Publications by authors named "Oliver Aalami"

31 Publications

Modest Gains After an 8-Week Exercise Program Correlate With Reductions in Non-traditional Markers of Cardiovascular Risk.

Front Cardiovasc Med 2021 17;8:669110. Epub 2021 Jun 17.

Division of Cardiovascular Medicine, Stanford University, Stanford, CA, United States.

Although engaging in physical exercise has been shown to reduce the incidence of cardiovascular events, the molecular mechanisms by which exercise mediates these benefits remain unclear. Based on epidemiological evidence, reductions in traditional risk factors only accounts for 50% of the protective effects of exercise, leaving the remaining mechanisms unexplained. The objective of this study was to determine whether engaging in a regular exercise program in a real world clinical setting mediates cardiovascular protection via modulation of non-traditional risk factors, such as those involved in coagulation, inflammation and metabolic regulation. We performed a prospective, cohort study in 52 sedentary patients with cardiovascular disease or cardiovascular risk factors at two tertiary medical centers between January 1, 2016 and December 31, 2019. Prior to and at the completion of an 8-week exercise program, we collected information on traditional cardiovascular risk factors, exercise capacity, and physical activity and performed plasma analysis to measure levels of fibrinolytic, inflammatory and metabolic biomarkers to assess changes in non-traditional cardiovascular risk factors. The median weight change, improvement in physical fitness, and change in physical activity for the entire cohort were: -4.6 pounds (IQR: +2 pounds, -11.8 pounds), 0.37 METs (IQR: -0.076 METs, 1.06 METs), and 252.7 kcals/week (IQR: -119, 921.2 kcals/week). In addition to improvement in blood pressure and cholesterol, patients who lost at least 5 pounds, expended at least 1,000 additional kcals/week, and/or achieved ≥0.5 MET increase in fitness had a significant reduction in plasminogen activator inhibitor-1 [9.07 ng/mL (95% CI: 2.78-15.35 ng/mL); = 0.026], platelet derived growth factor beta [376.077 pg/mL (95% CI: 44.69-707.46 pg/mL); = 0.026); and angiopoietin-1 [(1104.11 pg/mL (95% CI: 2.92-2205.30 pg/mL); = 0.049)]. Modest improvements in physical fitness, physical activity, and/or weight loss through a short-term exercise program was associated with decreased plasma levels of plasminogen activator inhibitor, platelet derived growth factor beta, and angiopoietin, which have been associated with impaired fibrinolysis and inflammation.
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http://dx.doi.org/10.3389/fcvm.2021.669110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245677PMC
June 2021

Activity data from wearables as an indicator of functional capacity in patients with cardiovascular disease.

PLoS One 2021 24;16(3):e0247834. Epub 2021 Mar 24.

Division of Vascular Surgery, Department of Surgery, Stanford University, Stanford, California, United States of America.

Background: Smartphone and wearable-based activity data provide an opportunity to remotely monitor functional capacity in patients. In this study, we assessed the ability of a home-based 6-minute walk test (6MWT) as well as passively collected activity data to supplement or even replace the in-clinic 6MWTs in patients with cardiovascular disease.

Methods: We enrolled 110 participants who were scheduled for vascular or cardiac procedures. Each participant was supplied with an iPhone and an Apple Watch running the VascTrac research app and was followed for 6 months. Supervised 6MWTs were performed during clinic visits at scheduled intervals. Weekly at-home 6MWTs were performed via the VascTrac app. The app passively collected activity data such as daily step counts. Logistic regression with forward feature selection was used to assess at-home 6MWT and passive data as predictors for "frailty" as measured by the gold-standard supervised 6MWT. Frailty was defined as walking <300m on an in-clinic 6MWT.

Results: Under a supervised in-clinic setting, the smartphone and Apple Watch with the VascTrac app were able to accurately assess 'frailty' with sensitivity of 90% and specificity of 85%. Outside the clinic in an unsupervised setting, the home-based 6MWT is 83% sensitive and 60% specific in assessing "frailty." Passive data collected at home were nearly as accurate at predicting frailty on a clinic-based 6MWT as was a home-based 6MWT, with area under curve (AUC) of 0.643 and 0.704, respectively.

