = 24) for 24-96 hours prior to introduction of acetaminophen (150 - 300 mg/kg). The drug (in aqueous solution containing 10% ethyl alcohol by volume) was given orally by a gavage procedure and after the administration of acetaminophen mice were additionally suspended for 30 min, 1 and 2 hours. Control mice (n = 24) received the same dose of acetaminophen and were kept freely all the time. Blood specimens were obtained either from retroorbital venous sinuses or from heart. Acetaminophen concentration was measured in plasma by the fluorescent polarization immunoassay and the AxSYM analyzer (Abbott Laboratories). In control mice peak acetaminophen concentration was achieved at 30 min. By 1 hour the concentration decreased to less than 50% of the peak level and at 2 hours the drug was almost undetectable in the serum. HLU for 24 hours significantly altered the acetaminophen pharmacokinetic: at 30 min the acetaminophen concentrations were significantly (both statistically and medically significant) lower than in control mice. The concentrations also reduced less

  7. Chronic lower limb ischemia and advanced renal failure. Do we possess sufficient therapeutic knowledge?

    PubMed

    Gacka, M; Adamiec, R

    2013-08-01

    Chronic lower limb ischemia diminishes the quality of life and is associated with a higher risk of limb amputation and cardiovascular mortality. Coexisting chronic renal disease can modulate the response to pharmacotherapy and revascularization, and thus influence prognosis. This paper reviews current literary evidence regarding therapeutic problems observed in patients with obliterative atherosclerosis and renal failure. We reviewed articles from peer-reviewed medical journals which were published between 2000 and 2011. The poorer clinical response in the discussed patients is not only connected with the direct failure of surgical and endovascular procedures, but first of all with the high mortality of the patients. There is still a lack of sufficient evidence on the effectiveness of currently used anti-atherosclerotic agents in patients with end-stage renal failure. A certain priority is the search for an effective therapeutic strategy that would reduce mortality associated with cardiovascular conditions in this particular group of patients. Identifying patients who can benefit most from costly endovascular procedures is another vital issue.

  8. 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.

  9. Role of the femorofemoral crossover graft in acute lower limb ischemia due to acute type B aortic dissection.

    PubMed

    Corfield, Lorraine; McCormack, David J; Bell, Rachel; Taylor, Peter; Reidy, John

    2014-04-01

    Acute limb ischemia due to type B aortic dissection is rare and continues to be a management challenge. A case series is presented here with the aim of assessing the outcomes of treatment with a femorofemoral crossover graft with or without thoracic stent graft insertion. This is a combined retrospective and prospective review of nine cases of acute lower limb ischemia secondary to acute type B aortic dissection. The presenting features, radiological findings, treatment and outcomes were reviewed. Five patients had a femorofemoral crossover graft (FFXO) alone, two an FFXO with a thoracic stent graft and the eighth a thoracic and iliac stent. The other case was initially treated conservatively but subsequently required an FFXO. The mean follow-up was 16 (3-51) months. A further two thoracic stents were placed during the follow-up period. Thus five out of nine patients (56%) required aortic stenting. This series suggests that an FFXO is a reliable treatment for acute limb ischemia due to type B aortic dissection. However, these patients are often complex with ischemia in other vascular beds and are at risk of subsequent aneurysmal dilation.

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

    PubMed

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

    2017-06-01

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

  11. 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.

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

    PubMed

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

    2016-09-01

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

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

    PubMed Central

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

    2017-01-01

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

  14. Acute upper limb ischemia, a rare presentation of giant cell arteritis.

    PubMed

    Almeida-Morais, Luís; Galego, Sofia; Marques, Nélia; Pack, Tiago; Rodrigues, Hugo; Abreu, Rodolfo; Vasconcelos, Leonor; Marques, Hugo; Sousa Guerreiro, António

    2016-04-01

    Giant cell arteritis (GCA) is a systemic large vessel vasculitis, with extracranial arterial involvement described in 10-15% of cases, usually affecting the aorta and its branches. Patients with GCA are more likely to develop aortic aneurysms, but these are rarely present at the time of the diagnosis. We report the case of an 80-year-old Caucasian woman, who reported proximal muscle pain in the arms with morning stiffness of the shoulders for eight months. In the previous two months, she had developed worsening bilateral arm claudication, severe pain, cold extremities and digital necrosis. She had no palpable radial pulses and no measurable blood pressure. The patient had normochromic anemia, erythrocyte sedimentation rate of 120 mm/h, and a negative infectious and autoimmune workup. Computed tomography angiography revealed concentric wall thickening of the aorta extending to the aortic arch branches, particularly the subclavian and axillary arteries, which were severely stenotic, with areas of bilateral occlusion and an aneurysm of the ascending aorta (47 mm). Despite corticosteroid therapy there was progression to acute critical ischemia. She accordingly underwent surgical revascularization using a bilateral carotid-humeral bypass. After surgery, corticosteroid therapy was maintained and at six-month follow-up she was clinically stable with reduced inflammatory markers. GCA, usually a chronic benign vasculitis, presented exceptionally in this case as acute critical upper limb ischemia, resulting from a massive inflammatory process of the subclavian and axillary arteries, treated with salvage surgical revascularization. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

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

    PubMed

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

    2015-02-01

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

  16. 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

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

    PubMed

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

    2014-09-16

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

  18. 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

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

    PubMed

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

    2016-06-01

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

  20. 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.

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

    PubMed

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

    2015-11-01

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

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

    PubMed

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

    2017-09-12

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

  3. The Redox Enzyme p66Shc Contributes to Diabetes and Ischemia-Induced Delay in Cutaneous Wound Healing

    PubMed Central

    Fadini, Gian Paolo; Albiero, Mattia; Menegazzo, Lisa; Boscaro, Elisa; Pagnin, Elisa; Iori, Elisabetta; Cosma, Chiara; Lapolla, Annunziata; Pengo, Vittorio; Stendardo, Massimo; Agostini, Carlo; Pelicci, Pier Giuseppe; Giorgio, Marco; Avogaro, Angelo

    2010-01-01

    OBJECTIVE The redox enzyme p66Shc produces hydrogen peroxide and triggers proapoptotic signals. Genetic deletion of p66Shc prolongs life span and protects against oxidative stress. In the present study, we evaluated the role of p66Shc in an animal model of diabetic wound healing. RESEARCH DESIGN AND METHODS Skin wounds were created in wild-type (WT) and p66Shc−/− control and streptozotocin-induced diabetic mice with or without hind limb ischemia. Wounds were assessed for collagen content, thickness and vascularity of granulation tissue, apoptosis, reepithelialization, and expression of c-myc and β-catenin. Response to hind limb ischemia was also evaluated. RESULTS Diabetes delayed wound healing in WT mice with reduced granulation tissue thickness and vascularity, increased apoptosis, epithelial expression of c-myc, and nuclear localization of β-catenin. These nonhealing features were worsened by hind limb ischemia. Diabetes induced p66Shc expression and activation; wound healing was significantly faster in p66Shc−/− than in WT diabetic mice, with or without hind limb ischemia, at 1 and 3 months of diabetes duration and in both SV129 and C57BL/6 genetic backgrounds. Deletion of p66Shc reversed nonhealing features, with increased collagen content and granulation tissue thickness, and reduced apoptosis and expression of c-myc and β-catenin. p66Shc deletion improved response to hind limb ischemia in diabetic mice in terms of tissue damage, capillary density, and perfusion. Migration of p66Shc−/− dermal fibroblasts in vitro was significantly faster than WT fibroblasts under both high glucose and hypoxia. CONCLUSIONS p66Shc is involved in the delayed wound-healing process in the setting of diabetes and ischemia. Thus, p66Shc may represent a potential therapeutic target against this disabling diabetes complication. PMID:20566667

  4. Perioperative iloprost and endothelial progenitor cells in uremic patients with severe limb ischemia undergoing peripheral revascularization.

