Impact of routine surveillance duplex ultrasound and subsequent reintervention after superficial femoral artery stenting.

OBJECTIVE: Superficial femoral artery (SFA) stenting is a common treatment for peripheral artery disease. It is effective in the short term; however, in-stent restenosis (ISR) limits long-term success. Surveillance with duplex ultrasound (DUS) can identify patients who develop ISR leading to early reintervention, but data to support this practice is sparce. The purpose of this study was to evaluate whether surveillance and subsequent reintervention improves outcomes in patients with SFA stents. METHODS: A single-center, retrospective study was performed with patients undergoing SFA stenting between 2005 and 2020 who had a follow-up with DUS. Five groups were identified based on the presence of ISR on DUS (ISR vs no ISR [NISR]), recurrence of symptoms (symptomatic [SX] vs asymptomatic [ASX]), and if any reintervention was performed (reintervention [R] vs no reintervention [NR]): (1) ISR+SX+R; (2) ISR+SX+NR; (3) ISR+ASX+R; (4) ISR+ASX+NR; and (5) NISR+NR. The primary endpoint was amputation-free survival, and the secondary endpoint was patency. Predictors of mortality and surveillance were identified by multivariable logistic regressions and Cox multivariate regression models. Survival curves were presented as Kaplan-Meier plots using log-rank test for subgroup comparison. RESULTS: Two hundred fifty-seven patients were included in the analysis. The indication for intervention was claudication in 28% and chronic limb-threatening ischemia in 72%. A total of 161 patients (63%) underwent reintervention for ISR. Of patients who had restenosis on DUS, those who were symptomatic and did not undergo reintervention (ISR+SX+NR) did the worst, with 50% amputation rate. In contrast, those who were asymptomatic but did undergo reintervention (ISR+ASX+R) had the lowest amputation rate of 13%. Active smoking was a predictor of both loss of patency and amputation (1.72; 95% confidence interval [CI], 1.00-2.98; P = .050; 3.55; 95% CI, 1.53-8.25; P = .003). Post procedure dual antiplatelet therapy had a positive association with limb salvage (hazard ratio [HR], 0.23; 95% CI, 0.09-0.58; P = .001), whereas diabetes (HR, 2.61; 95% CI, 1.21-6.01; P = .019), stent occlusion (HR, 17.0; 95% CI, 5.93-63.1; P < .001), and chronic limb-threatening ischemia presentations (HR, 4.31; 95% CI, 1.86-11.7; P=.002) were negatively associated with limb salvage. CONCLUSIONS: Routine surveillance DUS and subsequent reintervention on ISR after SFA stenting is associated with improved patency and amputation-free survival. Surveillance DUS should be routine for patients after stenting, with reintervention strongly considered if ISR is identified for both symptomatic and asymptomatic.

Long-term outcomes of staged iliofemoral endoconduits prior to complex endovascular aortic aneurysm repair.

OBJECTIVE: Adverse iliofemoral anatomy may preclude complex endovascular aortic aneurysm repair (EVAR). In our practice, staged iliofemoral endoconduits (ECs) are planned prior to complex EVAR to improve vascular access and decrease operative time while allowing the stented vessel to heal. This study describes the long-term results of iliofemoral ECs prior to complex EVAR. METHODS: Between 2012 and 2023, 59 patients (44% male; median age, 75 ± 6 years) underwent ECs before complex EVAR using self-expanding covered stents (Viabahn). For common femoral artery (CFA) disease, ECs were delivered percutaneously from contralateral femoral access and extended into the CFA to preserve the future access site for stent graft delivery. Internal iliac artery patency was maintained when feasible. During complex EVAR, the EC extended into the CFA was directly accessed and sequentially dilated until it could accommodate the endograft. Technical success was defined as successful access, closure, and delivery of the endograft during complex EVAR. Endpoints were vascular injury or EC disruption, secondary interventions, and EC patency. RESULTS: Unilateral EC was performed in 45 patients (76%). ECs were extended into the CFA in 21 patients (35%). Median diameters of the native common iliac, external iliac, and CFA were 7 mm (interquartile range [IQR], 6-8 mm), 6 mm (IQR, 5-7 mm), and 6 mm (IQR, 6-7 mm), respectively. Internal iliac artery was inadvertently excluded in 10 patients (17%). Six patients (10%) had an intraoperative vascular injury during the EC procedure, and six patients (10%) had EC disruption during complex EVAR, including five EC collapses requiring re-stenting and one EC fracture requiring open cut-down and reconstruction with patch angioplasty. In 23 patients (39%), 22 Fr OD devices were used; 20 Fr were used in 22 patients (37%), and 18 Fr in 14 patients (24%). Technical success for accessing EC was 89%. There was no difference in major adverse events at 30 days between the iliac ECs and iliofemoral ECs. Primary patency by Kaplan-Meier estimates at 1, 3, and 5 years were 97.5%, 89%, and 82%, respectively. There was no difference in primary patency between iliac and iliofemoral ECs. Six secondary interventions (10%) were required. The mean follow-up was 34 ± 27 months; no limb loss or amputations occurred during the follow-up. CONCLUSIONS: ECs improve vascular access, and their use prior to complex EVAR is associated with low rates of vascular injury, high technical success, and optimal long-term patency. Complex EVAR procedures can be performed percutaneously by accessing the EC directly under ultrasound guidance and using sequential dilation to avoid EC disruption.

