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High Apolipoprotein E Levels Predict Adverse Limb Events in Patients with Peripheral Artery Disease Due to Peripheral Artery Disease Undergoing Endovascular Treatment and On-Statin Treatment.
Fukase, T, Dohi, T, Kato, Y, Chikata, Y, Takahashi, N, Endo, H, Doi, S, Nishiyama, H, Okai, I, Iwata, H, et al
International heart journal. 2021;(4):872-878
Abstract
Little is known about the association between limb prognosis in peripheral artery disease and apolipoprotein E (apoE). We evaluated the long-term impact of apoE on adverse limb events in patients with intermittent claudication receiving statin treatment.A total of 218 consecutive patients (mean age, 73 ± 8 years; 81% men) with intermittent claudication who underwent their first intervention between 2009 and 2020 were included in this study. All patients had achieved LDL-C < 100 mg/dL on statin treatment and were divided into two groups based on the apoE value (≥ 4.7 or < 4.7 mg/dL). We evaluated the incidence of major adverse limb events (MALEs), including vessel revascularization and limb ischemia development.A total of 39 and 179 patients were allocated to the higher and lower apoE groups, respectively. Compared to the lower apoE group, the higher apoE group had a significantly higher total cholesterol level, triglyceride level, and non-high-density lipoprotein cholesterol level. During the median follow-up period of 3.6 years, 30 patients (13.8%) developed MALEs. Kaplan-Meier analysis revealed that the cumulative incidence of MALEs in the higher apoE group was significantly higher than that in the lower apoE group (44.0% versus 21.6%, log-rank test, P = 0.002). During multivariable Cox hazard analysis, higher apoE level (≥ 4.7 mg/dL) (hazard ratio, 2.61; 95% confidence interval, 1.18-5.70, P = 0.019) was the only strong independent predictor of MALEs.ApoE levels could be a strong predictor and residual risk for long-term limb prognosis in patients with intermittent claudication and achieving LDL-C < 100 mg/dL with statin treatment.
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CORP: Measurement of upper and lower limb muscle strength and voluntary activation.
Nuzzo, JL, Taylor, JL, Gandevia, SC
Journal of applied physiology (Bethesda, Md. : 1985). 2019;(3):513-543
Abstract
Muscle strength, the maximal force-generating capacity of a muscle or group of muscles, is regularly assessed in physiological experiments and clinical trials. An understanding of the expected variation in strength and the factors that contribute to this variation is important when designing experiments, describing methodologies, interpreting results, and attempting to replicate methods of others and reproduce their findings. In this review (Cores of Reproducibility in Physiology), we report on the intra- and inter-rater reliability of tests of upper and lower limb muscle strength and voluntary activation in humans. Isometric, isokinetic, and isoinertial strength exhibit good intra-rater reliability in most samples (correlation coefficients ≥0.90). However, some tests of isoinertial strength exhibit systematic bias that is not resolved by familiarization. With the exception of grip strength, few attempts have been made to examine inter-rater reliability of tests of muscle strength. The acute factors most likely to affect muscle strength and serve as a source of its variation from trial-to-trial or day-to-day include attentional focus, breathing technique, remote muscle contractions, rest periods, temperature (core, muscle), time of day, visual feedback, body and limb posture, body stabilization, acute caffeine consumption, dehydration, pain, fatigue from preceding exercise, and static stretching >60 s. Voluntary activation, the nervous system's ability to drive a muscle to create its maximal force, exhibits good intra-rater reliability when examined with twitch interpolation (correlation coefficients >0.80). However, inter-rater reliability has not been formally examined. The methodological factors most likely to influence voluntary activation are myograph compliance and sensitivity; stimulation location, intensity, and inadvertent stimulation of antagonists; joint angle (muscle length); and the resting twitch.
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Modeling and evaluation of a high-resolution CMOS detector for cone-beam CT of the extremities.