    PubMed

    Coppolino, Giuseppe; Buemi, Antoine; Bolignano, Davide; Lacquaniti, Antonio; La Spada, Michele; Stilo, Francesco; De Caridi, Giovanni; Benedetto, Francesco; Loddo, Saverio; Buemi, Michele; Spinelli, Francesco

    2009-11-01

    The incidence of severe limb ischemia (SLI) is high among haemodialysis (HD) patients. Limb rescue rate after surgical revascularization is relatively poor compared with patients with normal renal function. Prostanoids are an interesting category as adjuvants to revascularization. New vessel growth develops not exclusively by proliferation of endothelial cells in vascular extremities but also by cells mobilized from the bone marrow (HSC), transformed into endothelial progenitor cells (EPC) contributing to both re-endothelialization and neovascularization. Basal number of HSC and EPC is significantly reduced in HD patients and correlated with a subsequent defective neovascularization. The aim of this study was to evaluate the effects of perioperative treatment with iloprost in uremic patients with acute ischemia of lower limbs, undergoing surgical revascularization, on endothelial progenitor cells, hypothesizing a possible biological mechanism induced by the prostanoids. A search was also made for vascular remodeling processes through the analysis of the concentrations of soluble adhesion molecules (i-CAM, v-CAM, e-selectin), biochemical markers of endothelial activation. Thirty HD patients with SLI undergoing peripheral revascularization were enrolled (15 were treated with iloprost and 15 with a placebo). Iloprost was administered as an intra-arterial bolus of 3000 ng over 1 to 3 min immediately after revascularization and in the same affected artery. Serum samples were taken before revascularization (T0), at 6 (T6) and 24 h (T24) after infusion to measure sICAM-1, sE-selectin, and sVCAM-1, and for quantification of HSC and EPC. Progenitors were identified by specific surface markers CD34+, CD133+ and VEGFR2+. Count was conducted using PROCOUNT performed in a TRUCOUNT tube and with a FACSort flow cytometer. Before revascularization, all patients showed a decreased number of HSC and EPC. After 6 h, HSC augmented significantly compared with T0 in both groups. The

  5. 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.

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

    PubMed

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

    2017-08-01

    The Society for Vascular Surgery Wound, Ischemia, foot Infection (WIfI) system aims to stratify threatened limbs according to their anticipated natural history and estimate the likelihood of benefit from revascularization, but whether it accurately stratifies outcomes in limbs undergoing aggressive treatment for limb salvage is unknown. We investigated whether the WIfI stage correlated with the intensity of limb treatment required and patient-centered outcomes. We stratified limbs from a prospectively maintained database of consecutive patients referred to a limb preservation center according to WIfI stage (October 2013-May 2015). Comorbidities, multimodal limb treatment, including foot operations and revascularization, and patient-centered outcomes (wound healing, limb salvage, amputation-free survival, maintenance of ambulatory and independent living status, and mortality) were compared among WIfI stages. Multivariate analysis was performed to identify predictors of wound healing and limb salvage. We identified 280 threatened limbs encompassing all WIfI stages in 257 consecutive patients: stage 1, 48 (17%); stage 2, 67 (24%); stage 3, 64 (23%); stage 4, 83 (30%); and stage 5 (unsalvageable), 18 (6%). Operative foot débridement, minor amputation, and use of revascularization increased with increasing WIfI stage (P ≤ .04). Revascularization was performed in 106 limbs (39%), with equal use of open and endovascular procedures. Over a median follow-up of 209 days (interquartile range, 95, 340) days, 1-year Kaplan-Meier wound healing cumulative incidence was 71%, and the proportion with complete wound healing decreased with increasing WIfI stage. Major amputation was required in 26 stage 1 to 4 limbs (10%). Increasing WIfI stage was associated with decreased 1-year Kaplan-Meier limb salvage (stage 1: 96%, stage 2: 84%, stage 3: 90%, and stage 4: 78%; P = .003) and amputation-free survival (P = .006). Stage 4 WIfI independently predicted amputation (hazard ratio

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

    PubMed

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

    2016-07-01

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

  8. 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.

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

    PubMed

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

    2012-10-01

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

  10. 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.

  11. The ILAILL Study: Iloprost as Adjuvant to Surgery for Acute Ischemia of Lower Limbs

    PubMed Central

    de Donato, Gaetano; Gussoni, Gualberto; de Donato, Gianmarco; Andreozzi, Giuseppe Maria; Bonizzoni, Erminio; Mazzone, Antonino; Odero, Attilio; Paroni, Giovanni; Setacci, Carlo; Settembrini, Piergiorgio; Veglia, Fabrizio; Martini, Romeo; Setacci, Francesco; Palombo, Domenico

    2006-01-01

    Summary Background Data: High rate of complications has been reported following revascularization for acute limb ischemia (ALI). No adjuvant pharmacologic treatment, apart from anticoagulation and standard perioperative care, has been shown clinically effective. Objective: Aim of this study was to evaluate the effects of the prostacyclin analog iloprost as adjuvant to surgery for ALI. Methods: A total of 300 patients were randomly assigned to receive perioperative iloprost (intra-arterial, intraoperative bolus of 3000 ng, plus intravenous infusion of 0.5–2.0 ng/kg/min for 6 hours/day for 4–7 days following surgery), or placebo. The primary endpoint was the combined incidence of death and amputation at 3-month follow-up. Secondary endpoints were the incidence of each single major complication, total event rate, symptomatology, and tolerability. Results: The combined incidence of death and amputation was 19.9% in the placebo and 14.1% in the iloprost group (relative risk, 1.56; 95% confidence interval, 0.89–2.75, P = 0.12, Cox regression analysis). A statistically significant lower mortality (4.7%) was reported in patients receiving iloprost, compared with controls (10.6%; relative risk, 2.61; 95% confidence interval, 1.07–6.37, P = 0.03). The overall incidence of fatal plus major cardiovascular events was 33.1% and 22.8% in placebo and iloprost groups, respectively (relative risk, 1.61; 95% confidence interval, 1.04–2.49, P = 0.03). No serious adverse reactions occurred after iloprost administration, nor differences in the incidence of bleeding or hypotension between treatment groups. Conclusions: Although at lower levels than previously reported, our results confirm the severity of ALI. Iloprost as adjuvant to surgery significantly reduced mortality and overall major event rate. Further data are needed to support this finding, and to face a still open medical issue. PMID:16858180

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

    PubMed

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

    2015-04-01

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

  13. 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.

  14. 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

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

    PubMed

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

    2013-01-01

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

  16. 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.

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

    PubMed

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

    2012-02-01

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

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

    PubMed

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

    2016-05-01

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

  19. 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.

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

    PubMed

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

    2016-12-01

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

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

    PubMed

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

    2017-05-01

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

  2. 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.

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

    PubMed

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

    2016-12-01

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

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

    PubMed

    Farber, Alik; Rosenfield, Kenneth; Menard, Matthew

    2014-09-01

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

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

    PubMed

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

    2008-04-01

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

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

    PubMed

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

    2016-01-23

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

  7. Successful Endovascular Repair of an Iatrogenic Perforation of the Superficial Femoral Artery Using Self-Expanding Nitinol Supera Stents in a Patient with Acute Thromboembolic Limb Ischemia.

