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Introduction: Mitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus (T2DM) is a major risk factor for PAD development and progression to CLI and may also independently be related to mitochondrial dysfunction. We set out to determine the effect of T2DM in the relationship between CLI and muscle mitochondrial respiratory capacity and coupling control., Methods: We studied CLI patients undergoing revascularization procedures or amputation, and non-CLI patients with or without T2DM of similar age. Mitochondrial respiratory capacity and function were determined in lower limb permeabilized myofibers by high-resolution respirometry., Results: Fourteen CLI patients (65 ± 10y) were stratified into CLI patients with (n = 8) or without (n = 6) T2DM and were compared to non-CLI patients with (n = 18; 69 ± 5y) or without (n = 19; 71 ± 6y) T2DM. Presence of CLI but not T2DM had a marked impact on all mitochondrial respiratory states in skeletal muscle, adjusted for the effects of sex. Leak respiration (State 2, P < 0.025 and State 4 o , P < 0.01), phosphorylating respiration (P < 0.001), and maximal respiration in the uncoupled state (P < 0.001), were all suppressed in CLI patients, independent of T2DM. T2DM had no significant effect on mitochondrial respiratory capacity and function in adults without CLI., Conclusions: Skeletal muscle mitochondrial respiratory capacity was blunted by ∼35% in patients with CLI. T2DM was not associated with muscle oxidative capacity and did not moderate the relationship between muscle mitochondrial respiratory capacity and CLI., (Copyright © 2023. Published by Elsevier Inc.)

Peripheral artery disease (PAD) is a serious but relatively underdiagnosed and undertreated clinical condition associated with a marked reduction in functional capacity and a heightened risk of morbidity and mortality. The pathophysiology of lower extremity PAD is complex, and extends beyond the atherosclerotic arterial occlusion and subsequent mismatch between oxygen demand and delivery to skeletal muscle mitochondria. In this review, we evaluate and summarize the available evidence implicating mitochondria in the metabolic myopathy that accompanies PAD. Following a short discussion of the available in vivo and in vitro methodologies to quantitate indices of muscle mitochondrial function, we review the current evidence implicating skeletal muscle mitochondrial dysfunction in the pathophysiology of PAD myopathy, while attempting to highlight questions that remain unanswered. Given the rising prevalence of PAD, the detriment in quality of life for patients, and the associated significant healthcare resource utilization, new alternate therapies that ameliorate lower limb symptoms and the functional impairment associated with PAD are needed. A clear understanding of the role of mitochondria in the pathophysiology of PAD may contribute to the development of novel therapeutic interventions.

Surgeons increasingly encounter patients on clopidogrel therapy who are preparing to undergo surgery. The goal of this study was to examine the change in platelet function after the common clinical scenario of discontinuing chronic clopidogrel therapy in those patients preparing to undergo an elective surgery, and the time course of platelet function recovery after clopidogrel discontinuation. Patients on clopidogrel therapy scheduled for an elective surgical procedure had their platelet function tested using a VerifyNow P2Y12 device (Accumetrics, San Diego, CA). Platelet inhibition was evaluated at baseline before clopidogrel discontinuation, and subsequently studied every other day in the week before their scheduled procedure. Mean platelet inhibition was 32.1 per cent on Day 0 (before clopidogrel discontinuation), decreasing to 3.7 per cent on Day 4. Platelet inhibition decreased significantly after discontinuation of clopidogrel in a time-dependent manner (P = 0.011), although a considerable interindividual variability of P2Y12 reaction units values was observed over the study period. Patients on concomitant proton pump inhibitors and clopidogrel demonstrated a decreased effect of clopidogrel. In conclusion, individual platelet function monitoring may assist the surgeon in perioperative decision-making in patients receiving clopidogrel therapy preparing to undergo elective surgery.

