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Cao L.L.,Yeshiva University | Riascos-Bernal D.F.,Yeshiva University | Chinnasamy P.,Yeshiva University | Dunaway C.M.,Yeshiva University | And 10 more authors.
Nature | Year: 2016

Mitochondrial products such as ATP, reactive oxygen species, and aspartate are key regulators of cellular metabolism and growth. Abnormal mitochondrial function compromises integrated growth-related processes such as development and tissue repair, as well as homeostatic mechanisms that counteract ageing and neurodegeneration, cardiovascular disease, and cancer. Physiologic mechanisms that control mitochondrial activity in such settings remain incompletely understood. Here we show that the atypical Fat1 cadherin acts as a molecular brake' on mitochondrial respiration that regulates vascular smooth muscle cell (SMC) proliferation after arterial injury. Fragments of Fat1 accumulate in SMC mitochondria, and the Fat1 intracellular domain interacts with multiple mitochondrial proteins, including critical factors associated with the inner mitochondrial membrane. SMCs lacking Fat1 (Fat1 KO) grow faster, consume more oxygen for ATP production, and contain more aspartate. Notably, expression in Fat1 KO cells of a modified Fat1 intracellular domain that localizes exclusively to mitochondria largely normalizes oxygen consumption, and the growth advantage of these cells can be suppressed by inhibition of mitochondrial respiration, which suggest that a Fat1-mediated growth control mechanism is intrinsic to mitochondria. Consistent with this idea, Fat1 species associate with multiple respiratory complexes, and Fat1 deletion both increases the activity of complexes I and II and promotes the formation of complex-I-containing supercomplexes. In vivo, Fat1 is expressed in injured human and mouse arteries, and inactivation of SMC Fat1 in mice potentiates the response to vascular damage, with markedly increased medial hyperplasia and neointimal growth, and evidence of higher SMC mitochondrial respiration. These studies suggest that Fat1 controls mitochondrial activity to restrain cell growth during the reparative, proliferative state induced by vascular injury. Given recent reports linking Fat1 to cancer, abnormal kidney and muscle development, and neuropsychiatric disease, this Fat1 function may have importance in other settings of altered cell growth and metabolism. © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


Flynn A.,St Louis University Hospital | Chokkalingam Mani B.,Thomas Jefferson University | Mather P.J.,Thomas Jefferson University
Heart Failure Reviews | Year: 2010

Cardiac dysfunction is a well-recognized complication of severe sepsis and septic shock. Cardiac dysfunction in sepsis is characterized by ventricular dilatation, reduction in ejection fraction and reduced contractility. Initially, cardiac dysfunction was considered to occur only during the "hypodynamic" phase of shock. But we now know that it occurs very early in sepsis even during the "hyperdynamic" phase of septic shock. Circulating blood-borne factors were suspected to be involved in the evolution of sepsis induced cardiomyopathy, but it is not until recently that the cellular and molecular events are being targeted by researchers in a quest to understand this enigmatic process. Septic cardiomyopathy has been the subject of investigation for nearly half a century now and yet controversies exist in understanding it's pathophysiology. Here, we discuss our understanding of the pathogenesis of septic cardiomyopathy and the complex roles played by nitric oxide, mitochondrial dysfunction, complements and cytokines. © 2010 Springer Science+Business Media, LLC.


Bjerregaard P.,Washington University in St. Louis | Nallapaneni H.,St Louis University Hospital | Gussak I.,NewCardio Inc.
Journal of Electrocardiology | Year: 2010

The last ten years have seen a growing interest in clinical scenarios, where a short QT interval may play a role, especially because of an increased risk of sudden cardiac death in some situations. One such entity is Short QT Syndrome, which has emerged as a rare, but very malignant disease, in particular when the QT interval is very short. A short QT interval has also been noticed in some patients with other arrhythmic syndromes such as Idiopathic Ventricular Fibrillation, Brugade Syndrome and Early Repolarization Syndrome, but the role of a short QT interval in these settings is so far not known. Hypercalcemia often leads to shortening of the QT interval, but there are no data in humans to suggest an increased risk of sudden cardiac death in this setting. In addition, a shorterthan-usual QT interval has been reported in patients with Chronic Fatigue Syndrome and in response to atropine, catecholamine and Hyperthermia. When a short QT interval is encountered in daily clinical practice, these various scenarios needs to be considered, but it is still not possible to come up with clear guidelines for how to work up and risk stratify such individuals. Genetic testing is only useful in very few and the value of an electrophysiologic study, Holter monitoring or stress testing to assess QT adaptation to heart rate and T wave morphology analysis may all be helpful, but not well-established, tests in this setting. Published by Elsevier Inc.