Cao, Q, Sisniega, A, Brehler, M, Stayman, JW, Yorkston, J, Siewerdsen, JH, Zbijewski, W
Medical physics. 2018;(1):114-130
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PURPOSE Quantitative assessment of trabecular bone microarchitecture in extremity cone-beam CT (CBCT) would benefit from the high spatial resolution, low electronic noise, and fast scan time provided by complementary metal-oxide semiconductor (CMOS) x-ray detectors. We investigate the performance of CMOS sensors in extremity CBCT, in particular with respect to potential advantages of thin (<0.7 mm) scintillators offering higher spatial resolution. METHODS A cascaded systems model of a CMOS x-ray detector incorporating the effects of CsI:Tl scintillator thickness was developed. Simulation studies were performed using nominal extremity CBCT acquisition protocols (90 kVp, 0.126 mAs/projection). A range of scintillator thickness (0.35-0.75 mm), pixel size (0.05-0.4 mm), focal spot size (0.05-0.7 mm), magnification (1.1-2.1), and dose (15-40 mGy) was considered. The detectability index was evaluated for both CMOS and a-Si:H flat-panel detector (FPD) configurations for a range of imaging tasks emphasizing spatial frequencies associated with feature size aobj. Experimental validation was performed on a CBCT test bench in the geometry of a compact orthopedic CBCT system (SAD = 43.1 cm, SDD = 56.0 cm, matching that of the Carestream OnSight 3D system). The test-bench studies involved a 0.3 mm focal spot x-ray source and two CMOS detectors (Dalsa Xineos-3030HR, 0.099 mm pixel pitch) - one with the standard CsI:Tl thickness of 0.7 mm (C700) and one with a custom 0.4 mm thick scintillator (C400). Measurements of modulation transfer function (MTF), detective quantum efficiency (DQE), and CBCT scans of a cadaveric knee (15 mGy) were obtained for each detector. RESULTS Optimal detectability for high-frequency tasks (feature size of ~0.06 mm, consistent with the size of trabeculae) was ~4× for the C700 CMOS detector compared to the a-Si:H FPD at nominal system geometry of extremity CBCT. This is due to ~5× lower electronic noise of a CMOS sensor, which enables input quantum-limited imaging at smaller pixel size. Optimal pixel size for high-frequency tasks was <0.1 mm for a CMOS, compared to ~0.14 mm for an a-Si:H FPD. For this fine pixel pitch, detectability of fine features could be improved by using a thinner scintillator to reduce light spread blur. A 22% increase in detectability of 0.06 mm features was found for the C400 configuration compared to C700. An improvement in the frequency at 50% modulation (f50 ) of MTF was measured, increasing from 1.8 lp/mm for C700 to 2.5 lp/mm for C400. The C400 configuration also achieved equivalent or better DQE as C700 for frequencies above ~2 mm-1 . Images of cadaver specimens confirmed improved visualization of trabeculae with the C400 sensor. CONCLUSIONS The small pixel size of CMOS detectors yields improved performance in high-resolution extremity CBCT compared to a-Si:H FPDs, particularly when coupled with a custom 0.4 mm thick scintillator. The results indicate that adoption of a CMOS detector in extremity CBCT can benefit applications in quantitative imaging of trabecular microstructure in humans.
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Heparin-induced thrombocytopenia-associated thrombosis: from arterial to venous to venous limb gangrene.
Warkentin, TE
Journal of thrombosis and haemostasis : JTH. 2018;(11):2128-2132
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Heparin-induced thrombocytopenia (HIT) is an acquired immune-mediated hypercoagulability state that is strongly associated with thrombosis. During the 1970s and 1980s, the prevailing concept was that HIT was associated only with arterial thrombosis, through its unique pathogenesis via heparin-dependent, platelet-activating IgG antibodies. However, in 1990, when I began to encounter HIT in my clinical practice, I found that most such patients developed symptomatic venous thrombosis. This historical sketch summarizes some of the research that challenged the dogma of HIT being a mainly arterial prothrombotic disorder. Two studies - one a substudy of a randomized trial of post-orthopedic surgery thromboprophylaxis, and the second a retrospective five-hospital analysis of consecutive patients with positive test results for HIT antibodies - showed a marked predominance of venous over arterial thrombosis complicating HIT (~ 4 : 1). By the end of the 1990s, an even more dramatic manifestation of HIT-associated venous thrombosis was recognized: venous limb gangrene. Here, ischemic limb necrosis occurs despite palpable arterial pulses, as a result of both macrovascular and microvascular venous thrombosis. The surprising explanation was natural anticoagulant impairment (severe depletion of protein C, a vitamin K-dependent anticoagulant) resulting from treatment of HIT-associated deep vein thrombosis with warfarin (vitamin K antagonist). These insights from HIT research helped to elucidate the pathogenesis of ischemic limb losses in other intense non-HIT hypercoagulability states, including warfarin-associated venous limb gangrene complicating cancer-associated hypercoagulability, and symmetrical peripheral gangrene complicating disseminated intravascular coagulation of critical illness, in which proximate 'shock liver' helps to explain the profound failure of natural anticoagulant systems (protein C; antithrombin) in predisposing to peripheral limb microthrombosis in circulatory shock.
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Dexmedetomidine for prevention of skeletal muscle ischaemia-reperfusion injury in patients with chronic limb ischaemia undergoing aortobifemoral bypass surgery: A prospective double-blind randomized controlled study.