    PubMed

    Eisele, Tom; Muenz, Benedikt M; Korosoglou, Grigorios

    2016-01-01

    The treatment of acute thromboembolic limb ischemia includes well-established surgical thrombectomy procedures and, in recent times, also percutaneous rotational thrombectomy using Straub Rotarex® system. This modality not only enables efficient treatment of such thrombotic occlusion but also in rare cases may imply the risk of perforation of the occluded artery. Herein, we report the case of a perforation of the superficial femoral artery (SFA) in an elderly female patient with thromboembolic limb ischemia. The perforation was successfully treated by implantation of self-expanding nitinol Supera stents and without the need for implantation of a stent graft.

  8. Successful Endovascular Repair of an Iatrogenic Perforation of the Superficial Femoral Artery Using Self-Expanding Nitinol Supera Stents in a Patient with Acute Thromboembolic Limb Ischemia

    PubMed Central

    Eisele, Tom; Muenz, Benedikt M.

    2016-01-01

    The treatment of acute thromboembolic limb ischemia includes well-established surgical thrombectomy procedures and, in recent times, also percutaneous rotational thrombectomy using Straub Rotarex® system. This modality not only enables efficient treatment of such thrombotic occlusion but also in rare cases may imply the risk of perforation of the occluded artery. Herein, we report the case of a perforation of the superficial femoral artery (SFA) in an elderly female patient with thromboembolic limb ischemia. The perforation was successfully treated by implantation of self-expanding nitinol Supera stents and without the need for implantation of a stent graft. PMID:27213074

  9. The Effect of Transcutaneous Electrical Acupoint Stimulation on Inflammatory Response in Patients Undergoing Limb Ischemia-Reperfusion

    PubMed Central

    Mo, Yunchang; Chen, Sijia; Yang, Lili; Huang, Ledan; Jin, Dan; Yu, Zhi; Wang, Leilei; Wang, Liangrong; Luo, Shan

    2017-01-01

    Reperfusion after tourniquet use can induce inflammation and cause remote organ injury. We evaluated the therapeutic effect of transcutaneous electrical acupoint stimulation (TEAS) on inflammatory mediators and lung function in patients receiving lower limb tourniquets. Forty patients undergoing unilateral lower extremity surgery with tourniquet were randomly assigned to two groups: the TEAS group and ischemia-reperfusion (I/R) group. The C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8 (CXCL8), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNF-α), and arterial blood gas analysis were measured preoperatively and 6 h after tourniquet removal. The levels of CXCL8, IL-1, IL-6, TNF-α, and CCL2 were significantly increased compared to baseline values in both groups, but the increase was significantly smaller in the TEAS group. In the TEAS group, the partial pressure of oxygen and arterial-alveolar oxygen tension ratio were significantly decreased, and the alveolar-arterial oxygen tension difference and respiratory index were significantly increased, compared to those in the I/R group at 6 h after reperfusion. In conclusion, TEAS diminished the upregulation of proinflammatory factors in response to lower limb ischemia-reperfusion and improved pulmonary gas exchange. PMID:28804223

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

    PubMed

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

    2016-11-01

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

  11. Endoscopic thoracic sympathectomy for upper limb ischemia. A 16 year follow-up in a single center.

    PubMed

    Coveliers, Hans; Hoexum, Frank; Rauwerda, Jan A; Wisselink, Willem

    2016-10-01

    The aim of our study was to evaluate the long term results of Endoscopic Thoracic Sympathectomy (ETS) in the management of upper limb ischemia (ULI). We retrospectively reviewed the records of all consecutive patients who underwent ETS for ULI between January 1994 and May 2009. A standardized questionnaire was used to evaluate the long term success, morbidity and overall patient satisfaction. Thirty-five patients (20 female, mean age 49 years (range 23-79)) underwent bilateral (n = 9) and unilateral (n = 27) ETS procedures, respectively. Six patients had Primary (idiopathic) Raynaud Disease. Twenty-nine patients had upper limb ischemia secondary to systemic disorders (n = 12), embolic disease (n = 10), occlusion of the arteries of the arm (n = 5) or hypothenar hammer syndrome (n = 2). Tissue loss at time of surgery was present in nineteen patients. Short term beneficial effects were reported by 12 patients (63%). Eleven of the 35 patients experienced a total of 13 complications or adverse events, whereof 11 were minor or transient. Limb salvage was unsuccessful in three patients because of major amputations (n = 2) or severe functional impairment (n = 1). Necrotectomies or minor amputations without functional impairment were performed in 9 patients. Medium or long term follow up (mean 98 months (range 18-198) was available in 19 out of 22 living patients(86%). Long term beneficial effects were reported by 10 (53%). Overall patient satisfaction was 56%. Compensatory sweating was experienced by 11 patients (58%). Although the long term efficacy of ETS in our study was moderate (53%), due to its low invasiveness ETS is a valuable option in the management of ULI. Copyright © 2016. Published by Elsevier Ltd.

  12. 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.

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2017-01-01

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

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

    PubMed

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

    2015-09-01

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

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

    PubMed Central

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

    2017-01-01

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

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

    PubMed

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

    2000-08-01

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

  18. 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

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

    PubMed Central

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

    2014-01-01

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

  20. [Effectiveness of mesoglycan therapy in patients with ischemia of the lower limbs. Preliminary results of a new therapeutic protocol].

    PubMed

    Raso, A M; Maggio, D; Trogolo, M; Rispoli, P; Sandrone, N; Pezzuto, D; Bellan, A; Melloni, C D

    1997-01-01

    Mesoglycan is a natural glycosaminoglycans preparation, with antithrombotic and pro-fibrinolytic activities, which has been shown to be clinically effective in a number of vascular atherosclerotic disorders with thrombotic risk. In the present investigation we studied the effect of mesoglycan in patients with acute episodes of relative lower limb ischemia (Stage IIb according to Leriche-Fontaine classification) coming to our observation. Mesoglycan was administered according to the following schedule: a 10-days period of endovenous mesoglycan (90 mg/day), given in day-hospital regimen, followed by a 20-days period of oral mesoglycan (100 mg/day). The treatment schedule was repeated for two months and then patient continued with oral mesoglycan. We present the preliminary results obtained on 36 patients which were followed for a mean period of 12 months. From February 1995 thirty-six patients, 24 males and 12 females, aged between 45 and 83 years (mean +/- SD: 69.8 +/- 7.5) coming to our observation for acute relative lower limb ischemia were enrolled. At baseline, the diagnosis was Fontaine's IIb stage (walking distance < or = 200 m) in all patients, 17 patients presenting walking distance < 100 m. After 3 and 6 months of mesoglycan treatment a significant improvement of symptoms and signs was observed in all patients but one. At the end of the 6-months period, 29 patients (81% of the study population) became to a Fontaine's IIa degree, with a significant increase in walking distance (in 70% three times their basal value) and improvement of symptoms and recovery time. After treatment, Winsor Index was not significantly modified. Similar results were obtained after 12 months of follow-up. During the study period only one patient included in the trial needed surgical revascularisation. The administration of mesoglycan was well tolerated, with only minor complaints in two patients (one case of headache and one of diarrhea). During the endovenous administration of

  1. Acute Stroke and Limb Ischemia Secondary to Catastrophic Massive Intracardiac Thrombus in a 40-Year-Old Patient With Dilated Cardiomyopathy

    PubMed Central

    Jeon, Gi Jung; Song, Bong Gun; Park, Yong Hwan; Kang, Gu Hyun; Chun, Woo Jung; Oh, Ju Hyeon

    2012-01-01

    Dilated cardiomyopathy has been associated with left ventricular (LV) thrombosis which leads to substantial morbidity and mortality as a site for systemic emboli. We report an interesting case of a stroke and acute limb ischemia secondary to a large mobile pedunculated LV thrombus in 40-year-old patient with dilated cardiomyopathy.

  2. 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.

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

    PubMed Central

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

    2015-01-01

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

  4. 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.