Sadaka F.,St. John's University | Veremakis C.,St Louis University Hospital
Brain Injury | Year: 2012

Background: Traumatic brain injury (TBI) is a major source of death and severe disability worldwide. Raised Intracranial pressure (ICP) is an important predictor of mortality in patients with severe TBI and aggressive treatment of elevated ICP has been shown to reduce mortality and improve outcome. The acute post-injury period in TBI is characterized by several pathophysiologic processes that start in the minutes to hours following injury. All of these processes are temperature-dependent; they are all aggravated by fever and inhibited by hypothermia. Methods: This study reviewed the current clinical evidence in support of the use of therapeutic hypothermia (TH) for the treatment of intracranial hypertension (ICH) in patients with severe TBI. Results: This study identified a total of 18 studies involving hypothermia for control of ICP; 13 were randomized controlled trials (RCT) and five were observational studies. TH (32-34°C) was effective in controlling ICH in all studies. In the 13 RCT, ICP in the TH group was always significantly lower than ICP in the normothermia group. In the five observational studies, ICP during TH was always significantly lower than prior to inducing TH. Conclusions: Pending results from large multi-centre studies evaluating the effect of TH on ICH and outcome, TH should be included as a therapeutic option to control ICP in patients with severe TBI. © 2012 Informa UK Ltd.


Gardner Z.S.,University of Vermont | Ruppel G.L.,St Louis University Hospital | Kaminsky D.A.,University of Vermont
Chest | Year: 2011

Background: The severity of obstructive pulmonary disease is determined by the FEV 1 % predicted based on the American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. In patients with coexisting restrictive lung disease, the decrease in FEV 1 can overestimate the degree of obstruction. We hypothesize that adjusting the FEV 1 for the decrease in total lung capacity (TLC) results in a more appropriate grading of the severity of obstruction. Methods: We examined a large pulmonary function test database and identified patients with both restrictive (TLC < 80% predicted) and obstructive (FEV 1 /FVC < the lower limit of normal) lung disease. FEV 1 % predicted was adjusted for the degree of restriction by dividing it by TLC % predicted. We compared the distribution of severity grading between adjusted and unadjusted values according to ATS/ERS criteria and determined how the distribution of severity would change based on asthma and COPD guidelines. Results: We identified 199 patients with coexisting restrictive and obstructive lung disease. By ATS/ERS grading, the unadjusted data categorized 76% of patients as having severe or very severe obstruction and 11% as having mild or moderate obstruction. The adjusted data classified 33% with severe or very severe obstruction and 44% with mild or moderate obstruction. Of the corrected values, 83% resulted in a change to less severe obstruction by ATS/ERS guidelines, and 44% and 70% of patients, respectively, would be reclassified as having less severe obstruction by current asthma and COPD guidelines. Conclusions: This method results in a more appropriate distribution of severity of obstruction, which should lead to more accurate treatment of obstruction in these patients. © 2011 American College of Chest Physicians.


Ostrum R.F.,University of North Carolina at Chapel Hill | Tornetta III P.,Boston University | Watson J.T.,St Louis University Hospital | Christiano A.,Boston University | Vafek E.,Wake forest University
Clinical Orthopaedics and Related Research | Year: 2014

Background: Although not common, proximal femoral fractures associated with ipsilateral shaft fractures present a difficult management problem. A variety of surgical options have been employed with varying results. Questions/purposes: We investigated the use of hip screws and a reamed retrograde intramedullary (IM) nail for the treatment of this combined fracture pattern in terms of postoperative alignment (malunion), nonunion, and complications. Methods: Between May 2002 and October 2011, a total of 95 proximal femoral fractures with associated shaft fractures were treated at three participating Level 1 trauma centers; all were treated with hip screw fixation (cannulated screws or sliding hip screws) and retrograde reamed IM nails. The medical records of these patients were reviewed retrospectively for alignment, malunion, nonunion, and complications. Followup was available on 92 of 95 (97%) of the patients treated with hip screws and a retrograde nail. Forty were treated with a sliding hip screw, and 52 were treated with cannulated screws. Results: There were five proximal malunions in this series (5%). The union rate was 98% (90 of 92) for the femoral neck fractures and 91.3% (84 of 92) for the femoral shaft fractures after the initial surgery. There were two nonunions of comminuted femoral neck fractures after cannulated screw fixation. There was no difference in femoral neck union or alignment when comparing cannulated screws to a sliding hip screw. Four open comminuted femoral shaft fractures went on to nonunion and required secondary surgery to obtain union, and one patient developed symptomatic avascular necrosis. Conclusions: The treatment of ipsilateral proximal femoral neck and shaft fractures with hip screw fixation and a reamed retrograde nail demonstrated a high likelihood of union for the femoral neck fractures and a low risk of malunion. Comminution and initial displacement of the proximal femoral fracture may still lead to a small incidence of malunion or nonunion, and open comminuted femoral shaft fractures still may progress to nonunion despite appropriate surgical management. Level of Evidence: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. © 2013 The Association of Bone and Joint Surgeons®.


Smeds M.R.,St Louis University Hospital
Journal of vascular surgery | Year: 2012

A 66-year-old man with an abdominal aortic aneurysm previously repaired with an endovascular stent graft presented to our facility with worsening midabdominal and back pain. Previous postoperative surveillance computed tomography scans were unremarkable, showing excellent stent-wall apposition and a shrinking aneurysm sac; however, imaging done on his arrival identified a contained rupture at the level of the celiac artery containing a perforating suprarenal stent. We repaired this rupture with a surgeon-modified fenestrated stent graft. To our knowledge, this is the first reported case of penetration of the native aorta by a suprarenal stent in the absence of infection or trauma. Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.