Early Experience with Patient-Specific Unibody Bifurcated Fenestrated-Branched Devices for Complex Endovascular Aortic Aneurysm Repair.

OBJECTIVE: Short distances between the lowest visceral/renal artery and the aortic bifurcation are technically challenging during complex endovascular aortic aneurysm repair (EVAR), particularly after previous infrarenal repair. Traditionally, inverted limb bifurcated devices have been used in addition to fenestrated-branched (FB) endografts, but short overlap, difficult cannulation, and potential crushing of bridging stents are limitations for their use. This study reviews the early experience of patient-specific company manufactured devices (PS-CMD) with a unibody bifurcated FB design for complex EVAR. METHODS: Consecutive complex EVAR procedures over a 34-month period with unibody bifurcated FB-devices as part of physician-sponsored investigational device exemption studies at two institutions were reviewed. Unibody bifurcated FB-designs included fenestrated-branched bifurcated or fenestrated inverted limb devices. Endpoints included technical success, survival, frequency of type I or III endoleaks, limb occlusion, and secondary interventions. RESULTS: Among 168 patients undergoing complex EVAR, 33 (19.6%) patients (78.7% male; mean age 77) received unibody bifurcated FB PS-CMDs. Fenestrated-branched bifurcated and fenestrated inverted limb devices were used in 31 (93.9%) and 2 (6.06%) patients, respectively. Median maximum aneurysm diameter was 61 mm (interquartile range [IQR] 55-69). Prior EVAR was reported by 29 (87.9 %) patients, of which 2 (6.06%) had suprarenal stents. A short distance between the lowest renal artery and aortic bifurcation was demonstrated in 30 (90.9%) patients, with median distance of 47 mm (IQR 38-54). Preloaded devices were used in 23 patients (69.7%). A total of 128 fenestrations were planned; 22 (17.2%) were preloaded with guidewires, and 5 (3.9%) with catheters. The median operative time was 238 min (226-300), with a median fluoroscopy time of 65.5 min (IQR 56.0-77.7) and a median dose area product of 147 mGy*cm2 (IQR 105-194). Exclusive femoral access was used in 14 (42.4%) procedures. Technical success was 100%. Target vessel primary patency was 100% at median follow-up time of 11.7 months (IQR 3.5-18.6). Two (6.06%) patients required reintervention for iliac occlusion; one patient required stenting and the other a femoral-femoral bypass. No aortic-related deaths occurred after the procedure. During follow-up, 11 (33.3 %) type II endoleaks and one (3.03%) type Ib endoleak were detected; the latter was treated with leg extension. No type Ia or III endoleaks occurred. CONCLUSION: Complex EVAR using unibody bifurcated FB-PS-CMDs is a simple, safe, and cost-effective alternative for the treatment of patients with short distances between the renal arteries and the aortic bifurcation. Further studies are required to assess benefits and durability of unibody bifurcated FB-devices.