Conclusions: In this longitudinal observational study, passive activity data acquired by an iPhone and Apple Watch were an accurate predictor of in-clinic 6MWT performance. This finding suggests that frailty and functional capacity could be monitored and evaluated remotely in patients with cardiovascular disease, enabling safer and higher resolution monitoring of patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247834PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990307PMC
October 2021

Applications of Mobile Health Technology in Surgical Innovation.

JAMA Surg 2021 May;156(5):414-415

Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California.

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http://dx.doi.org/10.1001/jamasurg.2020.6251DOI Listing
May 2021

Erratum: Author Correction: Clinical validation of smartphone-based activity tracking in peripheral artery disease patients.

NPJ Digit Med 2020 7;3:105. Epub 2020 Aug 7.

Division of Vascular & Endovascular Surgery, Department of Surgery, Stanford University, Stanford, CA 94305 USA.

[This corrects the article DOI: 10.1038/s41746-018-0073-x.].
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http://dx.doi.org/10.1038/s41746-020-00316-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414868PMC
August 2020

Telemedicine platforms and their use in the coronavirus disease-19 era to deliver comprehensive vascular care.

J Vasc Surg 2021 Feb 2;73(2):392-398. Epub 2020 Jul 2.

Division of Vascular and Endovascular Surgery, Southern Illinois University School of Medicine, Springfield, Ill; Society for Vascular Surgery, Chicago, Ill.

Implementation of telemedicine for patient encounters optimizes personal safety and allows for continuity of patient care. Embracing telehealth reduces the use of personal protective equipment and other resources consumed during in-person visits. The use of telehealth has increased to historic levels in response to the coronavirus disease 2019 (COVID-19) pandemic. Telehealth may be a key modality to fight against COVID-19, allowing us to take care of patients, conserve personal protective equipment, and protect health care workers all while minimizing the risk of viral spread. We must not neglect vascular health issues while the coronavirus pandemic continues to flood many hospitals and keep people confined to their homes. Patients are not immune to diseases and illnesses such as stroke, critical limb ischemia, and deep vein thrombosis while being confined to their homes and afraid to visit hospitals. Emerging from the COVID-19 crisis, incorporating telemedicine into routine medical care is transformative. By leveraging digital technology, the authors discuss their experience with the implementation, workflow, coding, and reimbursement issues of telehealth during the COVID-19 era.
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http://dx.doi.org/10.1016/j.jvs.2020.06.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329688PMC
February 2021

National assessment of availability, awareness, and utilization of supervised exercise therapy for peripheral artery disease patients with intermittent claudication.

J Vasc Surg 2020 05 4;71(5):1702-1707. Epub 2019 Nov 4.

Division of Vascular Surgery, Stanford Hospital, Palo Alto, Calif. Electronic address:

Background: Supervised exercise therapy (SET) is an inexpensive, low-risk, and effective option when compared with invasive therapies for the treatment of patients with peripheral artery disease (PAD) and intermittent claudication. Randomized, controlled trials have demonstrated the benefits of SET in improving maximum walking distance in intermittent claudication patients, and society guidelines recommend SET as first-line therapy. In 2017, the Centers for Medicare & Medicaid Services (CMS) added coverage of SET. We aimed to evaluate the availability and use of SET programs, determine the awareness of SET CMS coverage in the United States, and gauge the academic interest in SET in the vascular community.

Methods: An eight-question online survey regarding SET coverage, reimbursement, barriers to prescription, and SET use was sent to 900 vascular surgeons, cardiologists, and vascular medicine physicians across the United States. The most recent 2-year programs for the Vascular Annual Meeting, Midwestern Vascular Society, Eastern Vascular Society, and Western Vascular Society were reviewed to identify SET-related abstracts and gauge academic interest and awareness for SET within the vascular surgery community.

Results: We received 135 physician responses (15%) to the survey. All 50 states were represented. The majority of responders (54%) stated that there was no SET program at their facility, and 5% did not know if there was a SET program available. Of those who did have a SET program available, 81% were associated with cardiac rehabilitation and 19% had a PAD-specific program. A significant number of physicians (49%) had never referred a patient for SET. Twenty-six percent were not aware that CMS covered SET sessions. Of the physicians who were aware of CMS reimbursement, 36% had never referred a patient to a SET program. Of all surveyed, 98% indicated they would refer patients to a SET program if one was available. Top barriers to use of a SET program included (1) no SET center availability and (2) significant cost or travel expense to the patient. A review of major vascular surgery meeting programs for the last 2 years yielded no identification of a SET-related abstract.