Kundra, TS, Thimmarayappa, A, Dhananjaya, M, Manjunatha, N
Annals of cardiac anaesthesia. 2018;(1):22-25
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BACKGROUND Dexmedetomidine is a selective α-2 agonist used for sedation. It has also been shown to have myocardial protective effect and prevent ischemia-reperfusion injury in off-pump coronary artery bypass patients. The aim of our study was to assess the effect of dexmedetomidine for prevention of skeletal muscle ischemia-reperfusion injury in patients undergoing aortobifemoral bypass surgery. METHODOLOGY Sixty adult patients (Group dexmedetomidine n = 30, Group normal saline n = 30) undergoing aortobifemoral bypass surgery were recruited over 3 months. Randomization was done using a computer-generated random table. The attending anesthesiologist would be blinded to whether the drug/normal saline was being administered. He would consider each unlabeled syringe as containing dexmedetomidine and calculate the volume to be infused via a syringe pump accordingly. Dexmedetomidine infusion (1 mcg/kg) over 15 minutes was given as a loading dose, followed by maintenance infusion of 0.5 mcg/kg/h till 2 h postprocedure in Group dexmedetomidine (D) while the same volume of normal saline was given in the control Group C till 2 h postprocedure. Creatine phosphokinase (CPK) values were noted at baseline (T0), 6 h (T1), 12 h (T2), and 24 h (T3) after the procedure. Hemodynamic variables (heart rate [HR] and mean blood pressure [MAP]) were recorded at T0, T1, T2, and T3. Results were analyzed using unpaired Student's t-test, P < 0.05 was considered statistically significant. RESULTS MAP and HR significantly decreased in Group D as compared to control group (P < 0.05). However, the decrease was never <20% of the baseline. The CPK values at 6, 12, and 24 h were statistically significant between the two groups. CONCLUSION Dexmedetomidine prevents skeletal muscle ischemia-reperfusion injury in patients undergoing aortobifemoral bypass surgery.
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Meta-analysis of remote ischemic conditioning in patients with acute myocardial infarction.
Man, C, Gong, D, Zhou, Y, Fan, Y
Scientific reports. 2017;:43529
Abstract
Effects of remote ischemic conditioning (RIC) in acute myocardial infarction (AMI) patients remain conflicting. We performed this meta-analysis of randomized clinical trials (RCTs) to evaluate the benefits of the RIC in patients with AMI. Potentially relevant RCTs were identified by searching PubMed, Embase, Cochrane Library, VIP, CNKI, and Wanfang database until November 2016. RCTs evaluating RIC using intermittent limb ischemia-reperfusion in AMI patients were included. Thirteen RCTs were identified and analyzed. Meta-analysis showed that RIC significantly reduced the area under the curve (AUC) of creatine kinase-myocardial band (CK-MB) (standardized mean difference [SMD] -0.29; 95% confidence intervals [CI] -0.44 to -0.14; P = 0.0002) and AUC of troponin T (SMD -0.22; 95% CI -0.37 to -0.08; P = 0.003). Risk ratio (RR) for ≥70% ST-segment resolution favored RIC group than the control group (RR 1.39; 95% CI 1.03-1.86; P = 0.03). RIC also significantly reduced all-cause mortality (RR 0.33; 95%CI 0.17-0.64; P = 0.001). Subgroup analyses on the CK-MB AUC and ST-segment resolution ≥70% rate showed that the effects of RIC appeared to be affected by the limb used, duration of RIC, and clinical setting. RIC may offer cardioprotective effects by improving ST-segment resolution and reducing the infarct size in AMI patients.
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Improvement in asymmetric dimethylarginine and oxidative stress in patients with limb salvage after autologous mononuclear stem cell application for critical limb ischemia.