  5. LOX-1 plays an important role in ischemia-induced angiogenesis of limbs.

    PubMed

    Shiraki, Takeru; Aoyama, Takuma; Yokoyama, Chiharu; Hayakawa, Yuka; Tanaka, Toshiki; Nishigaki, Kazuhiko; Sawamura, Tatsuya; Minatoguchi, Shinya

    2014-01-01

    LOX-1, lectin-like oxidized low-density lipoprotein (LDL) receptor-1, is a single transmembrane receptor mainly expressed on endothelial cells. LOX-1 mediates the uptake of oxidized LDL, an early step in atherosclerosis; however, little is known about whether LOX-1 is involved in angiogenesis during tissue ischemia. Therefore, we examined the role of LOX-1 in ischemia-induced angiogenesis in the hindlimbs of LOX-1 knockout (KO) mice. Angiogenesis was evaluated in a surgically induced hindlimb ischemia model using laser Doppler blood flowmetry (LDBF) and histological capillary density (CD) and arteriole density (AD). After right hindlimb ischemia, the ischemic/nonischemic hindlimb blood flow ratio was persistently lower in LOX-1 KO mice than in wild-type (WT) mice. CD and AD were significantly smaller in LOX-1 KO mice than in WT mice on postoperative day 14. Immunohistochemical analysis revealed that the number of macrophages infiltrating ischemic tissues was significantly smaller in LOX-1 KO mice than in WT mice. The number of infiltrated macrophages expressing VEGF was also significantly smaller in LOX-1 KO mice than in WT mice. Western blot analysis and ROS production assay revealed that LOX- KO mice show significant decrease in Nox2 expression, ROS production and HIF-1α expression, the phosphorylation of p38 MAPK and NF-κB p65 subunit as well as expression of redox-sensitive vascular cell adhesion molecule-1 (VCAM-1) and LOX-1 itself in ischemic muscles, which is supposed to be required for macrophage infiltration expressing angiogenic factor VEGF. Reduction of VEGF expression successively suppressed the phosphorylation of Akt and eNOS, which accelerated angiogenesis, in the ischemic leg of LOX-1 KO mice. Our findings indicate that LOX-1 plays an important role in ischemia-induced angiogenesis by 1) Nox2-ROS-NF-κB activation, 2) upregulated expression of adhesion molecules: VCAM-1 and LOX-1 and 3) promoting macrophage infiltration, which expresses angiogenic

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

    PubMed

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

    2017-05-01

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

  7. Impact of angiosome- and non-angiosome-targeted peroneal bypass on limb salvage and healing in patients with chronic limb-threatening ischemia.

    PubMed

    Ricco, Jean-Baptiste; Gargiulo, Mauro; Stella, Andrea; Abualhin, Mohammad; Gallitto, Enrico; Desvergnes, Mathieu; Belmonte, Romain; Schneider, Fabrice

    2017-07-26

    Direct (DIR) or indirect (IND) revascularization of pedal angiosomes in patients with chronic limb-threatening ischemia (CLTI) has an unclear impact on limb salvage and healing. The aim of this study was to evaluate the outcomes of DIR and IND revascularization in patients with a peroneal bypass and tissue loss. We conducted a retrospective study of a prospectively maintained database in two European university centers from 2004 to 2015. We extracted from this database all patients with CLTI and tissue loss who had received a bypass to the peroneal artery. All patients underwent angiography before bypass. Revascularization was considered DIR if the wound was in a peroneal angiosome. Wounds, ischemia, and infection were categorized according to the Wound, Ischemia, and foot Infection (WIfI) classification. Limb salvage and amputation-free survival were calculated using the Kaplan-Meier method. Cox regression was used to compare the role of patient characteristics, including diabetes, peroneal runoff, pedal arch angiosome, WIfI grade, chronic kidney disease, and diabetes, in amputation-free-survival. From January 2004 through October 2015, there were 120 peroneal bypasses performed in 120 patients with CLTI and foot tissue loss. Only 55 wounds (46%) could be ascribed to a peroneal angiosome. At 3 years, amputation-free survival in patients with DIR revascularization was 54.9% ± 7.3% compared with 56.5% ± 6.3% in patients with IND revascularization (P = .44), with no significant difference in wound healing. Amputation-free survival at 3 years in patients with two patent peroneal branches was 74.8% ± 6.9% compared with 45.0% ± 6.0% in patients with one patent peroneal branch (P = .003). Amputation-free survival at 3 years in patients with a patent pedal arch (Rutherford 0-1) was 73.0% ± 7.0% vs 45.7% ± 6.0% in patients with incomplete pedal arch (Rutherford 2-3; P = .0002). Amputation-free survival at 3 years in patients with grade 1 or grade 2 WIf

  8. 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

  9. 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

  10. Acute Limb Ischemia and Reperfusion Impairs rhBMP-2 Mediated Fracture Healing

    DTIC Science & Technology

    2017-03-22

    scans at each of the 2, 4 and 6 weeks timepoints to determine the percent of bone regenerated in the defect area. Prior to sacrifice at 6 weeks , TA...SD only group at both the 4 and 6 week timepoints (Fig. 1A & C). There were no differences in bone volume fraction between those groups with...musculature, functional deficits owing to transient ischemia are fully resolved prior to the 6 week timepoint, while deficits owing to VML persist. The

  11. Liposome-encapsulated hemoglobin improves energy metabolism in skeletal muscle ischemia and reperfusion in the rat.

    PubMed

    Kurita, Daisuke; Kawaguchi, Akira T; Aso, Kensuke; Yamano, Mariko; Minamitani, Haruyuki; Haida, Munetaka

    2012-02-01

    The effect of liposome-encapsulated hemoglobin (LEH) was tested in a rodent model of limb ischemia and reperfusion--causing local reperfusion injury and a cascade of systemic responses. Intracellular pH (pHi) and phosphocreatine (PCr)/inorganic phosphate (Pi) ratio were serially monitored using ³¹P-nuclear magnetic resonance spectroscopy with a 2-cm solenoid coil on a rodent hind limb. After baseline measurements, the right hind limb underwent ischemia for 70 min, followed 10 min later by intravenous administration of LEH (10 mL/kg, n = 6), homologous red blood cells (RBCs, n = 6), saline (n = 6), or no treatment (n = 6). Reperfusion was then observed for an additional 60 min. While pHi decreased precipitously after the onset of ischemia and even following reperfusion, LEH-treated rats had significantly milder intracellular acidosis compared with all other groups during ischemia, and after reperfusion as well throughout the observation with the saline-treated rats. In contrast, the PCr/Pi ratio decreased regardless of treatment after ischemia until reperfusion, when the ratio returned toward normal or the energy status improved only in the LEH-treated rats, while the ratio remained depressed in the control animals receiving RBC, saline, or no treatment. Morphological studies 7 days later revealed a tendency toward suppressed mononuclear cell infiltration with preservation of muscular mass and structure in the LEH-treated rats. LEH treatment after early limb ischemia appeared to improve intracellular energy metabolism and eventually preserve skeletal muscle in a rodent model of limb ischemia and reperfusion.