Outcomes of Elective and Non-elective Fenestrated-branched Endovascular Aortic Repair for Treatment of Thoracoabdominal Aortic Aneurysms.

OBJECTIVE: To describe outcomes after elective and non-elective fenestrated-branched endovascular aortic repair (FB-EVAR) for thoracoabdominal aortic aneurysms (TAAAs). BACKGROUND: FB-EVAR has been increasingly utilized to treat TAAAs; however, outcomes after non-elective versus elective repair are not well described. METHODS: Clinical data of consecutive patients undergoing FB-EVAR for TAAAs at 24 centers (2006-2021) were reviewed. Endpoints including early mortality and major adverse events (MAEs), all-cause mortality, and aortic-related mortality (ARM), were analyzed and compared in patients who had non-elective versus elective repair. RESULTS: A total of 2603 patients (69% males; mean age 72±10 year old) underwent FB-EVAR for TAAAs. Elective repair was performed in 2187 patients (84%) and non-elective repair in 416 patients [16%; 268 (64%) symptomatic, 148 (36%) ruptured]. Non-elective FB-EVAR was associated with higher early mortality (17% vs 5%, P <0.001) and rates of MAEs (34% vs 20%, P <0.001). Median follow-up was 15 months (interquartile range, 7-37 months). Survival and cumulative incidence of ARM at 3 years were both lower for non-elective versus elective patients (50±4% vs 70±1% and 21±3% vs 7±1%, P <0.001). On multivariable analysis, non-elective repair was associated with increased risk of all-cause mortality (hazard ratio, 1.92; 95% CI] 1.50-2.44; P <0.001) and ARM (hazard ratio, 2.43; 95% CI, 1.63-3.62; P <0.001). CONCLUSIONS: Non-elective FB-EVAR of symptomatic or ruptured TAAAs is feasible, but carries higher incidence of early MAEs and increased all-cause mortality and ARM than elective repair. Long-term follow-up is warranted to justify the treatment.

Early Results and Feasibility of Total Endovascular Aortic Arch Repair Using 3-Vessel Company-Manufactured and Physician-Modified Stent-Grafts.

OBJECTIVE: Total endovascular repair of aortic arch aneurysms is feasible in select patients. This study aims to evaluate the feasibility and early outcomes of total endovascular arch repair using 3-vessel company-manufactured devices (CMDs) and physician-modified endo grafts (PMEGs). METHODS: Patients unfit for open repair who underwent 3-vessel total arch repair at a single institution from 2018 to 2021 were reviewed. Patients received either 3-vessel inner-branch CMDs or PMEGs. Three-vessel designs were used to incorporate the innominate, left common carotid, and left subclavian arteries. The antegrade inner branches in both devices were accessed via right brachial or carotid approach. The left carotid was accessed via carotid cutdown or femoral approach. The left subclavian artery was accessed via transfemoral approach. The study endpoints included procedural technical success, patient survival, neurologic events, cardiac complications, reinterventions, and target artery patency. RESULTS: Nine patients underwent treatment. Four patients were treated with PMEGs, and 5 with CMDs. Procedural technical success was 100%. There were no in-hospital deaths. There were no strokes, transient ischemic attacks, myocardial infarction, or spinal ischemia in the perioperative period. Major adverse events occurred in 3 patients (33%). Two (22%) vascular access complications and one (11%) acute kidney injury occurred. One (11%) patient required early reintervention for an access complication. The median follow-up period was 358 days (CMD, 392 days; PMEG, 198 days). There was a late reintervention and conversion to open repair at 142 days of follow-up in a patient with a PMEG that developed an aortic infection, leading to death on postoperative day 239. The mean length of stay was 7±4 days. Computed tomography imaging obtained during the immediate postoperative period revealed endoleak in 6 (66%) patients, out of which 5 resolved spontaneously and 1 required reintervention via left subclavian artery stenting. Target artery patency was 100% at the end of the follow-up period. CONCLUSIONS: Three-vessel total endovascular aortic arch repair using a CMD or PMEG is feasible with optimal early outcomes. Physician-modified stent-grafts are a feasible option for patients who do not meet anatomic criteria for CMDs. CLINICAL IMPACT: Management of aortic arch disease remains a significant challenge in vascular surgery. This study showcases the feasibility and safety of using a total endovascular approach to repair the aortic arch, which could potentially reduce morbidity and mortality associated with traditional surgical approaches. The results suggest that this minimally invasive technique could be an alternative treatment option for high-risk patients and could significantly improve outcomes for those requiring aortic arch repair. Overall, this study represents a promising development in the field of endovascular surgery and highlights the potential to improve patient outcomes.