Adult paratesticular rhabdomyosarcoma (PRMS) with invasion of the retroperitoneum and involvement of the infrarenal aorta and inferior vena cava (IVC) is rare. We describe a 23-year-old male diagnosed with PRMS in 2008, previously treated with right orchiectomy, chemotherapy, and radiation, who presented with new onset of lower back pain. Computed tomography (CT) scan revealed a 4.8 × 4.2 cm mass involving both the infrarenal aorta and the IVC. We resected the tumor en bloc with in situ reconstruction of the aorta utilizing a Dacron graft and the IVC with a bovine pericardium roll graft. His postoperative period was uneventful, and he was discharged on postoperative day 6 in stable condition. At 2-month follow-up, the patient recovered well from the surgery, patent grafts on CT scan with no clinical signs of lower extremity ischemia or edema, and he continues to receive cycles of chemotherapy.

Background: Exhaustion of upper extremity dialysis access options is becoming more prevalent due to the longer survival of this patient population. In addition, central venous occlusive disease (CVOD) increases the risk of losing access viability in the ipsilateral extremity., Purpose: We describe a novel technique of lower extremity arteriovenous graft (AVG) placement in which the external iliac artery and vein are utilized, as illustrated in 2 selected cases., Methods: Two dialysis patients presented with exhausted upper extremity access options and bilateral intrathoracic CVOD. In patient 1, a venogram demonstrated complete occlusion of the left common iliac vein and severe stenosis of the right common femoral vein, rendering these unsuitable for access creation. In patient 2, with a history of peripheral arterial disease, an arteriogram revealed that the common and superficial femoral arteries were inadequate for access creation bilaterally. A retroperitoneal approach was utilized for a right external iliac artery and vein arteriovenous graft tunneled under the inguinal ligament to the anterior thigh., Results: Adequate thrill and uneventful postoperative course were observed in both cases. At 10 months, patient 1 has done well on hemodialysis without the need for further intervention. Patient 2 has only recently had the procedure and is not yet using her graft., Conclusions: As the number of patients requiring lower extremity vascular access increases, new surgical techniques will become available to handle the clinical and anatomic challenges encountered in this population.

Objective: Hybrid thoracic endovascular aortic repair (TEVAR) has expanded the surgical management of complex thoracic aneurysms. Aortic arch debranching generally requires a sternotomy. We describe our experience performing a right anterior minithoracotomy for hybrid TEVAR., Method: During a 3-year period, 7 patients (aged 76 ± 15 years; 57% were male) with aortic arch aneurysms underwent hybrid TEVAR via a right anterior minithoracotomy. Of all with prior thoracic or abdominal aortic surgery, 4 had a prior sternotomy. All patients included in this series had an American Society of Anesthesiology score of 4 or greater., Results: Repairs were performed via a 5-cm incision at the third to fourth intercostal space to access the ascending arch. A Satinsky clamp on the ascending aorta facilitated bypass with the 10-mm arm of a bifurcated 10/12-mm graft to the innominate artery or right common carotid artery (12-mm arm: endoprosthesis conduit). The remaining arch vessels were bypassed as needed; subsequently, a thoracic stent graft was deployed by the 12- or 14-mm arm. Primary technical success was 86% (6 patients); 1 patient required conversion to sternotomy secondary to bleeding. Complications included cerebrovascular accident in 2 patients (28%) and respiratory failure in 2 patients (28%). The average length of stay was 12 days with no wound infection. One death occurred during the 30-day period., Conclusions: Right anterior minithoracotomy is a compelling, less invasive technique for hybrid TEVAR. Further experience will be necessary to completely evaluate the merits of this approach., (Copyright © 2011. Published by Mosby, Inc.)

Patients undergoing hemodialysis are known to develop central venous occlusion and exhaust all options for vascular access to upper extremity sites; therefore, creating and maintaining vascular access is paramount in such patients. The present case report describes the condition of a 34-year-old woman with failed upper extremity access, frequent catheter-related issues, and multiple central venous occlusions. As a last resort, access to the lower extremity was pursued as follows: an inferior vena cava bypass was combined with a right femoral transposition fistula and a distal revascularization interval ligation procedure. This complex procedure that was carried out for the purpose of vascular access is a unique, albeit aggressive, surgical solution that resulted in autologous vascular access with a 6-month patency and also served to improve the quality of life in the seemingly hopeless case., (Copyright © 2011. Published by Elsevier Inc.)

