4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila.

Dietary restriction (DR) extends lifespan in multiple species. To examine the mechanisms of lifespan extension upon DR, we assayed genome-wide translational changes in Drosophila. A number of nuclear encoded mitochondrial genes, including those in Complex I and IV of the electron transport chain, showed increased ribosomal loading and enhanced overall activity upon DR. We found that various mitochondrial genes possessed shorter and less structured 5'UTRs, which were important for their enhanced mRNA translation. The translational repressor 4E-BP, the eukaryotic translation initiation factor 4E binding protein, was upregulated upon DR and mediated DR dependent changes in mitochondrial activity and lifespan extension. Inhibition of individual mitochondrial subunits from Complex I and IV diminished the lifespan extension obtained upon DR, reflecting the importance of enhanced mitochondrial function during DR. Our results imply that translational regulation of nuclear-encoded mitochondrial gene expression by 4E-BP plays an important role in lifespan extension upon DR. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.

Gender, racial and ethnic disparities in index hospitalization operations for symptomatic carotid stenosis in Texas hospitals.

BACKGROUND: Recent literature and societal recommendations support early revascularization of symptomatic carotid patients over the traditional six-week period. Nonetheless, the timing of these interventions can vary widely among populations. The goal of this study is to identify any factors influencing carotid revascularization during the index hospitalization for patients with symptomatic disease. METHODS: The Texas Department of State Health Services database was queried to identify all patients > 45 years old admitted to nonfederal Texas Hospitals between 2009 to 2013 with an admission diagnosis of carotid artery stenosis and either transient ischemic attack (TIA), cerebrovascular accident (CVA), or amaurosis fugax. Diagnoses codes and demographic data were also used to adjust for clinical, social, and demographic factors (including area of residence and treatment). Descriptive statistics and multivariable logistic regression were used to identify significant factors for index admission revascularization. RESULTS: A total of 29,046 symptomatic patients were identified among the 153,484 patients who had an eligible admission diagnosis. This included 16,244 (55.9%) males and 12,802 (44.1%) females. Only 4,594 (15.8%) patients were revascularized during the index hospitalization. The majority of these patients presented with amaurosis (OR 5.58; 95% CI 4.84-6.44) instead of CVAs (OR 0.48; 95% CI 0.45-0.51) or TIAs . Adjusting for hospital volume, insurance coverage, residence, and other clinical factors, rates of index admission carotid intervention remained significantly lower for women (OR 0.85; 95% CI 0.79-0.91), persons categorized as black (OR 0.60; 95% CI 0.53-0.69), and persons categorized as Hispanic (OR 0.77; 95% CI 0.70-0.86). CONCLUSIONS: Gender, race and ethnicity appear to correlate with rates of carotid intervention at index hospitalization despite thorough risk adjustment for clinical, social and demographic factors. Efforts should be directed towards reducing these disparities.

Evaluating a Novel Telescoping Catheter Set for Treatment of Central Venous Occlusions.

BACKGROUND: Central venous occlusive disease (CVOD) is a prevalent problem in patients with end-stage renal disease (ESRD) and can lead to access malfunction or ligation for symptomatic relief. The purpose of this study is to evaluate the efficacy of the TriForce® Peripheral Crossing Set (Cook Medical), a novel reinforced telescoping catheter set designed to provide additional support for crossing difficult central venous occlusions. METHODS: This is a single-center retrospective study from a quaternary referral center. We identified 37 patients over a 17-month period who underwent 56 attempts at endovascular recanalization for the treatment of central venous occlusion. Technical success rates, procedural data, and outcomes were compared between those undergoing recanalization using traditional wire/catheter sets versus the TriForce catheter set. RESULTS: Average age was 48 ± 2 years. Comorbidities were similar between the two cohorts and included ESRD (61%), deep venous thrombosis (30%), and May-Thurner syndrome (7%). Forty attempts were made with traditional wire/catheter sets and 16 attempts with the TriForce catheter set to treat 2.1 ± 0.2 and 1.9 ± 0.3 occluded venous segments, respectively (P = 0.74). Technical success rates were significantly higher for the group undergoing recanalization using the TriForce catheter (69% versus 38%, P = 0.04) and 4 patients were successfully recanalized using the TriForce catheter set after a failed attempt with traditional wire/catheter sets. Mean fluoroscopy time and radiation dose were 13 ± 3 min and 14,623 ± 2,775 µGy∗m2 for traditional techniques versus 30 ± 6 min and 30,408 ± 10,433 µGy∗m2 for the novel telescoping catheter set (P = 0.01 and 0.09, respectively). Freedom from reintervention at 1 year was 60% for the TriForce cohort versus 44% for the traditional wire/catheter cohort (P = 0.25). CONCLUSIONS: The novel TriForce reinforced telescoping catheter set is a useful adjunct that may improve recanalization rates of CVOD compared with traditional wire/catheter sets.