Conclusions: There is a lack of both availability and use of SET for patients with PAD with claudication, despite guideline recommendations and CMS reimbursement for SET sessions in the United States. When SET is offered, it is typically through cardiac rehabilitation programs which is not focused on PAD. Travel distance, lack of SET program availability, and low reimbursement rates are primary areas that could be addressed to improve use.
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http://dx.doi.org/10.1016/j.jvs.2019.08.238DOI Listing
May 2020

Clinical validation of smartphone-based activity tracking in peripheral artery disease patients.

NPJ Digit Med 2018 11;1:66. Epub 2018 Dec 11.

1Division of Vascular & Endovascular Surgery, Department of Surgery, Stanford University, Stanford, CA 94305 USA.

Peripheral artery disease (PAD) is a vascular disease that leads to reduced blood flow to the limbs, often causing claudication symptoms that impair patients' ability to walk. The distance walked during a 6-min walk test (6MWT) correlates well with patient claudication symptoms, so we developed the VascTrac iPhone app as a platform for monitoring PAD using a digital 6MWT. In this study, we evaluate the accuracy of the built-in iPhone distance and step-counting algorithms during 6MWTs. One hundred and fourteen (114) participants with PAD performed a supervised 6MWT using the VascTrac app while simultaneously wearing an ActiGraph GT9X Activity Monitor. Steps and distance-walked during the 6MWT were manually measured and used to assess the bias in the iPhone CMPedometer algorithms. The iPhone CMPedometer step algorithm underestimated steps with a bias of -7.2% ± 13.8% (mean ± SD) and had a mean percent difference with the Actigraph (Actigraph-iPhone) of 5.7% ± 20.5%. The iPhone CMPedometer distance algorithm overestimated distance with a bias of 43% ± 42% due to overestimation in stride length. Our correction factor improved distance estimation to 8% ± 32%. The Ankle-Brachial Index (ABI) correlated poorly with steps ( = 0.365) and distance ( = 0.413). Thus, in PAD patients, the iPhone's built-in distance algorithm is unable to accurately measure distance, suggesting that custom algorithms are necessary for using iPhones as a platform for monitoring distance walked in PAD patients. Although the iPhone accurately measured steps, more research is necessary to establish step counting as a clinically meaningful metric for PAD.
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http://dx.doi.org/10.1038/s41746-018-0073-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550212PMC
December 2018

Septic Pulmonary Emboli From Peripheral Suppurative Thrombophlebitis: A Case Report and Literature Review.

Vasc Endovascular Surg 2018 Nov 18;52(8):633-635. Epub 2018 Jun 18.

1 Division of Vascular Surgery, Department of Surgery, Stanford Health Care, Stanford, CA, USA.

Background:: We report the case of a 90-year old woman who presented with septic pulmonary emboli due to suppurative thrombophlebitis at an old peripheral intravenous site.

Methods:: After unsuccessful treatment with antibiotics, the patient was taken to the operating room for excision and drainage of the purulent superficial vein.

Results:: We review the literature and discuss the presentation, risk factors, treatment options, and complications of this often-overlooked disease entity.

Conclusions:: Suppurative thrombophlebitis is a rare but morbid disease that requires a high level of clinical suspicion to diagnose.
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http://dx.doi.org/10.1177/1538574418779469DOI Listing
November 2018

Utilizing Smartphone-Based Machine Learning in Medical Monitor Data Collection: Seven Segment Digit Recognition.

AMIA Annu Symp Proc 2017 16;2017:1564-1570. Epub 2018 Apr 16.

Stanford University, Palo Alto, California.

Biometric measurements captured from medical devices, such as blood pressure gauges, glucose monitors, and weighing scales, are essential to tracking a patient's health. Trends in these measurements can accurately track diabetes, cardiovascular issues, and assist medication management for patients. Currently, patients record their results and date of measurement in a physical notebook. It may be weeks before a doctor sees a patient's records and can assess the health of the patient. With a predicted 6.8 billion smartphones in the world by 2022, health monitoring platforms, such as Apple's HealthKit, can be leveraged to provide the right care at the right time. This research presents a mobile application that enables users to capture medical monitor data and send it to their doctor swiftly. A key contribution of this paper is a robust engine that can recognize digits from medical monitors with an accuracy of 98.2%.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977613PMC
April 2019

A Cross-Sectional Study of Prominent US Mobile Health Applications: Evaluating the Current Landscape.