  12. Pretreatment with Fish Oil-Based Lipid Emulsion Modulates Muscle Leukocyte Chemotaxis in Murine Model of Sublethal Lower Limb Ischemia

    PubMed Central

    Shih, Yao-Ming; Shih, Juey-Ming; Yeh, Chiu-Li; Li, Cheng-Che

    2017-01-01

    This study investigated the effects of a fish oil- (FO-) based lipid emulsion on muscle leukocyte chemotaxis and inflammatory responses in a murine model of limb ischemia-reperfusion (IR) injury. Mice were assigned randomly to 1 sham (sham) group, 2 ischemic groups, and 2 IR groups. The sham group did not undergo the ischemic procedure. The mice assigned to the ischemic or IR groups were pretreated intraperitoneally with either saline or FO-based lipid emulsion for 3 consecutive days. The IR procedure was induced by applying a 4.5 oz orthodontic rubber band to the left thigh above the greater trochanter for 120 min and then cutting the band to allow reperfusion. The ischemic groups were sacrificed immediately while the IR groups were sacrificed 24 h after reperfusion. Blood, IR-injured gastrocnemius, and lung tissues were collected for analysis. The results showed that FO pretreatment suppressed the local and systemic expression of several IR-induced proinflammatory mediators. Also, the FO-pretreated group had lower blood Ly6ChiCCR2hi monocyte percentage and muscle M1/M2 ratio than the saline group at 24 h after reperfusion. These findings suggest that FO pretreatment may have a protective role in limb IR injury by modulating the expression of proinflammatory mediators and regulating the polarization of macrophage. PMID:28182087

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

    PubMed

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

    2012-01-01

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

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

    PubMed

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

    2005-03-01

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

  15. High-Mobility Group Box-1 Protein Promotes Angiogenesis After Peripheral Ischemia in Diabetic Mice Through a VEGF-Dependent Mechanism

    PubMed Central

    Biscetti, Federico; Straface, Giuseppe; De Cristofaro, Raimondo; Lancellotti, Stefano; Rizzo, Paola; Arena, Vincenzo; Stigliano, Egidio; Pecorini, Giovanni; Egashira, Kensuke; De Angelis, Giulia; Ghirlanda, Giovanni; Flex, Andrea

    2010-01-01

    OBJECTIVE High-mobility group box-1 (HMGB1) protein is a nuclear DNA-binding protein released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. Diabetic human and mouse tissues contain lower levels of HMGB1 than their normoglycemic counterparts. Deficient angiogenesis after ischemia contributes to worse outcomes of peripheral arterial disease in patients with diabetes. To test the hypothesis that HMGB1 enhances ischemia-induced angiogenesis in diabetes, we administered HMGB1 protein in a mouse hind limb ischemia model using diabetic mice. RESEARCH DESIGN AND METHODS After the induction of diabetes by streptozotocin, we studied ischemia-induced neovascularization in the ischemic hind limb of normoglycemic, diabetic, and HMGB1-treated diabetic mice. RESULTS We found that the perfusion recovery was significantly attenuated in diabetic mice compared with normoglycemic control mice. Interestingly, HMGB1 protein expression was lower in the ischemic tissue of diabetic mice than in normoglycemic mice. Furthermore, we observed that HMGB1 administration restored the blood flow recovery and capillary density in the ischemic muscle of diabetic mice, that this process was associated with the increased expression of vascular endothelial growth factor (VEGF), and that HMGB1-induced angiogenesis was significantly reduced by inhibiting VEGF activity. CONCLUSIONS The results of this study show that endogenous HMGB1 is crucial for ischemia-induced angiogenesis in diabetic mice and that HMGB1 protein administration enhances collateral blood flow in the ischemic hind limbs of diabetic mice through a VEGF-dependent mechanism. PMID:20200317

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

    PubMed

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

    2011-01-01

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

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

    PubMed

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

    2014-07-01

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

  18. 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.

  19. [The results in chronic ischemia of the lower limbs. The Granada-90 Geriatric Angiology Study (2)].

    PubMed

    Peñafiel Marfil, R; García Rospide, V; Moreno Padilla, F; González Ríos, F J; Ros Die, E

    1992-01-01

    Results of a study about the chronic ischaemia of the lower limbs and its correlation with age, sex and previous diagnosis, are presented. Also, a comparison between previous diagnosis and results following the methodology exposed, was made. Study group included 433 older patients, randomizadely selected and permanent residents of some geriatric centers of the Oriental Andalucy.

  20. 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.

  1. Cilostazol improves the response to ischemia in diabetic mice by a mechanism dependent on PPARγ.

    PubMed

    Biscetti, Federico; Pecorini, Giovanni; Arena, Vincenzo; Stigliano, Egidio; Angelini, Flavia; Ghirlanda, Giovanni; Ferraccioli, Gianfranco; Flex, Andrea

    2013-12-05

    Cilostazol is effective for the treatment of peripheral ischemia. This compound has several beneficial effects on platelet aggregation, serum lipids and endothelial cells, and we recently found that it enhances collateral blood flow in the ischemic hind limbs of mice. Peroxisome proliferator-activated receptor (PPAR)γ, a receptor for thiazolidinediones, plays a role in angiogenesis. The aim of this work was to investigate the underlying molecular mechanisms and effects of cilostazol in a model of peripheral ischemia in diabetic mice. We induced diabetes in mice by streptozotocin (STZ) administration and studied ischemia-induced angiogenesis in the ischemic hind limbs of cilostazol-treated and untreated control mice. We found that perfusion recovery was significantly improved in treated compared with control diabetic mice. Interestingly, we found that the expression of PPARγ is reduced in ischemic tissues of diabetic mice. Furthermore, we discovered that local inhibition of the activity of this nuclear receptor decreased the angiogenic response to cilostazol treatment. Finally, we noted that this phenomenon is dependent on VEGF and modulated by PPARγ. Cilostazol administration enhances collateral blood flow in the ischemic hind limbs of STZ-induced diabetic mice through a PPARγ-dependent mechanism.

  2. 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.

  3. Bypass Surgery With Heparin-Bonded Grafts for Chronic Lower Limb Ischemia.

    PubMed

    McAnelly, Sarah-Louise; Hajibandeh, Shahin; Hajibandeh, Shahab; Georgiadis, George S; Antoniou, Stavros A; Madan, Manmohan; Antoniou, George A

    2017-08-01

    Our objective was to assess the effects of heparin-bonded grafts in infrainguinal bypass surgery for patients with peripheral arterial disease of the lower limbs. We searched electronic information sources (MEDLINE, EMBASE, CINAHL, CENTRAL) and bibliographic lists of relevant articles to identify studies reporting comparative outcomes of heparin-bonded grafts in patients undergoing infrainguinal bypass. We used the Cochrane collaboration tool for risk of bias assessment of randomized controlled trials (RCTs) and the Newcastle-Ottawa scale to assess the methodological quality of observational studies. Dichotomous outcome measures were calculated using odds ratio (OR) and 95% confidence interval (CI). Summary estimates of ORs were determined using the fixed-effect or random-effects model. The study protocol was registered in PROSPERO (CRD42016039185). We included 11 articles (3 RCTs) in qualitative and quantitative synthesis reporting a total of 2892 bypasses. Seven studies compared heparin-bonded grafts with vein grafts and another four compared heparin-bonded grafts with standard prosthetic grafts. We noted heterogeneity in disease severity and distal anastomotic level. We found a significantly lower perioperative mortality (OR, 2.30; 95% CI: 1.11-4.77), a trend toward better limb salvage at 1 year (OR, 0.50; 95% CI: 0.25-0.99), and a significantly higher limb salvage rate at 3 years (OR, 0.40; 95% CI: 0.23-0.69) in patients undergoing a vein bypass compared to those treated with heparin-bonded grafts. No differences were identified in graft patency or survival between the heparin-bonded and vein bypass graft group. No differences in primary patency were identified between heparin-bonded grafts and standard prosthetic grafts. Heparin-bonded grafts showed comparable results to autologous vein in terms of graft patency and survival but lower limb salvage rates. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. 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.