Barner H.B.,St Louis University Hospital
Korean Journal of Thoracic and Cardiovascular Surgery | Year: 2012

This second report in the series on coronary artery bypass presents the authors experience and personal views on the internal thoracic artery (ITA) which date to 1966. There has been a very gradual evolution in the acceptance of this conduit which was initially compared with the saphenous vein and viewed as an improbable alternative to it. As is common with concepts and techniques which are 'outside the box' there was skepticism and criticism of this new conduit which was more difficult and time consuming to harvest for the surgeon who had to do it all. It was viewed as small, fragile, spastic and its flow capacity was questioned. Only a few surgeons employed it because of these issues and some of them would frequently graft it to the diagonal artery as it was thought not to supply adequate flow for the left anterior descending unless it was small. After a decade, angiographic data revealed superior patency to vein grafts. Even this evidence and survival benefit reported a few years later did not convince many surgeons that their concerns about limitations justified its use. Thus widespread adaption of the ITA as the conduit of choice for the anterior descending required another decade and bilateral use is only now expanding to more than 5% of patients in the US and somewhat faster in other countries. © The Korean Society for Thoracic and Cardiovascular Surgery. 2012.


Brescia A.A.,St Louis University Hospital | Wickers B.M.,St Louis University Hospital | Correa J.C.,St Louis University Hospital | Smeds M.R.,University of Arkansas for Medical Sciences | Jacobs D.L.,St Louis University Hospital
Journal of Vascular Surgery | Year: 2015

Objective The Supera stent (Abbott Laboratories, Abbott Park, Ill) has a unique biomimetic design allowing axial and longitudinal flexibility and fracture resistance. The aim of this retrospective study was to assess the midterm patency of Supera stents used to treat patients with superficial femoral and popliteal arterial disease by a single practice. Methods From April 2010 to December 2011, 53 patients and 59 limbs with symptomatic femoropopliteal lesions underwent angioplasty and stenting with the Supera stent. Five patients had no follow-up and were excluded. Demographics of the patients, radiographic images, morphologic features of the lesions, procedural reports, reinterventions, and follow-up clinical visit notes were reviewed. Primary patency was defined as clinical resolution of symptoms with no secondary interventions. Primary and secondary patency rates at 12, 24, and 36 months were estimated by Kaplan-Meier analysis. Results A total of 48 patients (42 men, six women; 54 limbs; mean age, 64.3 years [range, 51-87]) received Supera stents and had at least one follow-up visit as part of their treatment for femoropopliteal disease. Primary indications for intervention included claudication, rest pain, and tissue loss, at rates of 54% (29 of 54), 26% (14 of 54), and 20% (11 of 54), respectively; 22% of lesions were TransAtlantic Inter-Society Consensus type A or B and 78% were type C or D. Mean lesion length was 24.0 cm (range, 3-51). Mean follow-up was 27.5 months (range, 1-45). The ankle-brachial index increased from 0.58 ± 0.20 preoperatively to 0.77 ± 0.18 postoperatively (P =.00004). Primary, primary assisted, and secondary patency rates at latest follow-up were 79.6%, 88.9%, and 92.3%, respectively. Cumulative primary patency rates by Kaplan-Meier analysis at 12, 24, and 36 months were 85.6%, 83.1%, and 76.7%, respectively. Secondary patency rates by Kaplan-Meier estimates at 12, 24, and 36 months were 93.8%, 93.8%, and 89.3%, respectively. No stent fractures were found at the time of any reinterventions. Long lesions >30 cm (n = 18) showed equivalent patency to lesions of 1 to 15 cm (n = 18) and lesions 15 to 30 cm in length (n = 18). Conclusions Our midterm results show that Supera stents are durable in treating femoropopliteal lesions, with notably high patency rates in patients with long lesion lengths. © 2015 Society for Vascular Surgery.


Barner H.B.,St Louis University Hospital
Korean Journal of Thoracic and Cardiovascular Surgery | Year: 2013

This is the third in a series on coronary artery bypass which reviews three alternative arterial conduits. The radial artery has become the most widely used of the three and accumulating experience demonstrates better patency at 10 years versus saphenous vein. Drawbacks are a long incision on the forearm, the propensity for spasm and persistent sensory disturbance in about 10%. The first is answered by endoscopic harvest which may yield a shorter conduit but reduces sensory nerve injury. Spasm is managed pharmacologically and by less harvest trauma. The gastroepiploic artery is used in situ and free and although the abdominal cavity is entered complications are minimal and patency compares favorably with the radial artery. Use of the inferior epigastric artery remains minimal and its similar length often requires composite use but limited patency data are supportive. Other arteries have had rare use and this is unlikely to change because the three presented here have significant advantages and acceptance. © The Korean Society for Thoracic and Cardiovascular Surgery 2013.

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