Redo Fenestrated-Branched Endovascular Aortic Repair (F-BEVAR) for Failed F-BEVAR.

Failed fenestrated-branched endovascular aortic repair (F-BEVAR) requiring a redo F-BEVAR is a rare event. In this study, we report 2 cases of a failed F-BEVAR secondary to a type IIIb endoleak from tears on the fabric graft successfully treated with redo F-BEVAR. This is a technically challenging procedure that requires meticulous planning, advanced imaging technologies and experienced operators. Redo F-BEVAR appears to be a feasible and safe treatment option. However, larger series and long-term follow-up are needed to confirm effectiveness and durability.

Investigating theobromine as a potential anti-human coronaviral agent.

Coronaviruses (CoVs) have long been known to infect humans, mainly alpha-CoV and beta-CoV. The vaccines developed for SARS-CoV-2 are likely not effective against other coronavirus species, whereas the risk of the emergence of new strains that may cause the next epidemic/pandemic is high. The development of antiviral drugs that are effective across different CoVs represents a viable strategy for improving pandemic preparedness. In this study, we aim to identify pan-coronaviral agents by targeting the conserved main protease (Mpro). For drug screening, the catalytic dyad of four human CoVs (HCoVs: SARS-CoV-2, and seasonal CoV NL63, OC43, and 229E) was targeted by molecular docking. The identified leading candidate theobromine, a xanthine derivative, was further tested in cell culture models of coronavirus infection. Theobromine binds strongly with the catalytic dyad (His41 and Cys144/145) of SARS-CoV-2 and HCoV-NL63 Mpro, mildly with HCoV-OC43, but not with HCoV-229E. However, theobromine only shows dose-dependent inhibition in Calu3 cells inoculated with SARS-CoV-2, but not in cells inoculated with seasonal CoVs. Theobromine exerts antiviral activity against coronavirus infections potentially through targeting Mpro. However, the antiviral potency is distinct among different CoVs.

Evaluation of interleukin-33 & sST2 levels in type-2 diabetic mellitus patients with or without metabolic syndrome.

Background & objectives: Diabetes mellitus (DM) is characterized by increase in blood glucose levels due to defective insulin secretion or insulin sensitivity. Interleukins (ILs) are known to play an important role in the pathogenesis of DM. The aim of this study was to investigate the serum concentration of IL-33 and its receptor soluble ST2 (sST2) in patients with diabetes and draw a correlation between their serum levels and different standard glycaemic indices of patients affected with type-2 diabetes with or without metabolic syndrome. Methods: Thirty type-2 diabetic individuals and 30 healthy controls were recruited for this study. Serum and plasma were separated by centrifugation of blood for quantitative measurement of IL-33, sST2 and other biochemical parameters. Results: It was observed that serum IL-33 levels were significantly less and sST2 levels were significantly high in type-2 diabetic individuals as compared to healthy controls. A significant correlation between the serum IL-33 concentration and fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels were also found. Additionally, data also elucidated that serum levels of high-density lipoprotein, low-density lipoprotein or triglyceride in type-2 diabetics did not influence the serum levels of IL-33 and sST2, thereby excluding these factors as the major drivers of changes in serum IL-33 and sST2 concentration. Interpretation & conclusions: This study demonstrated alteration in serum levels of IL-33 and sST2 in type-2 diabetic individuals. Further mechanistic studies, focusing on the progression of type-2 diabetes could elucidate the involvement of IL-33 in the cellular acquisition of insulin resistance as observed in type-2 diabetics.

Perioperative neurologic outcomes of right versus left upper extremity access for fenestrated-branched endovascular aortic aneurysm repair.