Short- and midterm results for internal jugular vein extension for short right renal vein kidney transplant.

Renal transplantation remains the definitive treatment for end-stage renal disease (ESRD). The shorter renal vein in right donor nephrectomies is associated with higher incidence of technical failure. We present here our experience with autologous internal jugular vein (IJV) conduits to facilitate living-donor transplants. Six patients underwent right, living-donor kidney transplant with simultaneous IJV harvest over a 1-year period. All had bilateral jugular duplex scans preoperatively and were placed on aspirin 81 mg postoperatively. Patient demographics, comorbidities, and laboratories were retrospectively queried. Postoperative follow-up and examination were performed per institutional protocol. The mean age and BMI were 51 ± 4.6 years and 30 ± 1.4 kg/m2 , respectively. An average 4.5 ± 0.5 cm of IJV was taken, and anastomosed exsitu, end to end to the renal vein. One patient developed a perinephric hematoma requiring reexploration and another expired during follow-up from septic shock of unknown etiology; there were no harvest site complications or deep vein thrombosis. All had immediate and stable graft function at 3.8 ± 1.7 (range: 0.7-11.3) months follow-up. Mean serum creatinine and estimated glomerular filtration rate were 1.3 ± 0.1 mg/dL and 55 ± 2.4 mL/min/1.73 m2 , respectively. Internal jugular vein extension of short right renal veins for kidney transplant is a viable technique for ESRD patients with promising results.

Single-center retrospective review of ultrasound-accelerated versus traditional catheter-directed thrombolysis for acute lower extremity deep venous thrombosis.

Objective Systemic anticoagulation remains the standard for acute lower extremity (LE) deep venous thrombosis (DVT), but growing interest in catheter-directed thrombolysis (CDT) and its potential to reduce the incidence of post-thrombotic syndrome (PTS) has led to advent of ultrasound-accelerated CDT (US-CDT). Few studies to date have examined the outcomes of US-CDT against traditional CDT (T-CDT). Methods This is a retrospective, single-center review of all patients treated for acute LE DVT over a five-year period with either US- and T-CDT. Patients were stratified based on demographics, presentation, co-morbidities, risk factors, and peri-procedural data. Results Seventy-six limbs in 67 patients were treated; 51 limbs in 42 patients were treated with US-CDT, and 25 limbs in 25 patients were treated with T-CDT. Adjuncts include: pharmacomechanical thrombolysis ( n = 28 vs. 20, p = 0.04), angioplasty ( n = 22 vs. 18, p = 0.11), stenting ( n = 30 vs. 6, p ≤ 0.001), and IVC filter insertion ( n = 5 vs. 0, p = 0.07). Mean lysis times were 21 ± 1.7 and 24 ± 1.8 h for US- and T-CDT, respectively ( p = 0.26). Thirty (25 ultrasound, 5 traditional) limbs had complete lysis. Thirty-one (22 ultrasound, 9 traditional) limbs had incomplete lysis. Fifteen (4 ultrasound, 11 traditional) limbs had ineffective lysis ( p = 0.002 in favor of ultrasound). Four patients (3 US-CDT, 1 T-CDT) had recurrent ipsilateral thrombosis within 30 days ( p = 0.60). By Kaplan-Meier analysis, there were no significant difference between primary patency, primary-assisted patency, secondary patency, re-thrombosis, and recurrent symptoms at 6, 12, and 24 months. Conclusion US-CDT does not significantly improve mid-term patencies but results in greater acute clot burden reduction in patients with acute LE DVTs compared to T-CDT, which may be beneficial in reducing the long-term incidence of PTS.

Right Brachial to Atrial Xenograft Conduit for Hemodialysis Access: A Case Report.