  5. Approach to the patient with acute limb ischemia: diagnosis and therapeutic modalities.

    PubMed

    Henke, Peter K

    2002-11-01

    Good patient outcomes depend on the rapidity and completeness with which re-establishment of arterial blood flow to the limbs occurs. Patients with a greater magnitude of ischemic tissue--such as with an acute aortic occlusion--have worse outcomes than patients with a segmental artery occlusion such as a popliteal arterial thrombosis. Limb loss is high in any situation in which a delay in diagnosis occurs. It is unclear whether or not endovascular therapy will supercede traditional surgery because the etiologies of ALI are too broad to make sweeping conclusions at this time. The author and others [14,15], including those who have promulgated the use of thrombolytic therapy, have come to reasonable conclusions regarding how to deal with ALI: The diagnosis of ALI should be established rapidly. Determine its classification based on the patient's history and physical examination, and promptly institute anticoagulant therapy. Determine whether or not the patient should be taken emergently for surgical thromboembolectomy or a revascularization procedure versus arteriogram and possible thrombolysis. Adjunctive therapy such as antiplatelet agents (e.g., GIIb/IIIa antagonists) and other anticoagulant agents must be better investigated before recommendations can be made. Save life over limb. Emergent guillotine amputation is sometimes required to save a patient's life.

  6. 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

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

    PubMed

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

    2011-06-01

    The purpose of this Phase I open label nonrandomized trial was to assess the safety and efficacy of autologous bone marrow mononuclear cell (ABMNC) therapy in promoting amputation-free survival (AFS) in patients with critical limb ischemia (CLI). Between September 2005 and March 2009, 29 patients (30 limbs), with a median age of 66 years (range, 23-84 years; 14 male, 15 female) with CLI were enrolled. Twenty-one limbs presented with rest pain (RP), six with RP and ulceration, and three with ulcer only. All patients were not candidates for surgical bypass due to absence of a patent artery below the knee and/or endovascular approaches to improving perfusion was not possible as determined by an independent vascular surgeon. Patients were treated with an average dose of 1.7 ± 0.7 × 10(9) ABMNC injected intramuscularly in the index limb distal to the anterior tibial tuberosity. The primary safety end point was accumulation of serious adverse events, and the primary efficacy end point was AFS at 1 year. Secondary end points at 12 weeks posttreatment were changes in first toe pressure (FTP), toe-brachial index (TBI), ankle-brachial index (ABI), and transcutaneous oxygen measurements (TcPO(2)). Perfusion of the index limb was measured with positron emission tomography-computed tomography (PET-CT) with intra-arterial infusion of H(2)O(15). RP, using a 10-cm visual analogue scale, quality of life using the VascuQuol questionnaire, and ulcer healing were assessed at each follow-up interval. Subpopulations of endothelial progenitor cells were quantified prior to ABMNC administration using immunocytochemistry and fluorescent-activated cell sorting. There were two serious adverse events; however, there were no procedure-related deaths. Amputation-free survival at 1 year was 86.3%. There was a significant increase in FTP (10.2 ± 6.2 mm Hg; P = .02) and TBI (0.10 ± 0.05;P = .02) and a trend in improvement in ABI (0.08 ± 0.04; P = .73). Perfusion index by PET-CT H(2)O(15

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

    PubMed

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

    2016-07-01

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

  9. 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.

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

    PubMed

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

    2017-08-11

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

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

    PubMed

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

    2009-01-01

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

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

    PubMed

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

    2008-05-01

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

  13. 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.

  14. 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.

  15. Modulating the Vascular Response to Limb Ischemia Angiogenic and Cell Therapies

    PubMed Central

    Cooke, John P.; Losordo, Douglas W.

    2016-01-01

    The age-adjusted prevalence of peripheral arterial disease in the US population has been estimated to approach 12%. The clinical consequences of occlusive peripheral arterial disease include pain on walking (claudication), pain at rest, and loss of tissue integrity in the distal limbs; the latter may ultimately lead to amputation of a portion of the lower extremity. Surgical bypass techniques and percutaneous catheter-based interventions may successfully reperfuse the limbs of certain patients with peripheral arterial disease. In many patients, however, the anatomic extent and distribution of arterial occlusion is too severe to permit relief of pain and healing of ischemic ulcers. No effective medical therapy is available for the treatment of such patients, for many of whom amputation represents the only hope for alleviation of symptoms. The ultimate failure of medical treatment and procedural revascularization in significant numbers of patients has led to attempts to develop alternative therapies for ischemic disease. These strategies include administration of angiogenic cytokines, either as recombinant protein or as gene therapy, and more recently, to investigations of stem/progenitor cell therapy. The purpose of this review is to provide an outline of the preclinical basis for angiogenic and stem cell therapies, review the clinical research that has been done, summarize the lessons learned, identify gaps in knowledge, and suggest a course toward successfully addressing an unmet medical need in a large and growing patient population. PMID:25908729

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

    PubMed

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

    2017-03-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2017-09-05

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

  19. 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.

  20. 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.

  1. Effect of thymoquinone, a constituent of Nigella sativa L., on ischemia-reperfusion in rat skeletal muscle.

    PubMed

    Hosseinzadeh, Hossein; Taiari, Samaneh; Nassiri-Asl, Marjan

    2012-05-01

    Thymoquinone have been shown to decrease ischemia-reperfusion injury (IRI) in some tissues such as gastric mucosa and brain. In this study, the effect of thymoquinone was evaluated on an animal model of IRI in the rat hind limb. Hind limb ischemia was induced by clamping the common femoral artery and vein. After 2 h ischemia, the clamp on the femoral vessels was taken off and the animal underwent 1 h reperfusion. Muscle injuries were evaluated by recording the electromyographic (EMG) potentials and performing some biochemical analysis including thiobarbituric acid reactive substances (TBARS), total sulfhydryl (SH) groups, and antioxidant capacity of muscle using ferric reducing ability of plasma (FRAP) assay. Ischemia was induced using free-flap surgery in skeletal muscle. Thymoquinone (20, 40 and 80 mg/kg) and normal saline (10 ml/kg) were administered intraperitoneally 1 h prior to reperfusion. The average peak-to-peak amplitude during ischemic reperfusion was significantly increased in thymoquinone groups in comparison with the control group. Following thymoquinone administration, the total SH contents and antioxidant capacity were elevated in muscle flap. The malondialdehyde (MDA) level was declined significantly in test groups. It is concluded that thymoquinone have some protective effects against the muscle tissue injury caused by lower limb ischemia-reperfusion.

  2. Common femoral artery endarterectomy for lower-extremity ischemia: evaluating the need for additional distal limb revascularization.

    PubMed

    Malgor, Rafael D; Ricotta, Joseph J; Bower, Thomas C; Oderich, Gustavo S; Kalra, Manju; Duncan, Audra A; Gloviczki, Peter

    2012-10-01

    The role of common femoral artery endarterectomy (CFE) and the need for distal revascularization is challenging in certain clinical scenarios. For some patients with claudication or rest pain CFE alone may suffice, however, some surgeons advocated that in-line flow must be re-established in patients with major tissue loss for wound healing purposes. The decision when to perform CFE with or without distal revascularization is sometimes difficult. The objective of this study was to evaluate the outcomes of common femoral artery endarterectomy (CFE) to define predictive factors for additional distal revascularization. Retrospective review of 262 consecutive CFEs in 230 patients with lower-extremity ischemia between 1997 and 2008. Patients were divided into two groups: group A (n = 169; CFE alone) and group B (n = 93; CFE + distal revascularization). Concomitant iliac intervention was included only if performed by endovascular approach. Patients were analyzed by Rutherford category (RC) and TransAtlantic InterSociety Consensus (TASC) II classification. Primary end points were mortality, patency, reintervention, and limb salvage. Demographics, preoperative Society for Vascular Surgery score assessment, and TASC II classification did not differ between groups. Mean follow-up was 75 months (range: 1-128 months). Technical success was obtained in all patients. RC (3 ± 1.2 vs. 5 ± 1.4; P = 0.001), diabetes (33% vs. 52%; P = 0.005), mean operative time (+154 minutes; P < 0.001), and length of hospital stay (+1.7 days; P = 0.03) were higher in group B. Reintervention rates were higher in group B than group A (12% vs. 3%; P = 0.015). For patients with RC 5/TASC D lesions and patients with RC 6 regardless of TASC, initial distal revascularization (group B) was associated with fewer reinterventions or major amputations (29%) than CFE alone (67%) (P = 0.002). The cumulative 5-year primary patencies for groups A and group B were 96% and 92%, respectively. Secondary patency was

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

    PubMed

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

    2014-04-01

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

  4. 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.