Background: Creation and preservation of dialysis access in patients with central venous occlusive disease (CVOD) is a complex problem. The surgical approach and decision-making process remains poorly defined. We evaluated our experience in the surgical management of hemodialysis-related CVOD. Surgical technique, demographics, complications, reinterventions, access function rates, and factors influencing morbidity and mortality were examined., Methods: From January 2006 to May 2010, we performed a total of 1,703 dialysis access-related procedures, 1,021 arteriovenous fistulas (AVFs), 335 arteriovenous grafts (AVGs), and 314 access revisions including endovascular salvage procedures. Seventeen patients (10 women [58%] with a mean age of 44 ± 27 years) with CVOD who were not suitable for peritoneal dialysis or kidney transplant underwent 20 complex vascular access procedures. The indications were need for access creation in 14 cases (70%) and preservation in the remaining 6 (30%). Polytetrafluoroethylene (PTFE) was used for all surgical bypass grafts (BPG). All patients had previously undergone multiple access surgeries and had failed percutaneous interventions for CVOD., Results: The surgical planning centered on finding venous outflow for an arteriovenous (AV) access; central venous reconstructions were necessary in 10 (50%) cases (seven [35%] in the thoracic central venous system and three [15%] in infradiaphragmatic vessels) and extracavitary venous BPG in two (10%) cases. Non-venous access options included axillary arterial-arterial chest wall BPG in five (25%) cases and brachial artery to right atrium BPG in three (15%). Technical success was achieved in all cases (100%). Mean follow-up was 14.1 months, both BPG and AV access patency rates were 66% at 6 months and overall average AV access function time was 9.2 months. Of these, 85% of patients were discharged home and following 19 (95%) cases they returned or improved their baseline functional status. One death occurred from multiorgan failure during the 30-day postoperative period. Four additional patients died within 3 years of the procedure secondary to nonsurgical-related comorbidities., Conclusion: The need for complex vascular accesses will continue as the number of patients with end-stage renal disease increases. CVOD is an access surgical challenge and with this article we propose a decision-making algorithm., (Copyright © 2011 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: To report robot-assisted stenting of a stenosis at the pulmonary artery anastomosis following lung transplantation, a rare complication that conveys poor prognosis even after surgical correction., Technique: The technique is illustrated in a 72-year-old man with end-stage lung disease who received a left single lung transplant. On postoperative day 54, he was evaluated for recurrent dyspnea on exertion that was due to a severe stenosis at the site of the pulmonary artery anastomosis. Balloon angioplasty was performed, and a 10-mm stent was deployed, with marked clinical improvement. Fourteen months later, he presented with recurrent symptoms due to in-stent restenosis. Multiple attempts at catheterization and balloon angioplasty of the stent failed. Due to the technical difficulty involved in maneuvering the balloon while maintaining stability, it was decided to repeat the angioplasty with the assistance of a Hansen Sensei remote robotic navigation system. The robotic arm markedly enhanced stability and facilitated successful navigation of the stented site. A 16-mm-diameter Wallstent was placed through the previously placed balloon-expandable stent and postdilated., Conclusion: A remote robotic catheter navigation system was able to assist stenting of an anastomotic pulmonary artery stenosis following failure of conventional interventional techniques.