AMIA Annu Symp Proc 2017 16;2017:715-723. Epub 2018 Apr 16.

Stanford University School of Medicine, Department of Surgery, Division of Vascular Surgery, Palo Alto, United States.

Mobile health (mHealth) could offer unprecedented opportunity to provide medical support closer to the users. We have selected some relevant criteria to describe 100 apps from Google Play store and Apple's App Store's top suggestions in medical category. These characteristics were compared based on the paid or free nature of the apps, the target users: consumers or healthcare professionals, and the platform: Android or iOS. Seventeen provided functionalities and 27 medical subjects covered by these apps were also extracted. Our study shows that even in top rated mHealth apps, a high proportion lacks some basic criteria regarding the quality of the apps including the presence of a privacy policy, describing content sources, participation of the target users in the app development, etc. Paid apps did not ensure better quality compared to free apps. The current mHealth market is not mature enough to be used widely and recommended by healthcare professionals.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977729PMC
February 2019

Use of a proactive duplex ultrasound protocol for hemodialysis access.

J Vasc Surg 2016 Oct 13;64(4):1042-1049.e1. Epub 2016 May 13.

Division of Vascular Surgery, Stanford University, Stanford, Calif; Division of Vascular Surgery, VA Palo Alto Health Care System, Palo Alto, Calif. Electronic address:

Objective: Arteriovenous fistula (AVF) creation is the preferred approach for hemodialysis access; however, the maturation of AVFs is known to be poor. We established a proactive early duplex ultrasound (DUS) surveillance protocol for evaluating AVFs before attempted access. This study determined the effect of this protocol related to improving AVF maturation.

Methods: From 2008 to 2013, 153 patients received new upper extremity AVFs and an early DUS surveillance protocol at a single academic institution. The protocol involved an early DUS evaluation before hemodialysis cannulation of the AVF at 4 to 8 weeks after AVF creation. A positive DUS result was identified as a peak systolic velocity of >375 cm/s or a >50% stenosis on gray scale imaging, along with decreased velocity in the outflow vein. Patients with positive DUS findings underwent prophylactic endovascular or open intervention to assist with AVF maturation. Nature of secondary interventions, as well as AVF patency and maturation, were assessed. Overall clinical outcomes and fistula patency were investigated.

Results: During the study period, 183 upper extremity AVFs were created in 153 patients, including 82 radiocephalic, 63 brachiocephalic, and 38 brachiobasilic AVFs. A mortality rate of 43% (n = 66) was observed in a median follow-up period of 34.5 months (interquartile range, 19.6-46.9). A total of 164 early DUS were performed at a median of 6 weeks (interquartile range, 3.4-9.6 weeks) after the initial creation. Early DUS showed nine AVFs were occluded and were excluded from further analysis. Hemodynamically significant lesions were found in 62 AVFs (40%); however, only 17 (11%) were associated with an abnormal physical examination. Positive DUS finding prompted a secondary intervention in 81% of the patients. Among those with positive early DUS findings, AVF maturation was 70% in those undergoing a secondary intervention compared with 25% in those not undergoing a prophylactic intervention (P = .011). Primary-assisted patency for AVFs with early positive and negative DUS findings were 83% and 96% at 6 months, 64% and 89% at 1 year, and 52% and 82% at 2 years, respectively (P < .001).

Conclusions: Early DUS surveillance of AVFs before initial access is reasonable to identify problematic AVFs that may not be reliably detected on clinical examination. Although DUS criteria for AVFs have yet to be universally accepted, proactive early postoperative DUS interrogation assists in the early detection of dysfunctional AVFs and improvement of fistula maturation. Despite improved patency in those with positive DUS findings who undergo prophylactic secondary intervention, overall patency remains inferior to those without an abnormality detected on early DUS imaging.
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http://dx.doi.org/10.1016/j.jvs.2016.03.442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706077PMC
October 2016

Novel Use of Google Glass for Procedural Wireless Vital Sign Monitoring.