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

    PubMed

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

    2016-05-01

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

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

    PubMed Central

    2011-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2010-04-01

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

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2017-06-01

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

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. Simvastatin inhibits inflammation in ischemia-reperfusion injury.

    PubMed

    Zhao, Yilin; Feng, Qingzhao; Huang, Zhengjie; Li, Wenpeng; Chen, Baisheng; Jiang, Long; Wu, Binglin; Ding, Weiji; Xu, Gang; Pan, Heng; Wei, Wei; Luo, Weiyuan; Luo, Qi

    2014-10-01

    Ischemia/reperfusion (I/R) is associated with leukocyte accumulation and tissue injury. The aim of this research was to investigate the protective effect of simvastatin on hind limb I/R inflammation and tissue damage. Mice were subjected to hind limb ischemic insult for 2 h and were simultaneously administered an intraperitoneal injection of simvastatin (5 mg/kg); this was followed by 36 h of reperfusion. Myeloperoxidase (MPO) levels in the muscles of the hind limb were determined. CXC chemokines and pro-inflammatory cytokines, such as macrophage inflammatory protein (MIP)-2, cytokine-induced neutrophil chemoattractant (KC), interleukin (IL)-6, tumor necrosis factor (TNF)-α, and P-selectin, were assessed using enzyme-linked immunosorbent assay (ELISA). Leukocyte rolling and adhesion in vitro was assessed to indicate leukocyte recruitment at the site of inflammation. Quantitative measurement of skeletal muscle tissue injury was performed. The fluorescent dye level in tissue and serum was used to determine hind limb vascular leakage and tissue edema after I/R. Systemic and differentiated leukocytes were also counted. Simvastatin significantly reduced MIP-2, KC, TNF-α, MPO, IL-6, and P-selectin levels compared to the sham group and I/R plus pretreatment with phosphate-buffered saline (PBS) group (P<0.05). Compared to the sham group and I/R plus PBS group, the I/R plus simvastatin group had attenuated inflammation, vascular leakage, and muscular damage (P<0.05). Simvastatin also significantly inhibited leukocyte rolling and adhesion compared to PBS (P<0.05). Our results suggest that simvastatin may be an effective protectant against tissue injury associated with I/R.

  18. Putative role of ischemic postconditioning in a rat model of limb ischemia and reperfusion: involvement of hypoxia-inducible factor-1α expression.

    PubMed

    Wang, T; Zhou, Y T; Chen, X N; Zhu, A X

    2014-09-01

    Hypoxia-inducible factor-1α (HIF-1α) is one of the most potent angiogenic growth factors. It improves angiogenesis and tissue perfusion in ischemic skeletal muscle. In the present study, we tested the hypothesis that ischemic postconditioning is effective for salvaging ischemic skeletal muscle resulting from limb ischemia-reperfusion injury, and that the mechanism involves expression of HIF-1α. Wistar rats were randomly divided into three groups (n=36 each): sham-operated (group S), hindlimb ischemia-reperfusion (group IR), and ischemic postconditioning (group IPO). Each group was divided into subgroups (n=6) according to reperfusion time: immediate (0 h, T0), 1 h (T1), 3 h (T3), 6 h (T6), 12 h (T12), and 24 h (T24). In the IPO group, three cycles of 30-s reperfusion and 30-s femoral aortic reocclusion were carried out before reperfusion. At all reperfusion times (T0-T24), serum creatine kinase (CK) and lactate dehydrogenase (LDH) activities, as well as interleukin (IL)-6, IL-10, and tumor necrosis factor-α (TNF-α) concentrations, were measured in rats after they were killed. Histological and immunohistochemical methods were used to assess the skeletal muscle damage and HIF-1α expression in skeletal muscle ischemia. In groups IR and IPO, serum LDH and CK activities and TNF-α, IL-6, and IL-10 concentrations were all significantly increased compared to group S, and HIF-1α expression was up-regulated (P<0.05 or P<0.01). In group IPO, serum LDH and CK activities and TNF-α and IL-6 concentrations were significantly decreased, IL-10 concentration was increased, HlF-1α expression was down-regulated (P<0.05 or P<0.01), and the pathological changes were reduced compared to group IR. The present study suggests that ischemic postconditioning can reduce skeletal muscle damage caused by limb ischemia-reperfusion and that its mechanisms may be related to the involvement of HlF-1α in the limb ischemia-reperfusion injury-triggered inflammatory response.

  19. Platelet-derived miR-92a downregulates cysteine protease inhibitor cystatin C in type II diabetic lower limb ischemia

    PubMed Central

    ZHANG, YUNFENG; GUAN, QIANG; JIN, XING

    2015-01-01

    The aim of the present study was to investigate the effect of microRNA (miR)-92a on cystatin C expression in patients with type II diabetes and lower limb ischemia. A total of 199 patients diagnosed with type II diabetes were included in the study and divided into three experimental groups: Simple type II diabetes mellitus (T2DM; n=60) group; type II diabetes with light to moderate occlusion (LLI-LM; n=70) group; and the type II diabetes with severe occlusion (LLI-S; n=69) group according to the patient ankle-brachial index score. In addition, 60 healthy individuals were examined as a control population. The expression levels of various biochemical indices were detected, including cystatin C in the peripheral blood. The expression levels of miR-92a and cystatin C mRNA were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and the correlation between miR-92a, cystatin C and the pathological development of type II diabetic lower limb ischemia was analyzed. The protein expression levels of cystatin C were detected using western blot analysis. Bioinformatic analysis indicated that miR-92a was able to downregulate cystatin C expression, and this result was supported by endothelial cell transfection. In the transfection assay, an miR-92a mimic downregulated cystatin C expression, while an miR-92a inhibitor upregulated cystatin C expression. The results of the RT-qPCR indicated that the expression levels of miR-92a in the LLI-S group were reduced compared with those in the T2DM and LLI-LM groups, and significantly lower compared with those in the negative control group. Platelet-derived miR-92a appeared to downregulate cystatin C expression in patients with type II diabetes and lower limb ischemia. Therefore, the combined detection of miR-92a and cystatin C may be useful as a method for clinically screening patients with type II diabetes for lower limb ischemia. PMID:26136970

  20. Therapeutic metabolic inhibition: hydrogen sulfide significantly mitigates skeletal muscle ischemia reperfusion injury in vitro and in vivo.