OBJECTIVE: Upper extremity (UE) access is frequently used for fenestrated-branched endovascular aortic aneurysm repair (F-BEVAR), particularly for complex repairs. Traditionally, left-side UE access has been used to avoid crossing the arch and the origin of the supra-aortic vessels, which could potentially result in cerebral embolization and an increased risk of perioperative cerebrovascular events. More recently, right UE has been more frequently used as it is more convenient and ergonomic. The purpose of this study was to assess the outcomes and cerebrovascular events after F-BEVAR with the use of right- vs left-side UE access. METHODS: During an 8-year period, 453 patients (71% male) underwent F-BEVAR at a single institution. UE access was used in more complex repairs. Left UE access was favored in the past, whereas right UE access is currently the preferred UE access side. Brachial artery cutdown was used in all patients for the placement of a 12F sheath. Outcomes were compared between patients undergoing right vs left UE access. End points included cerebrovascular events, perioperative mortality, technical success, and local access-related complications. RESULTS: UE access was used in 361 (80%) patients. The right side was used in 232 (64%) and the left side in 129 (36%) patients for the treatment of 88 (25%) juxtarenal, 135 (38%) suprarenal, and 137 (38%) thoracoabdominal aortic aneurysms. Most procedures were elective (94%). Technical success was achieved in 354 patients (98%). In-patient or 30-day mortality was 3.3%. Five (1%) perioperative strokes occurred in patients undergoing right UE access, of which three were ischemic and two were hemorrhagic. No transient ischemic attacks occurred perioperatively. Two hemorrhagic strokes were associated with permissive hypertension to prevent spinal cord ischemia. No perioperative strokes occurred in patients undergoing left UE access (P = .16). Overall, perioperative strokes occurred with similar frequency in patients undergoing UE (5, 1%) and femoral access only (1, 1%) (P = .99). Arm access-related complications occurred in 15 (5%) patients, 11 (4.8%) on the right side and 4 (6%) on the left side (P = .74). CONCLUSIONS: Right UE access can be used for F-BEVAR with low morbidity and minimal risk of perioperative ischemic stroke or transient ischemic attacks. In general, UE access is not associated with an increased risk of perioperative stroke compared with femoral access only. Tight blood pressure control is, however, critical to avoid intracranial bleeding related to uncontrolled hypertension.

Anti-lung cancer properties of cyanobacterial bioactive compounds.

Lung cancer, the most prevalent gender-independent tumor entity in both men and women, is among the leading cause of cancer-related deaths worldwide. Despite decades of effort in developing improved therapeutic strategies including immunotherapies and novel chemotherapeutic agents, only modest improvements in outcome and long-term survival of lung cancer patients have been achieved. Therefore, exploring new and exceptional sources for bioactive compounds that might serve as anti-cancer agents might be the key to improving lung cancer therapy. On account of diverse forms, cyanobacteria might serve as a potential source for compounds with potential therapeutic applicability against malignant disorders, including cancer. The assorted arrays of metabolic mechanisms synthesize a plethora of bioactive compounds with immense biological potential. These compounds have been proven to be effective against various cancer cell lines and xenograft animal models. The present review provides an overview of the most promising cyanobacteria-derived bioactive compounds proven to exhibit anti-cancer properties in in-vitro and in-vivo studies and highlights their applicability as potential therapeutic agents with a focus on their anti-lung cancer properties.

Differing pan-coronavirus antiviral potency of boceprevir and GC376 in vitro despite discordant molecular docking predictions.

Given the structural similarities of the viral enzymes of different coronaviruses (CoVs), we investigated the potency of the anti-SARS-CoV-2 agents boceprevir and GC376 for counteracting seasonal coronavirus infections. In contrast to previous findings that both boceprevir and GC376 are potent inhibitors of the main protease (Mpro) of SARS-CoV-2, we found that GC376 is much more effective than boceprevir in inhibiting SARS-CoV-2 and three seasonal CoVs (NL63, 229E, and OC43) in cell culture models. However, these results are discordant with a molecular docking analysis that suggested comparable affinity of boceprevir and GC376 for the different Mpro enzymes of the four CoVs. Collectively, our results support future development of GC376 but not boceprevir (although it is an FDA-approved antiviral medication) as a pan-coronavirus antiviral agent. Furthermore, we caution against overinterpretation of in silico data when developing antiviral therapies.