Biologic grafts may be a viable alternative to their prosthetic counterparts in the patients who have exhausted conventional access alternatives given their superior patency rates and possible resilience to infection. This is a case report of a 66-year-old woman with end-stage renal disease and human immunodeficiency virus who has had multiple failed peripheral arteriovenous (AV) fistulas and grafts as well as inferior vena caval obstruction necessitating a transhepatic catheter for hemodialysis (HD). Given the patient's comorbidities and history, a right brachial artery-to-atrial conduit was created for long-term access. Biologic bovine carotid artery was used given its decreased susceptibility to infection and favorable patency rates. The AV access continues to function at 3.5-year follow-up and remains her primary means of HD. We present this novel use of a biologic graft as an option in patients with central venous obstruction and high risk of infection requiring exotic dialysis access.

Application of Intravascular Ultrasound in End-Stage Renal Patients with Central Venous Occlusive Disease.

Central venous occlusive disease is frequently observed in patients with end-stage renal disease. Venography remains the gold standard for diagnosis, but intravascular ultrasound is a potentially beneficial adjunct that may positively influence intervention.

DynaCT angiography for the diagnosis of bilateral bow hunter's syndrome.

We herein present a rare case of bilateral positional vertebrobasilar insufficiency secondary to mechanical obstruction of the V2 segment of the vertebral artery in a 71-year-old patient presenting with vertigo, occipital headache, tremors and respiratory irregularities. Two-dimensional digital subtraction angiography is the traditional diagnostic imaging standard but does not capture any peri-vascular bony or soft tissue abnormalities that are important to understand the three-dimensional pathophysiology. Intra-procedural cone-beam computed tomography (CT) is an increasingly used diagnostic adjunct, available in most modern angiographic suites that allows for the three-dimensional visualization of the vasculature as well as CT-like soft tissue visualization of its surrounding anatomy. In this case, we report the additional value of three-dimensional reconstructed cone-beam CT angiographic imaging that led to the successful diagnosis of bilateral positional vertebrobasilar disease. The patient subsequently received C4-C6 cervical decompression and fusion and remains symptom free at 1 year follow-up.

G.A.M.E.: GPU-accelerated mixture elucidator.

GPU acceleration is useful in solving complex chemical information problems. Identifying unknown structures from the mass spectra of natural product mixtures has been a desirable yet unresolved issue in metabolomics. However, this elucidation process has been hampered by complex experimental data and the inability of instruments to completely separate different compounds. Fortunately, with current high-resolution mass spectrometry, one feasible strategy is to define this problem as extending a scaffold database with sidechains of different probabilities to match the high-resolution mass obtained from a high-resolution mass spectrum. By introducing a dynamic programming (DP) algorithm, it is possible to solve this NP-complete problem in pseudo-polynomial time. However, the running time of the DP algorithm grows by orders of magnitude as the number of mass decimal digits increases, thus limiting the boost in structural prediction capabilities. By harnessing the heavily parallel architecture of modern GPUs, we designed a "compute unified device architecture" (CUDA)-based GPU-accelerated mixture elucidator (G.A.M.E.) that considerably improves the performance of the DP, allowing up to five decimal digits for input mass data. As exemplified by four testing datasets with verified constitutions from natural products, G.A.M.E. allows for efficient and automatic structural elucidation of unknown mixtures for practical procedures. Graphical abstract .

Robotic-Assisted Inferior Vena Cava Filter Retrieval.

Although anticoagulation remains the mainstay of therapy for patients with venous thromboembolism, guidelines recommend the use of inferior vena cava (IVC) filters in those who fail anticoagulation or have contraindications to its use. Short-term use of filters has proven effective in reducing the rate of pulmonary embolism. However, their extended use is associated with a variety of complications such as thrombosis, filter migration, or caval perforation, thus making a case for timely filter retrieval. This is the case of a 68-year-old female with a history of chronic oral anticoagulation use for multiple deep venous thrombi (DVT) and pulmonary emboli (PE) who required cervical and thoracic spinal intervention for spondylosis and foramina stenosis. Given her increased risk of recurrent DVT and PE perioperatively, we elected to place a Cook Celect™ IVC filter (Cook Medical, Bloomington, IN) after oral anticoagulation was stopped for the procedure. Her treatment course was prolonged due to wound-healing complications. We elected to use the Magellan Robotic Catheter System (Hansen Medical, Mountain View, CA) for filter retrieval when she presented 6 months later with caval perforation from the filter struts. With its ease of use, superior mechanical stability, and maneuverability, robot-assisted IVC filter retrieval may be a safer and more reliable substitute for traditional navigation techniques when presented with challenging filter retrievals.

Magnetic resonance venography and three-dimensional image fusion guidance provide a novel paradigm for endovascular recanalization of chronic central venous occlusion.