Surg Innov 2016 Aug 3;23(4):366-73. Epub 2016 Feb 3.

Stanford University School of Medicine, Stanford, CA, USA.

Purpose This study investigates the feasibility and potential utility of head-mounted displays for real-time wireless vital sign monitoring during surgical procedures. Methods In this randomized controlled pilot study, surgery residents (n = 14) performed simulated bedside procedures with traditional vital sign monitors and were randomized to addition of vital sign streaming to Google Glass. Time to recognition of preprogrammed vital sign deterioration and frequency of traditional monitor use was recorded. User feedback was collected by electronic survey. Results The experimental group spent 90% less time looking away from the procedural field to view traditional monitors during bronchoscopy (P = .003), and recognized critical desaturation 8.8 seconds earlier; the experimental group spent 71% (P = .01) less time looking away from the procedural field during thoracostomy, and recognized hypotension 10.5 seconds earlier. Trends toward earlier recognition of deterioration did not reach statistical significance. The majority of participants agreed that Google Glass increases situational awareness (64%), is helpful in monitoring vitals (86%), is easy to use (93%), and has potential to improve patient safety (85%). Conclusion In this early feasibility study, use of streaming to Google Glass significantly decreased time looking away from procedural fields and resulted in a nonsignificant trend toward earlier recognition of vital sign deterioration. Vital sign streaming with Google Glass or similar platforms is feasible and may enhance procedural situational awareness.
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http://dx.doi.org/10.1177/1553350616630142DOI Listing
August 2016

TElmisartan in the management of abDominal aortic aneurYsm (TEDY): The study protocol for a randomized controlled trial.

Trials 2015 Jun 17;16:274. Epub 2015 Jun 17.

Queensland Research Centre for Peripheral Vascular Disease, School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia.

Background: Experimental studies suggest that angiotensin II plays a central role in the pathogenesis of abdominal aortic aneurysm. This trial aims to evaluate the efficacy of the angiotensin receptor blocker telmisartan in limiting the progression of abdominal aortic aneurysm.

Methods/design: Telmisartan in the management of abdominal aortic aneurysm (TEDY) is a multicentre, parallel-design, randomised, double-blind, placebo-controlled trial with an intention-to-treat analysis. We aim to randomly assign 300 participants with small abdominal aortic aneurysm to either 40 mg of telmisartan or identical placebo and follow patients over 2 years. The primary endpoint will be abdominal aortic aneurysm growth as measured by 1) maximum infra-renal aortic volume on computed tomographic angiography, 2) maximum orthogonal diameter on computed tomographic angiography, and 3) maximum diameter on ultrasound. Secondary endpoints include change in resting brachial blood pressure, abdominal aortic aneurysm biomarker profile and health-related quality of life. TEDY is an international collaboration conducted from major vascular centres in Australia, the United States and the Netherlands.

Discussion: Currently, no medication has been convincingly demonstrated to limit abdominal aortic aneurysm progression. TEDY will examine the potential of a promising treatment strategy for patients with small abdominal aortic aneurysms.

Trial Registration: Australian and Leiden study centres: Australian New Zealand Clinical Trials Registry ACTRN12611000931976 , registered on 30 August 2011; Stanford study centre: clinicaltrials.gov NCT01683084 , registered on 5 September 2012.
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http://dx.doi.org/10.1186/s13063-015-0793-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482315PMC
June 2015

A prospective evaluation of using IVUS during percutaneous superficial femoral artery interventions.

Ann Vasc Surg 2015 Jan 3;29(1):28-33. Epub 2014 Sep 3.

Division of Vascular Surgery, VA Palo Alto Health Care System, Palo Alto, CA; Division of Vascular Surgery, Stanford University, Stanford, CA. Electronic address:

Background: The outcomes of endovascular interventions of the superficial femoral artery (SFA) are variable. Completion angiography is typically performed to confirm satisfactory outcomes after SFA angioplasty and/or stenting. However, two-dimensional angiography may not accurately reflect the extent of residual stenosis. We sought to determine whether intravascular ultrasound (IVUS) can help with residual disease assessment and procedure outcome.