Madaric, J, Valachovicova, M, Paulis, L, Pribojova, J, Mateova, R, Sebekova, K, Postulkova, L, Madaricova, T, Bucova, M, Mistrik, M, et al
Stem cell research & therapy. 2017;(1):165
Abstract
BACKGROUND Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, acts as an inhibitor of angiogenesis and is associated with an increased risk of cardiovascular mortality. Administration of stem cells may affect endogenous mechanisms that regulate ADMA production and metabolism. The aim of the present study was to analyze ADMA concentration and changes in oxidative stress in patients with advanced critical limb ischemia (CLI) after bone marrow-derived mononuclear cell (BM-MNC) therapy. METHODS Fifty patients (age 64 ± 11 years, 44 males, 6 females) with advanced CLI (Rutherford category 5 or 6) not eligible for revascularization were treated by intramuscular (n = 25) or intra-arterial (n = 25) injection of 40 ml BM-MNC concentrate. Patients with limb salvage and improved wound healing after 6 months were considered responders to cell therapy. The concentrations of markers of oxidative stress and angiogenesis were analyzed before, and at 3 and 6 months after BM-MNC delivery. RESULTS At 6-month follow-up, four patients died of reasons unrelated to stem cell therapy. Among the survivors, 80% (37/46) showed limb salvage and improved wound healing. At 6 months follow-up, ADMA concentration significantly decreased in patients with limb salvage (1.74 ± 0.66 to 0.90 ± 0.49 μmol/L, p < 0.001), in parallel with decreased tumor necrosis factor (TNF)-α (2.22 ± 0.16 to 1.94 ± 0.38 pg/ml, p < 0.001), and increased reduced glutathione (6.96 ± 3.1 to 8.67 ± 4.2 μmol/L, p = 0.02), superoxide dismutase activity (168 ± 50 to 218 ± 37 U/L, p = 0.002), and coenzyme Q10 concentration (468 ± 182 to 598 ± 283 μg/L, p = 0.02). The number of delivered BM-MNCs significantly correlated with the decrease in ADMA concentration at 3 months (p = 0.004, r = -0.48) and the decrease in TNF-α concentration at 6 months (p = 0.03, r = -0.44) after cell delivery. ADMA or TNF-α improvement did not correlate with the number of applied CD34+ cells, C-reactive protein concentration, leukocyte count, or the dose of atorvastatin. CONCLUSIONS The therapeutic benefit of BM-MNC therapy is associated with reduced ADMA levels and oxidative stress. Regulation of the ADMA-nitric oxide axis and improved antioxidant status may be involved in the beneficial effects of stem cell therapy. TRIAL REGISTRATION The study was approved and retrospectively registered by ISRCTN registry, ISRCTN16096154 . Registered on 26 July 2016.
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Phase I trial of neoadjuvant conformal radiotherapy plus sorafenib for patients with locally advanced soft tissue sarcoma of the extremity.
Canter, RJ, Borys, D, Olusanya, A, Li, CS, Lee, LY, Boutin, RD, Christensen, SD, Tamurian, RM, Monjazeb, AM
Annals of surgical oncology. 2014;(5):1616-23
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BACKGROUND Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent. METHODS For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4-6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). RESULTS Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8-29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥95 % tumor necrosis) was observed in three patients (38 %). CONCLUSION Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).
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An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease.
Maltais, F, Decramer, M, Casaburi, R, Barreiro, E, Burelle, Y, Debigaré, R, Dekhuijzen, PN, Franssen, F, Gayan-Ramirez, G, Gea, J, et al
American journal of respiratory and critical care medicine. 2014;(9):e15-62
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BACKGROUND Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.
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A phase I multi-institutional study of systemic sorafenib in conjunction with regional melphalan for in-transit melanoma of the extremity.
Beasley, GM, Coleman, AP, Raymond, A, Sanders, G, Selim, MA, Peterson, BL, Brady, MS, Davies, MA, Augustine, C, Tyler, DS
Annals of surgical oncology. 2012;(12):3896-3905
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BACKGROUND Isolated limb infusion with melphalan (ILI-M) corrected for ideal body weight (IBW) is a well-tolerated treatment for patients with in-transit extremity melanoma with an approximate 29 % complete response (CR) rate. Sorafenib, a multi-kinase inhibitor, has been shown to augment tumor response to chemotherapy in preclinical studies. METHODS A multi-institutional, dose-escalation, phase I study was performed to evaluate the safety and antitumor activity of sorafenib in combination with ILI-M. Patients with AJCC stage IIIB/IIIC/IV melanoma were treated with sorafenib starting at 400 mg daily for 7 days before and 7 days after ILI-M corrected for IBW. Toxicity, drug pharmacokinetics, and tumor protein expression changes were measured and correlated with clinical response at 3 months. RESULTS A total of 20 patients were enrolled at two institutions. The maximum tolerated dose (MTD) of sorafenib in combination with ILI-M was 400 mg. Four dose-limiting toxicities occurred, including soft tissue ulcerations and compartment syndrome. There were three CRs (15 %) and four partial responses (20 %). Of patients with the Braf mutation, 83 % (n = 6) progressed compared with only 33 % without (n = 12). Short-term sorafenib treatment did alter protein expression as measured with reverse phase protein array (RPPA) analysis, but did not inhibit protein expression in the MAP kinase pathway. Sorafenib did not alter melphalan pharmacokinetics. CONCLUSION This trial defined the MTD of systemically administered sorafenib in combination with ILI-M. Although some responses were seen, the addition of sorafenib to ILI-M did not appear to augment the effects of melphalan but did increase regional toxicity.