    PubMed

    Henderson, Peter W; Singh, Sunil P; Weinstein, Andrew L; Nagineni, Vijay; Rafii, Daniel C; Kadouch, Daniel; Krijgh, David D; Spector, Jason A

    2010-12-01

    Recent evidence suggests that hydrogen sulfide is capable of mitigating the degree of cellular damage associated with ischemia-reperfusion injury. The purpose of this study was to determine whether it is protective in skeletal muscle. This study used both in vitro (cultured myotubes subjected to sequential anoxia and normoxia) and in vivo (mouse hind-limb ischemia followed by reperfusion) models in which hydrogen sulfide (0 to 1000 μM) was delivered before the onset of oxygen deficiency. Injury score and apoptotic index were determined by analysis of specimens stained with hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, respectively. In vitro, hydrogen sulfide reduced the apoptotic index by as much as 99 percent (p=0.001), with optimal protection conferred by raising intravascular hydrogen sulfide to 10 μM. In vivo, 10 μM hydrogen sulfide delivered before 3 hours of hind-limb ischemia followed by 3 hours of reperfusion resulted in protection against ischemia-reperfusion injury-induced cellular changes, as evidenced by significant decreases in injury score and apoptotic index (by as much as 91 percent; p=0.001). These findings were consistent at 4 weeks after injury and reperfusion. These findings confirm that the preischemic delivery of hydrogen sulfide limits ischemia-reperfusion injury-induced cellular damage in myotubes and skeletal muscle and suggests that, when given in the appropriate dose, this molecule may have significant therapeutic applications in multiple clinical scenarios.

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

    PubMed

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

    2016-07-08

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

  2. 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

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

    PubMed

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

    2016-04-01

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

  4. 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.

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

    PubMed

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

    2017-02-16

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

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

    PubMed

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

    2010-09-01

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

  7. Transplantation of placenta-derived mesenchymal stem cells enhances angiogenesis after ischemic limb injury in mice.

    PubMed

    Xie, Nanzi; Li, Zhihong; Adesanya, Timothy M; Guo, Weixin; Liu, Yang; Fu, Minghuan; Kilic, Ahmet; Tan, Tao; Zhu, Hua; Xie, Xiaoyun

    2016-01-01

    Mesenchymal stem cell-based therapy has emerged as a promising approach for the treatment of peripheral arterial disease. The purpose of this study was to examine the potential effects of human placenta-derived mesenchymal stem cells (PMSCs) on mouse hindlimb ischemia. PMSCs were isolated from human placenta tissue and characterized by flow cytometry. An in vivo surgical ligation-induced murine limb ischemia model was generated with fluorescent dye (CM-DiI) labelled PMSCs delivered via intramuscular injection. Our data show that PMSCs treatment significantly enhanced microvessel density, improved blood perfusion and diminished pathologies in ischemic mouse hindlimbs as compared to those in the control group. Further immunostaining studies suggested that injected PMSCs can incorporate into the vasculature and differentiate into endothelial and smooth muscle cells to enhance angiogenesis in ischemic hind limbs. This may in part explain the beneficial effects of PMSCs treatment. Taken together, we found that PMSCs treatment might be an effective treatment modality for treatment of ischemia-induced injury to mouse hind limbs by enhancement of angiogenesis. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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

    PubMed

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

    2015-08-01

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

  9. A study of the relationships of changes in pain and gait after tourniquet-induced ischemia-reperfusion in rats

    PubMed Central

    Aihara, Kazuki; Ono, Takeya; Umei, Namiko; Tsumiyama, Wakako; Tasaka, Atsushi; Ishikura, Hideki; Sato, Yuta; Matsumoto, Tomohiro; Oki, Sadaaki

    2017-01-01

    [Purpose] The purpose of this study was to determine the relationships of changes in pain and gait after ischemia reperfusion was induced by tourniquet in rats. [Subjects and Methods] The subjects were six ten-week-old male Wistar rats. Ischemia was induced in the left lower limbs of the experimental rats at a pressure of 300 mmHg for 90 minutes. Pain behavior evaluations were measured using the von Frey test in all the rats’ hind limbs. A consistently increasing plantar stimulus was applied until the rats exhibited an escape behavior. For the evaluation of gait, a two-dimensional motion analysis system was used to measure the distance from the calcaneus to the floor (DCF) and toe extension angle (TEA) during gait. The evaluations were performed in the normal state, 3 hours after ischemia-reperfusion, and daily until 7 days after ischemia-reperfusion. [Results] Compared with the normal state, the means of the pain threshold showed a significant decrease until 4 days after ischemia. In addition, both TEA and DCF continued to show a significant decrease at 7 days after ischemia as compared with the normal state. [Conclusion] This study revealed that hyperalgesia occurs after ischemia-reperfusion, and recovery of hyperalgesia occurred earlier than gait dysfunction recovery. PMID:28210050

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

    PubMed Central

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

    2012-01-01

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

  11. 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

  12. 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.

  13. 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.

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

    PubMed

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

    2017-10-01

    To report the initial clinical experience with percutaneous deep vein arterialization (PDVA) to treat critical limb ischemia (CLI) via the creation of an arteriovenous fistula. Seven patients (median age 85 years; 5 women) with CLI and no traditional endovascular or surgical revascularization options (no-option CLI) were recruited in a pilot study to determine the safety of PDVA. All patients were diabetic; 4 had Rutherford category 6 ischemia. Six were classified at high risk of amputation based on the Society for Vascular Surgery WIfI (wound, ischemia, and foot infection) classification. The primary safety endpoints were major adverse limb events and major adverse coronary events through 30 days and serious adverse events through 6 months. Secondary objectives included clinical efficacy based on outcome measures including thermal measurement, transcutaneous partial pressure of oxygen (TcPO2), clinical improvement at 6 months, and wound healing. The primary safety endpoints were achieved in 100% of patients, with no deaths, above-the-ankle amputations, or major reinterventions at 30 days. The technical success rate was 100%. Two myocardial infarctions occurred within 30 days, each with minor clinical consequences. All patients demonstrated symptomatic improvement with formation of granulation tissue, resolution of rest pain, or both. Complete wound healing was achieved in 4 of 7 patients and 5 of 7 patients at 6 and 12 months, respectively, with a median healing time of 4.6 months (95% confidence interval 84-192). Median postprocedure peak TcPO2 was 61 mm Hg compared to a preprocedure level of 8 mm Hg (p=0.046). At the time of wound healing, 4 of 5 of patients achieved TcPO2 levels of >40 mm Hg. There were 2 major amputations, 1 above the knee after PDVA thrombosis and 1 below the knee for infection. Three patients died of causes unrelated to the procedure or study device at 6, 7, and 8 months, respectively. Limb salvage was 71% at 12 months. PDVA is an innovative

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

    PubMed

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

    2017-03-01

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

  16. A comparison of the reparative and angiogenic properties of mesenchymal stem cells derived from the bone marrow of BALB/c and C57/BL6 mice in a model of limb ischemia.

    PubMed

    Cunha, Flavia Franco; Martins, Leonardo; Martin, Priscila Keiko Matsumoto; Stilhano, Roberta Sessa; Han, Sang Won

    2013-07-26

    BALB/c mice and C57/BL6 mice have different abilities to recover from ischemia. C57/BL6 mice display increased vessel collateralization and vascular endothelial growth factor expression with a consequent rapid recovery from ischemia compared with BALB/c mice. Mesenchymal stem cells (MSCs) are one of the main cell types that contribute to the recovery from ischemia because, among their biological activities, they produce several proangiogenic paracrine factors and differentiate into endothelial cells. The objective of this study was to evaluate whether the MSCs of these two mouse strains have different inductive capacities for recovering ischemic limbs. MSCs from these two strains were obtained from the bone marrow, purified and characterized before being used for in vivo experiments. Limb ischemia was surgically induced in BALB/c mice, and MSCs were injected on the fifth day. The evolution of limb necrosis was evaluated over the subsequent month. Muscle strength was assessed on the 30th day after the injection, and then the animals were sacrificed to determine the muscle mass and perform histological analyses to detect cellular infiltration, capillary and microvessel densities, fibrosis, necrosis and tissue regeneration. The MSCs from both strains promoted high level of angiogenesis similarly,