OBJECTIVE: Endovascular recanalization is considered first-line therapy for chronic central venous occlusion (CVO). Unlike arteries, in which landmarks such as wall calcifications provide indirect guidance for endovascular navigation, sclerotic veins without known vascular branching patterns impose significant challenges. Therefore, safe wire access through such chronic lesions mostly relies on intuition and experience. Studies have shown that magnetic resonance venography (MRV) can be performed safely in these patients, and the boundaries of occluded veins may be visualized on specific MRV sequences. Intraoperative image fusion techniques have become more common to guide complex arterial endovascular procedures. The aim of this study was to assess the feasibility and utility of MRV and intraoperative cone-beam computed tomography (CBCT) image fusion technique during endovascular CVO recanalization. METHODS: During the study period, patients with symptomatic CVO and failed standard endovascular recanalization underwent further recanalization attempts with use of intraoperative MRV image fusion guidance. After preoperative MRV and intraoperative CBCT image coregistration, a virtual centerline path of the occluded segment was electronically marked in MRV and overlaid on real-time two-dimensional fluoroscopy images. Technical success, fluoroscopy times, radiation doses, number of venograms before recanalization, and accuracy of the virtual centerline overlay were evaluated. RESULTS: Four patients underwent endovascular CVO recanalization with use of intraoperative MRV image fusion guidance. Mean (± standard deviation) time for image fusion was 6:36 ± 00:51 mm:ss. The lesion was successfully crossed in all patients without complications. Mean fluoroscopy time for lesion crossing was 12.5 ± 3.4 minutes. Mean total fluoroscopy time was 28.8 ± 6.5 minutes. Mean total radiation dose was 15,185 ± 7747 µGy/m2, and mean radiation dose from CBCT acquisition was 2788 ± 458 µGy/m2 (18% of mean total radiation dose). Mean number of venograms before recanalization was 1.6 ± 0.9, whereas two lesions were crossed without any prior venography. On qualitative analysis, virtual centerlines from MRV were aligned with actual guidewire trajectory on fluoroscopy in all four cases. CONCLUSIONS: MRV image fusion is feasible and may improve success, safety, and the surgeon's confidence during CVO recanalization. Similar to arterial interventions, three-dimensional MRV imaging and image fusion techniques could foster innovative solutions for such complex venous interventions and have the potential to affect a great number of patients.

Directly monitor protein rearrangement on a nanosecond-to-millisecond time-scale.

In order to directly observe the refolding kinetics from a partially misfolded state to a native state in the bottom of the protein-folding funnel, we used a "caging" strategy to trap the ß-sheet structure of ubiquitin in a misfolded conformation. We used molecular dynamics simulation to generate the cage-induced, misfolded structure and compared the structure of the misfolded ubiquitin with native ubiquitin. Using laser flash irradiation, the cage can be cleaved from the misfolded structure within one nanosecond, and we monitored the refolding kinetics of ubiquitin from this misfolded state to the native state by photoacoustic calorimetry and photothermal beam deflection techniques on nanosecond to millisecond timescales. Our results showed two refolding events in this refolding process. The fast event is shorter than 20 ns and corresponds to the instant collapse of ubiquitin upon cage release initiated by laser irradiation. The slow event is ~60 µs, derived from a structural rearrangement in ß-sheet refolding. The event lasts 10 times longer than the timescale of ß-hairpin formation for short peptides as monitored by temperature jump, suggesting that rearrangement of a ß-sheet structure from a misfolded state to its native state requires more time than ab initio folding of a ß-sheet.

Robotic-Assisted Coil Embolization of Ascending Aortic Pseudoaneurysm.

A 62-year-old man with coronary artery disease and ischemic cardiomyopathy after coronary artery bypass grafting and insertion of a HeartMate II (Thoratec, Pleasanton, CA) left ventricular assist device (LVAD) presented with spontaneous incisional bleeding and an ascending aortic pseudoaneurysm. Aortic angiography revealed an anomalous connection between the pseudoaneurysm and the LVAD conduit. We were able to partially embolize the tract with standard techniques, but the patient returned with repeated bleeding. Using the additional stability and control afforded by the Magellan Robotic System (Hansen Medical, Mountain View, CA), a remotely steerable catheter, we were able to cannulate and completely embolize the pseudoaneurysm and occlude the anomalous tract.

Induction of DNA repair proteins, Ref-1 and XRCC1, in adult rat brain following kainic acid-induced seizures.