Methods: Patients with anticipated SFA disease were prospectively recruited to the study. Patients with primary SFA disease on diagnostic angiography were included. After SFA endovascular intervention with angioplasty and/or stenting, a completion angiogram was performed to confirm satisfactory results before IVUS evaluation. IVUS-detected maximal residual stenosis, maximal residual lesion volume, and number of nonconsecutive posttreatment SFA segments with >50% residual stenosis were evaluated. Periprocedural ankle-brachial indexes (ABIs), Short Form 36 (SF-36) surveys, and Walking Impairment Questionnaires were also collected.

Results: Fifty-nine patients were prospectively enrolled. Thirty-three received angioplasty only, and 26 received angioplasty and stenting. All patients were men, mean age was 67 years, and major comorbidities included coronary artery disease (53%), active smoking (56%), hypertension (88%), and diabetes (68%). The angioplasty-only cohort had more nonconsecutive areas of >50% residual stenosis (P = 0.004), greater residual stenosis (P = 0.03), and smaller minimal lumen diameters after treatment (P = 0.01) than the angioplasty and stenting cohort. However, there was no significant difference in ABI between the 2 groups and no difference in ABI improvement after intervention. Sixty-four percent of all patients demonstrated a >0.2 increase in postintervention ABI. Improvement in ABI at 1 month after procedure significantly correlated with postintervention SF-36 survey physical scores (r = 0.435, P = 0.007).

Conclusions: IVUS evaluation provides more-accurate intraprocedural insight on the extent of residual stenosis after SFA interventions. Future studies are warranted to determine whether IVUS-guided postangioplasty and/or stenting can impact long-term interventional outcome.
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http://dx.doi.org/10.1016/j.avsg.2014.07.026DOI Listing
January 2015

Regulation of reactive oxygen species by p53: implications for nitric oxide-mediated apoptosis.

Am J Physiol Heart Circ Physiol 2010 Jun 9;298(6):H2192-200. Epub 2010 Apr 9.

Division of Vascular Surgery, Northwestern Univ., 676 N. St. Clair, no. 650, Chicago, IL 60611, USA.

Nitric oxide (NO) induces vascular smooth muscle cell (VSMC) apoptosis in part through activation of p53. Traditionally, p53 has been thought of as the gatekeeper, determining if a cell should undergo arrest and repair or apoptosis following exposure to DNA-damaging agents, depending on the severity of the damage. However, our laboratory previously demonstrated that NO induces apoptosis to a much greater extent in p53(-/-) compared with p53(+/+) VSMC. Increased reactive oxygen species (ROS) within VSMC has been shown to induce VSMC apoptosis, and recently it was found that the absence of, or lack of, functional p53 leads to increased ROS and oxidative stress within different cell types. This study investigated the differences in intracellular ROS levels between p53(-/-) and p53(+/+) VSMC and examined if these differences were responsible for the increased susceptibility to NO-induced apoptosis observed in p53(-/-) VSMC. We found that p53 actually protects VSMC from NO-induced apoptosis by increasing antioxidant protein expression [i.e., peroxiredoxin-3 (PRx-3)], thereby reducing ROS levels and cellular oxidative stress. We also observed that the NO-induced apoptosis in p53(-/-) VSMC was largely abrogated by pretreatment with catalase. Furthermore, when the antioxidant protein PRx-3 and its specific electron acceptor thioredoxin-2 were silenced within p53(+/+) VSMC with small-interfering RNA, not only did these cells exhibit greater ROS production, but they also exhibited increased NO-induced apoptosis similar to that observed in p53(-/-) VSMC. These findings suggest that ROS mediate NO-induced VSMC apoptosis and that p53 protects VSMC from NO-induced apoptosis by decreasing intracellular ROS. This research demonstrates that p53 has antioxidant functions in stressed cells and also suggests that p53 has antiapoptotic properties.
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http://dx.doi.org/10.1152/ajpheart.00535.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2886652PMC
June 2010

Citric acid-based elastomers provide a biocompatible interface for vascular grafts.

