Objective: Discrete morphologic, enzymatic and functional changes in skeletal muscle mitochondria have been demonstrated in patients with peripheral arterial disease (PAD). We examined mitochondrial respiration in the gastrocnemius muscle of nine patients (10 legs) with advanced PAD and in nine control patients (nine legs) without evidence of PAD. Methods: Mitochondrial respiratory rates were determined with a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Muscle samples were obtained from the anteromedial aspect of the gastrocnemius muscle, at a level 10 cm distal to the tibial tuberosity. Mitochondria respiratory rate, calculated as nanoatoms of oxygen consumed per minute per milligram of noncollagen protein, were measured at baseline (V 0 ), after addition of substrates (malate and glutamate; (V SUB ), after addition of adenosine diphosphate (ADP) (V ADP ), and finally, after adenine nucleotide translocase inhibition with atractyloside (V AT ). The acceptor control ratio, a sensitive indicator of overall mitochondrial function, was calculated as the ratio of the respiratory rate after the addition of ADP to the respiratory rate after adenine nucleotide translocase inhibition with atractyloside (V ADP / V AT ). Results: Respiratory rate in muscle mitochondria from patients with PAD were not significantly different from control values at baseline (0.31 ؎ 0.06 vs 0.55 ؎ 0.12; P ؍ .09), but V sub was significantly lower in patients with PAD compared with control subjects (0.43 ؎ 0.07 vs 0.89 ؎ 0.20; P < .05), as was V ADP (0.69 ؎ 0.13 vs 1.24 ؎ 0.20; P < .05). Respiratory rates after atractyloside inhibition in patients with PAD were no different from those in control patients (0.47 ؎ 0.07 vs 0.45 ؎ P ؍ .08). Compared with control values, mitochondria from patients with PAD had a significantly lower acceptor control ratio (1.41 ؎ 0.10 vs 2.90 ؎ 0.20; P < .001). Conclusion: Mitochondrial respiratory activity is abnormal in lower extremity skeletal muscle in patients with PAD. When considered in concert with the ultrastructural and enzymatic abnormalities previously documented in mitochondria of chronically ischemic muscle, these data support the concept of defective mitochondrial function as a pathophysiologic component of PAD.
-Hydrogen sulfide (HS), generated by cystathionine γ lyase (CSE), is an important endogenous regulator of vascular function. The aim of the present study was to investigate the control and consequences of CSE activity in endothelial cells under physiological and pro-atherogenic conditions. -Endothelial cell CSE knock out mice were generated and lung endothelial cells were studied (gene expression, protein sulfhydration and monocyte adhesion). Mice were crossed onto the ApoE background and atherogenesis (partial carotid artery ligation) was monitored over 21 days. CSE expression, HS bioavailability and amino acid profiling were also performed using human material. -The endothelial cell-specific deletion of CSE selectively increased the expression of CD62E and elevated monocyte adherence in the absence of an inflammatory stimulus. Mechanistically, CD62E mRNA was more stable in endothelial cells from CSE-deficient mice, an effect attributed to the attenuated sulfhydration and dimerization of the RNA-binding protein HuR. CSE expression was upregulated in mice following partial carotid artery ligation as well as in atheromas from human subjects. Despite the increase in CSE protein, circulating and intra-plaque HS levels were reduced, a phenomenon that could be attributed to the serine phosphorylation (on Ser377) and inhibition of the enzyme, most likely due to increased IL-1β. Consistent with the loss of HS, HuR sulfhydration was attenuated in atherosclerosis, and resulted in the stabilization of HuR-target mRNAs e.g. CD62E and cathepsin S, both of which are linked with endothelial cell activation and atherosclerosis. The deletion of CSE from endothelial cells was associated with the accelerated development of endothelial dysfunction and atherosclerosis, effects that were reversed upon treatment with a HS donor. Finally, in mice and humans, plasma levels of the CSE substrate; L-cystathionine, negatively correlated with vascular reactivity and HS levels indicating its potential use as a biomarker for vascular disease. -The constitutive S-sulfhydration of HuR (on Cys13) by CSE-derived HS prevents its homo-dimerization and activity which attenuates the expression of target proteins such as CD62E and cathepsin S. However, as a consequence of vascular inflammation the beneficial actions of CSE-derived HS are lost due to the phosphorylation and inhibition of the enzyme.
Extraosseous Ewing sarcomas (EESs) are rare tumours originating from soft tissues. Their clinical picture depends mainly on the primary site of the sarcoma. Patient characteristics and outcomes seem to be different in EES compared to patients with skeletal Ewing sarcoma, with implications for patient care and prognosis. However, multimodality therapeutic strategies are recommended for all types of the Ewing tumour family. The available diagnostic tools include ultrasonographic evaluation and computed tomography (CT) or magnetic resonance imaging as well as histopathologic and immunohistochemical tissue examination. Several histologic and genetic biomarkers have been established, although their utilization needs to be further tested by larger prospective studies. Regarding localized disease, the recommended treatment remains surgery. However, chemotherapy can be added to achieve improved survival, with neoadjuvant regimens showing more promising results than adjuvant regimens. Radiotherapy is an option to obtain local control, although its complications have reduced its utilization. In metastatic or recurrent disease, systematic chemotherapy improves survival.
An aortoenteric fistula (AEF) is a communication between the aorta and an adjacent loop of the bowel. The three most useful diagnostic modalities for detecting AEF are abdominal computed tomography scan with intravenous contrast, esophagogastroduodenoscopy, and arteriography. The treatment of AEFs has improved in recent years, but despite the multiple surgical techniques reported, many of the patients do not survive or are left debilitated after treatment. Endovascular repair is an efficient and safe method to stabilize patients with life-threatening AEFs. The aim of this study is to provide a comprehensive and synthetic review of the latest advantages on the diagnosis and management of primary and secondary AEF.
Intrasac Doppler velocities can be used to predict whether a type II endoleak will spontaneously seal. High-velocity type II endoleaks are related to preoperative large branch vessel diameter and number and are resistant to endovascular treatment.
Fifty-five percent of patients considered for endovascular AAA repair in community hospitals in Northern California met the anatomical selection criteria for the AneuRx stent-graft. Men appeared to be twice as likely to meet the eligibility requirements as women. Unfavorable infrarenal neck anatomy was the primary exclusion criterion for endovascular repair in this community setting.
All types of investigated oxidative stress markers were significantly increased in human carotid plaques, but only ox-LDL levels were associated with clinical symptoms, while peroxynitrite products and MMP-9 were specifically related to plaque instability.
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