We evaluated the expression of DNA repair proteins, redox factor-1 (Ref-1) and X-ray repair cross-complementing protein 1 (XRCC1), relevant to neurodegeneration following kainic acid-induced seizures in rats. Neurons with oxidative DNA damage exhibited increased expression and colocalization of Ref-1 and XRCC1. Upregulation of DNA repair proteins was also associated with p53 induction and TUNEL. Coexpression of DNA repair proteins and cell death markers following seizures suggests that the DNA repair response may not be sufficient to prevent excitotoxin-induced neurodegeneration.

Case Report: En Bloc Resection of Pancoast Tumor with Adjuvant Aortic Endograft and Chemoradiation.

"Pancoast" tumors frequently require a multidisciplinary approach to therapy and are still associated with high morbidity and mortality. Due to their sensitive anatomic location, complex resections and chemoradiation regimens are typically required for treatment. Those with signs of aortic invasion pose an even greater challenge, given the added risks of cardiopulmonary bypass for aortic resection and interposition. Placement of an aortic endograft can facilitate resection if the tumor is in close proximity to or is invading the aorta. Prophylactic endografting to prevent radiation-associated aortic rupture has also been described. This case describes a 60-year-old female who presented with a stage IIIa left upper lobe undifferentiated non-small-cell carcinoma encasing the subclavian artery with thoracic aorta and bony invasion. Following carotid-subclavian bypass with Dacron, en bloc resection of the affected lung, ribs, and vertebral bodies was performed. The aorta was prophylactically reinforced with a Gore TAG thoracic endograft prior to adjuvant chemoradiation. The patient remains disease-free at more than 5 years follow-up after completing her treatment course. Endovascular stenting with subsequent chemoradiation may prove to be a viable alternative to palliation or open operative management and prevention of aortic injury during tumor resection and/or adjuvant therapy in select patients with aortic involvement.

May-Thurner syndrome associated with Klippel-Trenaunay syndrome.

We present an unusual case of a 23-year-old man who had symptomatic lower extremity varicosities that have been present since birth. He was complaining of pain and swelling of several years duration. Evaluation revealed Klippel-Trenaunay syndrome with associated compression of the left common iliac vein by the overriding left common iliac artery (May-Thurner syndrome). The patient was treated with left common iliac vein stenting followed by high ligation and inversion stripping of his grossly incompetent left small saphenous vein, stripping of his aberrant left lateral embryonic veins, and also by multiple stab phlebectomies, with excellent early result.

Left atrial compression and the mechanism of exercise impairment in patients with a large hiatal hernia.

OBJECTIVES: The purpose of this study was to determine the association between cardiac compression and exercise impairment in patients with a large hiatal hernia (HH). BACKGROUND: Dyspnea and exercise impairment are common symptoms of a large HH with unknown pathophysiology. Studies evaluating the contribution of cardiac compression to the pathogenesis of these symptoms have not been performed. METHODS: We collected clinical data from a consecutive series of 30 patients prospectively evaluated with resting and stress echocardiography, cardiac computed tomography, and respiratory function testing before and after laparoscopic HH repair. Left atrial (LA), inferior pulmonary vein, and coronary sinus compression was analyzed in relation to exercise capacity (metabolic equivalents [METs] achieved on Bruce treadmill protocol). RESULTS: Exertional dyspnea was present in 25 of 30 patients (83%) despite normal mean baseline respiratory function. Moderate to severe LA compression was qualitatively present in 23 of 30 patients (77%) on computed tomography. Right and left inferior pulmonary vein and coronary sinus compression was present in 11 of 30 (37%), 12 of 30 (40%), and 26 of 30 (87%) patients, respectively. Post-operatively, New York Heart Association functional class and exercise capacity improved significantly (number of patients in New York Heart Association functional classes I, II, III, and IV: 6, 11, 11, and 2 vs. 26, 4, 0, and 0, respectively, p < 0.001; METs [percentage predicted]: 75 ± 24% vs. 112 ± 23%, p < 0.001) and resolution of cardiac compression was observed. Absolute change in LA diameter on the echocardiogram was the only independent cardiorespiratory predictor of exercise capacity improvement post-operatively (p = 0.006). CONCLUSIONS: We demonstrate, for the first time, marked exercise impairment and cardiac compression in patients with a large HH and normal respiratory function. After HH repair, exercise capacity improves significantly and correlates with resolution of LA compression.