The value of re-staging chest CT at first local recurrence of extremity and trunk soft tissue sarcoma.

OBJECTIVE: To determine the prevalence of pulmonary metastases on re-staging chest CT at the time of first local recurrence (LR) of trunk or extremity soft tissue sarcoma (STS). MATERIALS AND METHODS: Retrospective review of all patients diagnosed with recurrent STS between May 2007 and April 2018. Data collected included patient age and sex, site of primary STS, time to LR, recurrence site, initial tumour grade, recurrent tumour grade, findings of initial staging chest CT, and prevalence of pulmonary metastases on re-staging chest CT. RESULTS: The study included 109 patients (males = 68, females = 41; mean age 56 years, range 9-92 years). The commonest tumour sub-types were myxofibrosarcoma (27.5%), undifferentiated pleomorphic/spindle cell sarcoma (20.2%), synovial sarcoma (10.1%), and malignant peripheral nerve sheath tumour (10.1%). Initial staging chest CT demonstrated pulmonary metastases in 1 of 77 (1.3%) patients for whom CT was available for review. The mean time to LR was 30.8 months (range 3-224 months). Pulmonary metastases were diagnosed on re-staging chest CT in 26 of 109 cases (23.9%), being commonest with grade 3 STS (36.1%). Pleomorphic sarcoma (85.7%) and undifferentiated spindle cell sarcoma (33.3%) were the 2 commonest tumour sub-types associated with pulmonary metastases at first LR. CONCLUSION: Re-staging chest CT at the time of first LR of STS identified a prevalence of 23.9% pulmonary metastases, which supports the need for chest CT at the time of LR in line with the UK guidelines for the management of bone and soft tissue sarcoma. KEY POINTS: • Pulmonary metastases were diagnosed in 1.3% of soft tissue sarcomas at presentation. • Pulmonary metastases were identified in ~ 24% of patients at first local recurrence of soft tissue sarcoma, most commonly with pleomorphic sarcoma and Trojani grade tumours. • No patient with a low-grade recurrence had pulmonary metastases.

NOS1-mediated macrophage and endothelial cell interaction in the progression of atherosclerosis.

Atherosclerosis is a chronic inflammatory disease arising due to an imbalance in lipid metabolism and maladaptive immune response driven by the accumulation of cholesterol-laden macrophages in the artery wall. Interactions between monocytes/macrophages and endothelial cells play an essential role in the pathogenesis of atherosclerosis. In our current study, nitric oxide synthase 1 (NOS1)-derived nitric oxide (NO) has been identified as a regulator of macrophage and endothelial cell interaction. Oxidized LDL (OxLDL) activates NOS1, which results in the expression of CD40 ligand in macrophages. OxLDL-stimulated macrophages produce some soluble factors which increase the CD40 receptor expression in endothelial cells. This increases the interaction between the macrophages and endothelial cells, which leads to an increase in the inflammatory response. Inhibition of NOS1-derived NO might serve as an effective strategy to reduce foam cell formation and limit the extent of atherosclerotic plaque expansion.

Natural compounds as antiatherogenic agents.

Atherosclerosis (AS) is a widespread pathological coronary heart disease (CHD), which, along with other cardiovascular diseases (CVDs), is the primary cause of global mortality. It is initiated by the accumulation of cholesterol-laden macrophages in the artery wall, thereby forming the foam-cells, the hallmark of AS. Increased influx of oxidized LDL and decreased efflux of free cholesterol from macrophages constitute major factors that mediate the progression of AS. Natural compounds treatment and prevention of AS being an effective approach for a long time. Currently, as interests in medicinally important natural products increased that including medicinal herbs, numerous studies on natural compounds effective forAS have been reported. In the current review, we shed light on the available plant-based natural compounds as AS modulators with underlying mechanisms that may lead to potential therapeutic implications.

Selective Versus Routine Spinal Drain Use for Fenestrated/Branched Endovascular Aortic Repair (F-BEVAR).