Objective: To examine contemporary operative techniques and outcomes for repair of isolated iliac artery aneurysms., Methods: We retrospectively reviewed the charts of all patients who underwent repair of an isolated iliac artery aneurysm from February 1995 to June 2007. Mycotic aneurysms and patients with concurrent infrarenal abdominal aortic aneurysms greater than 3.5 cm in diameter were excluded from analysis. Patients with prior abdominal aortic aneurysm repair were not excluded., Results: Fifty-six patients (96% male; mean age, 72 +/- 10 years) had either open (n = 24) or endovascular (n = 32) repair with median follow-up of 36 months. Seven patients were treated for rupture, six with open repair, and one with an endograft. Average aneurysm size for patients in the open and endovascular repair cohorts was 4.5 +/- 2.4 cm and 4.0 +/- 1.1 cm, respectively (P = .35). One episode of endograft limb thrombosis at five months was treated with catheter-directed thrombolytic therapy and stent placement. Thirty-day mortality for patients undergoing elective and emergent open repair was 1/18 (6%) and 1/6 (17%), respectively. There was no 30-day mortality for the endovascular group. Median length of stay was 10.5 days in the open group and one day in the endovascular elective group (P < .01). There was no mid-term aneurysm-related mortality in either group. Primary patency rates were similar between the open and endovascular groups at five years (100% vs. 96%, P = .07). Aneurysm sac diameter decreased in 67% (21/28) of patients that underwent endovascular repair. One patient with a Type III endoleak required relining of the endograft with a second endograft at 72 months., Conclusion: These data demonstrate that in appropriately selected patients, endovascular repair of isolated iliac artery aneurysms is a safe, effective alternative to open repair with mid-term follow-up. Endovascular repair is associated with a significantly reduced hospital length of stay and may be associated with decreased need for transfusion and mortality when compared with open repair.

Background: Apoptosis is important for normal cerebral cortical development. We previously showed that the Fas suicide receptor was expressed within the developing cerebral cortex, and that in vitro Fas activation resulted in caspase-dependent death. Alterations in cell-surface Fas expression may significantly influence cortical development. Therefore, in the following studies, we sought to identify developmentally relevant cell biological processes that regulate cell-surface Fas expression and reciprocal consequences of Fas receptor activation., Results: Flow-cytometric analyses identified two distinct neural sub-populations that expressed Fas on their cell surface at high (FasHi) or moderate (FasMod) levels. The anti-apoptotic protein FLIP further delineated a subset of Fas-expressing cells with potential apoptosis-resistance. FasMod precursors were mainly in G0, while FasHi precursors were largely apoptotic. However, birth-date analysis indicated that neuroblasts express the highest levels of cell-surface Fas at the end of S-phase, or after their final round of mitosis, suggesting that Fas expression is induced at cell cycle checkpoints or during interkinetic nuclear movements. FasHi expression was associated with loss of cell-matrix adhesion and anoikis. Activation of the transcription factor p53 was associated with induction of Fas expression, while the gonadal hormone estrogen antagonistically suppressed cell-surface Fas expression. Estrogen also induced entry into S-phase and decreased the number of Fas-expressing neuroblasts that were apoptotic. Concurrent exposure to estrogen and to soluble Fas-ligand (sFasL) suppressed p21/waf-1 and PCNA. In contrast, estrogen and sFasL, individually and together, induced cyclin-A expression, suggesting activation of compensatory survival mechanisms., Conclusions: Embryonic cortical neuronal precursors are intrinsically heterogeneous with respect to Fas suicide-sensitivity. Competing intrinsic (p53, cell cycle, FLIP expression), proximal (extra-cellular matrix) and extrinsic factors (gonadal hormones) collectively regulate Fas suicide-sensitivity either during neurogenesis, or possibly during neuronal migration, and may ultimately determine which neuroblasts successfully contribute neurons to the differentiating cortical plate.

This 7-year-old boy presented with a 2-week history of headache, nausea, vomiting, anorexia, lethargy, and unsteadiness of gait. Brain magnetic resonance imaging (MRI) revealed a cystic mass within the vermis of the cerebellum. A suboccipital craniectomy was performed to remove a tumor that contained primitive neuroectodermal cells with florid skeletal muscle differentiation. Immunohistochemical studies and electron microscopy confirmed the presence of both a primitive neuroectodermal component and rhabdomyoblastic differentiation, consistent with the diagnosis of medullomyoblastoma. This exceedingly rare tumor of the cerebellar vermis of children is characterized by two components: primitive neuroectodermal tumor cells and skeletal muscle. Although the histogenesis remains uncertain, advances in immunohistochemistry and electron microscopy suggest the origin of this tumor from a multipotential stem cell precursor.