J Biomed Mater Res A 2010 Apr;93(1):314-24

Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Prosthetic vascular bypass grafting is associated with poor long-term patency rates. Herein, we report on the mid-term performance of expanded polytetrafluoroethylene (ePTFE) vascular grafts modified with a citric acid-based biodegradable elastomer. Through a spin-shearing method, ePTFE grafts were modified by mechanically coating a layer of poly(1,8 octanediol citrate) (POC) onto the luminal nodes and fibrils of the ePTFE. Control and POC-ePTFE grafts were implanted into the porcine carotid artery circulation as end-to-side bypass grafts. Grafts were assessed by duplex ultrasonography, magnetic resonance angiography, and digital subtraction contrast angiography and were all found to be patent with no hemodynamically significant stenoses. At 4 weeks, POC-ePTFE grafts were found to be biocompatible and resulted in a similar extent of neointimal hyperplasia as well as leukocyte and monocyte/macrophage infiltration as control ePTFE grafts. Furthermore, POC supported endothelial cell growth. Lastly, scanning electron microscopy confirmed the presence of POC on the ePTFE grafts at 4 weeks. Thus, these data reveal that surface modification of blood-contacting surfaces with POC results in a biocompatible surface that does not induce any untoward effects or inflammation in the vasculature. These findings are important as they will serve as the foundation for the development of a drug-eluting vascular graft.
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http://dx.doi.org/10.1002/jbm.a.32537DOI Listing
April 2010

Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia.

Free Radic Biol Med 2008 Jan 25;44(1):73-81. Epub 2007 Sep 25.

Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Nitric oxide (NO)-based therapies effectively inhibit neointimal hyperplasia in animal models of arterial injury and bypass grafting, but are not available clinically. We created a simple, effective, locally applied NO-eluting therapy to prevent restenosis after vascular procedures. We investigated the efficacy of perivascular delivery of two distinctly different diazeniumdiolate NO donors, 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO) (short half-life) and diazeniumdiolated poly(acrylonitrile) (PAN/NO) (long half-life), in powder or gel form (30% poloxamer 407), at inhibiting neointimal hyperplasia using the rat carotid artery injury model. Two weeks postinjury, all of the NO-eluting therapies successfully reduced neointimal hyperplasia. However, most dramatically, PROLI/NO powder reduced intimal area by 91.2% (p<0.05) versus injury alone. PROLI/NO powder was noted to reduce the medial area (40.2% vs injury alone, p<0.05), whereas other groups showed no such effect. Three days postinjury, each NO treatment group significantly reduced cellular proliferation. However, inflammatory markers revealed a distinct pattern: PAN/NO groups displayed increased leukocyte infiltration (p<0.05), whereas PROLI/NO groups displayed less macrophage infiltration (p<0.05). In conclusion, perivascular delivery of diazeniumdiolate NO donors in powder or gel form effectively inhibits neointimal hyperplasia. Application of short-acting PROLI/NO powder most effectively inhibited neointimal hyperplasia and inflammation and may represent a simple, clinically applicable NO-eluting therapy to prevent neointimal hyperplasia and restenosis after open vascular interventions.
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http://dx.doi.org/10.1016/j.freeradbiomed.2007.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2174838PMC
January 2008

A reproducible porcine ePTFE arterial bypass model for neointimal hyperplasia.

J Surg Res 2008 Aug 30;148(2):230-7. Epub 2007 Aug 30.

Division of Vascular Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: Late failure of prosthetic vascular bypass grafting using expanded polytetrafluoroethylene (ePTFE) is secondary to the development of neointimal hyperplasia, most commonly at the distal anastomosis. To develop therapies that can improve upon current prosthetic vascular bypass grafting, a large animal model of prosthetic bypass grafting that results in reproducible neointimal hyperplasia is necessary.

Methods: We performed bilateral end-to-side carotid artery bypasses with 6 mm ePTFE in a porcine model (n = 11). We studied graft patency using magnetic resonance angiography (MRA, 3 wk), duplex ultrasonography (4 wk), and digital-subtraction contrast angiography (4 wk). Animals were sacrificed at 4 wk and morphometric analysis was performed.

Results: Of the 11 animals that underwent surgery, one pig died from respiratory compromise; of the remaining 10, graft patency was 90% at 4 wk. Peak systolic and end diastolic velocities were established for this model using ultrasonography. MRA, ultrasonography, and angiography confirmed graft patency and were complimentary tools to evaluate the grafts. Development of neointimal hyperplasia was reproducible at 4 wk in both the proximal and distal anastomoses (2.5 to 3 mm(2)) of the ePTFE bypass grafts.