BACKGROUND: Spinal drains are used to ameliorate spinal cord ischemia (SCI), but their use may result in inherent morbidity and mortality. Although prophylactic spinal drain has proven of benefit in open repairs, that is not the case for endovascular repairs. The aim of this study was to assess the outcomes of spinal cord protection with and without the routine use of spinal drains during fenestrated-branched endovascular repair (F-BEVAR). METHODS: A retrospective single center study was performed using a prospectively maintained dataset of all patients undergoing F-BEVAR over a 4-year period. The primary endpoint of the study was the frequency of SCI. Prophylactic spinal drain was placed pre-operatively in 33 patients (23%) with a median time for removal of 3 days (IQR, 2-3 days). Routine intraoperative neuromonitoring was used. Spinal cord protection relied primarily on maintaining a perioperative systolic blood pressure between 140 and 160 mm Hg or a mean arterial pressure >90 mm Hg, avoiding hypotension, preservation of as many collateral beds as possible, staged repairs and early lower extremity reperfusion based on neuromonitoring. RESULTS: A total of 145 patients, 104 men (71%) and 41 women (28%) with a median age of 70 years (interquartile range [IQR], 53-62) underwent F-BEVAR. Branched custom-made devices (CMDs) (11%), fenestrated CMDs (70%) and off-the-shelf T-Branch device (17%) were used with a median number of branches/fenestrations of 4 (IQR, 3-4). SVS classification of implantation zones were determined as follows: 9 (6%) zone 2, 21 (20%) zone 3, 26 (18%) zone 4 and 89 (61%) zone 5. SCI was present in 8 patients (5.5%) and classified according to the SVS SCI grading system as follows: 1 grade 1, 5 grade 2 and 2 grade 3a. When evaluating implantation zone independently of coverage length and patency of collateral beds, a high implantation zone (1-4) was not associated with SCI (P = 0.9). Similarly, prophylactic spinal drain did not demonstrate association with the occurrence of SCI (3[9%] vs. 5[4%], with and without spinal drain, respectively) (P = 0.3). For patients with high implantation zones, staged repair was performed in 38 patients (26%) at a median time of 2 months (IQR, 2-6 months). Among these patients, the frequency of SCI was 13%. Staged repair was associated with an 80% reduction in the frequency of SCI (OR, 0.19 [95% CI, 0.04-0.084]) (P = 0.02). CONCLUSION: F-BEVAR can be performed with a minimal risk of SCI without the need for routine prophylactic spinal drains. High implantation zones did not predict SCI after F-BEVAR; however, staged repair significantly decreased the risk of SCI after F-BEVAR.

Mitochondrial Lipid Homeostasis at the Crossroads of Liver and Heart Diseases.

The prevalence of NAFLD (non-alcoholic fatty liver disease) is a rapidly increasing problem, affecting a huge population around the globe. However, CVDs (cardiovascular diseases) are the most common cause of mortality in NAFLD patients. Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense LDL (low-density lipoprotein) particles, and decreased HDL-C (high-density lipoprotein cholesterol) levels, is often observed in NAFLD patients. In this review, we summarize recent genetic evidence, proving the diverse nature of metabolic pathways involved in NAFLD pathogenesis. Analysis of available genetic data suggests that the altered operation of fatty-acid ß-oxidation in liver mitochondria is the key process, connecting NAFLD-mediated dyslipidemia and elevated CVD risk. In addition, we discuss several NAFLD-associated genes with documented anti-atherosclerotic or cardioprotective effects, and current pharmaceutical strategies focused on both NAFLD treatment and reduction of CVD risk.

The Role of Mitochondrial Mutations and Chronic Inflammation in Diabetes.

Diabetes mellitus and related disorders significantly contribute to morbidity and mortality worldwide. Despite the advances in the current therapeutic methods, further development of anti-diabetic therapies is necessary. Mitochondrial dysfunction is known to be implicated in diabetes development. Moreover, specific types of mitochondrial diabetes have been discovered, such as MIDD (maternally inherited diabetes and deafness) and DAD (diabetes and Deafness). Hereditary mitochondrial disorders are caused by certain mutations in the mitochondrial DNA (mtDNA), which encodes for a substantial part of mitochondrial proteins and mitochondrial tRNA necessary for mitochondrial protein synthesis. Study of mtDNA mutations is challenging because the pathogenic phenotype associated with such mutations depends on the level of its heteroplasmy (proportion of mtDNA copies carrying the mutation) and can be tissue-specific. Nevertheless, modern sequencing methods have allowed describing and characterizing a number of mtDNA mutations associated with human disorders, and the list is constantly growing. In this review, we provide a list of mtDNA mutations associated with diabetes and related disorders and discuss the mechanisms of their involvement in the pathology development.