Introduction: Animal studies modeling fetal alcohol syndrome have demonstrated that developmental exposure to alcohol is associated with decreased brain weight and significant neuronal loss in multiple regions of the developing brain. Our previous data suggest that the Fas/Apo [apoptosis]-1 receptor is transiently expressed in the developing cerebral cortex during the peak period of naturally occurring apoptotic cell death and maximum sensitivity to alcohol. Therefore, we hypothesized that ethanol increases the expression of suicide receptors such as Fas/Apo-1 in the developing fetal cerebral cortex and leads to an upregulation or extension of the normal period of apoptosis and consequent disorganization of the neural circuitry., Methods: Ethanol was administered in one of four doses (120, 320, 630, and 950 mg/dl) to organotypic explant cultures of the developing cerebral cortex established from postnatal day 2 rats and maintained for 6 days in vitro. The number of cells expressing Fas/Apo-1 receptor mRNA was counted. Apoptosis was measured by the use of two independent assays; a cell death enzyme-linked immunosorbent assay for DNA fragmentation and flow cytometric analysis of Annexin-V binding to phosphatidylserine externalized to the outer leaflet of the plasma membrane. Necrosis was also estimated by two independent measures, the amount of lactate dehydrogenase released into culture medium and flow cytometric analysis of cells that were positive for both Annexin-V and propidium iodide., Results: A significantly larger number of developing cortical cells expressed Fas/Apo-1 mRNA at the lower doses (120 and 320 mg/dl) than at the higher doses (630 and 950 mg/dl). Furthermore, ethanol induced apoptosis in a dose-related manner, with peak apoptosis observed at a dose of 630 mg/dl in the case of DNA fragmentation and at 630 and 950 mg/dl in the case of phosphatidylserine translocation to the outer leaflet of the plasma membrane. Ethanol did not induce necrosis at any of the administered doses of ethanol., Conclusions: Our data suggest that ethanol induces a susceptibility to apoptotic signals at low doses by upregulating the expression of mRNAs for cytotoxic receptors such as Fas/Apo-1 in the developing cerebral cortex. However, ethanol itself specifically induces apoptosis in the developing cerebral cortex only at higher doses.

The developing cerebral cortex undergoes a period of substantial cell death. The present studies examine the role of the suicide receptor Fas/Apo[apoptosis]-1 in cerebral cortical development. Fas mRNA and protein are transiently expressed in subsets of cells within the developing rat cerebral cortex during the peak period of apoptosis. Fas-immunoreactive cells were localized in close proximity to Fas ligand (FasL)-expressing cells. The Fas-associated signaling protein receptor interacting protein (RIP) was expressed by some Fas-expressing cells, whereas Fas-associated death domain (FADD) was undetectable in the early postnatal cerebral cortex. FLICE-inhibitory protein (FLIP), an inhibitor of Fas activation, was also expressed in the postnatal cerebral cortex. Fas expression was more ubiquitous in embryonic cortical neuroblasts in dissociated culture compared to in situ within the developing brain, suggesting that the environmental milieu partly suppresses Fas expression at this developmental stage. Furthermore, FADD, RIP, and FLIP were also expressed by subsets of dissociated cortical neuroblasts in culture. Fas activation by ligand (FasL) or anti-Fas antibody induced caspase-dependent cell death in primary embryonic cortical neuroblast cultures. The activation of Fas was also accompanied by a rapid downregulation of Fas receptor expression, non-cell cycle-related incorporation of nucleic acids and nuclear translocation of the RelA/p65 subunit of the transcription factor NF-kappaB. Together, these data suggest that adult cortical cell number may be established, in part, by an active process of receptor-mediated cell suicide, initiated in situ by killer (FasL-expressing) cells and that Fas may have functions in addition to suicide in the developing brain.