Mitochondrial Mutations and Genetic Factors Determining NAFLD Risk.

NAFLD (non-alcoholic fatty liver disease) is a widespread liver disease that is often linked with other life-threatening ailments (metabolic syndrome, insulin resistance, diabetes, cardiovascular disease, atherosclerosis, obesity, and others) and canprogress to more severe forms, such as NASH (non-alcoholic steatohepatitis), cirrhosis, and HCC (hepatocellular carcinoma). In this review, we summarized and analyzed data about single nucleotide polymorphism sites, identified in genes related to NAFLD development and progression. Additionally, the causative role of mitochondrial mutations and mitophagy malfunctions in NAFLD is discussed. The role of mitochondria-related metabolites of the urea cycle as a new non-invasive NAFLD biomarker is discussed. While mitochondria DNA mutations and SNPs (single nucleotide polymorphisms) canbe used as effective diagnostic markers and target for treatments, age and ethnic specificity should be taken into account.

Inhibition of mitochondria ATP synthase suppresses prostate cancer growth through reduced insulin-like growth factor-1 secretion by prostate stromal cells.

Modulation of prostate stromal cells (PrSCs) within tumor tissues is gaining attention for the treatment of solid tumors. Using our original in vitro coculture system, we previously reported that leucinostatin (LCS)-A, a peptide mycotoxin, inhibited prostate cancer DU-145 cell growth through reduction of insulin-like growth factor 1 (IGF-I) expression in PrSCs. To further obtain additional bioactive compounds from LCS-A, we designed and synthesized a series of LCS-A derivatives as compounds that target PrSCs. Among the synthesized LCS-A derivatives, LCS-7 reduced IGF-I expression in PrSCs with lower toxicity to PrSCs and mice than LCS-A. As LCS-A has been suggested to interact with mitochondrial adenosine triphosphate (ATP) synthase, a docking study was performed to elucidate the mechanism of reduced IGF-I expression in the PrSCs. As expected, LCS-A and LCS-7 directly interacted with mitochondrial ATP synthase, and like LCS-A and LCS-7, other mitochondrial ATP synthase inhibitors also reduced the expression of IGF-I by PrSCs. Furthermore, LCS-A and LCS-7 significantly decreased the growth of mouse xenograft tumors. Based on these data, we propose that the mitochondrial ATP synthases-IGF-I axis of PrSCs plays a critical role on cancer cell growth and inhibition could be a potential anticancer target for prostate cancer.

Matrix metalloproteinase-8 (MMP-8) regulates the activation of hepatic stellate cells (HSCs) through the ERK-mediated pathway.

Hepatic stellate cells (HSCs) are known to play a key role in the progression of liver fibrosis by producing excessive extracellular matrix (ECM). Matrix metalloproteinases (MMPs) belong to a family of endopeptidases, which have a well-established role in the degradation of ECM. Our study suggests that, besides the degradation of the extracellular matrix, matrix metalloproteinase-8 (MMP-8) has a non-canonical role in activating the quiescent HSCs to myofibroblasts by regulating the expression of Col1A1 and αSMA. We have identified that MMP-8 secreted from macrophages as a response to LPS stimulation activates HSCs via ERK1/2-dependent pathway. In addition to this, we determined that MMP-8 may regulate the homodimerization of c-Jun in LX-2 cells, during the trans-differentiation process from quiescent HSC to activate myofibroblasts. Macrophage-released MMP-8 plays a master role in activating the dormant HSCs to activate myofibroblasts through the Erk-mediated pathway and Jun cellular translocation leading to liver fibrosis. Significance MMP-8 can be used as a therapeutic target against liver fibrosis.