Conclusion: We developed a reproducible porcine ePTFE carotid artery bypass model for studying neointimal hyperplasia. Not only does this model allow for the manipulation and evaluation of potential therapies, but patency and neointimal hyperplasia can be easily evaluated by traditional means, such as MRA, ultrasonography, and angiography. This preclinical model is ideal for evaluation of novel therapies in vivo designed to inhibit neointimal hyperplasia following arterial reconstruction with prosthetic bypass grafting.
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http://dx.doi.org/10.1016/j.jss.2007.08.003DOI Listing
August 2008

Differential gene expression between juvenile and adult dura mater: a window into what genes play a role in the regeneration of membranous bone.

Plast Reconstr Surg 2006 Sep;118(4):851-861

Stanford and San Francisco, Calif. From the Department of Surgery, Stanford University School of Medicine, Stanford University, and the Departments of Surgery and Cell and Tissue Biology, University of California, San Francisco.

Background: Although reossification of large calvarial defects is possible in children, adults lack this tissue engineering capacity. In this study, the authors compared the differences in gene expression between juvenile and adult dura mater using a mouse cDNA microarray with 42,000 unique elements.

Methods: Non-suture-associated parietal bone was harvested from 6-day-old and 60-day-old mice. The dura mater was carefully dissected from the calvarial disk and snap-frozen. RNA was extracted from pooled dura mater for microarray analysis. The 25 most differentially expressed genes were listed, as were selected bone-related genes. In addition, quantitative real-time reverse-transcriptase polymerase chain reaction confirmation of selected genes-BMP-2, BMP-4, and BMP-7; and osteopontin (OP), osteocalcin (OC), and FGFR-1-was performed.

Results: Juvenile dura mater expressed significantly greater amounts of BMP-2 and OP. Minimal difference in OC expression was observed between juvenile and adult dura mater. Extracellular matrix proteins (Col3a1, 5a1, 6a1, and fibronectin 1), osteoblast differentiation markers (Runx2/Cbfa1, Itm2a, and FGFR-1), and the growth factor Ptn were among other genes with greater expression in juvenile dura mater. Markers of osteoclasts (Acp5, MMP9, Ctsk) and the multiple candidate gene Ntrk2 were also expressed at higher levels in the juvenile dura mater.

Conclusions: These findings suggest a more differentiated osteoprogenitor population to exist along with a greater presence of osteoclasts in the juvenile dura mater relative to adults. In addition to establishing a baseline difference in gene expression between juvenile and adult dura mater, new genes potentially critical to the regenerative potential of juvenile calvaria were identified.
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http://dx.doi.org/10.1097/01.prs.0000232366.23897.2bDOI Listing
September 2006

Abdominal aortic aneurysm-repair devices.

Expert Rev Med Devices 2006 Mar;3(2):185-94

Northwestern University, Division of Vascular Surgery, Feinberg School of Medicine, Chicago, IL 60611, USA.

Traditional open aneurysm repair is associated with significant perioperative morbidity. The development of abdominal aneurysm-repair devices has provided a minimally invasive alternative to open repairs. The field of aneurysm-repair devices is burgeoning since the approval of the first device in 1999. A clear perioperative survival advantage and lower perioperative morbidity has been reported by multiple studies. In addition to benefiting the normal risk aortic aneurysm patient, this new technology is making the repair of aneurysms in older patients with high operative risk factors possible. Modifications to devices are introduced rapidly to overcome anatomical limitations and to improve on device-related complications such as endoleaks and migration. Limited long-term outcomes are available for newer devices, and life-long surveillance is still recommended for all patients. Patient selection and preoperative planning are the cornerstones to successful endovascular repair of abdominal aortic aneurysms.
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http://dx.doi.org/10.1586/17434440.3.2.185DOI Listing
March 2006

Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts.

Transplantation 2005 Nov;80(9):1283-92

Transplantation Immunology Laboratory, Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305-5407, and Antibacterials, Inflammation and Immunology, Pfizer Inc., Groton, CT, USA.

Background: Janus Kinase (JAK) 3 is a tyrosine kinase essential for proper signal transduction downstream of selected cytokine receptors and for robust T-cell and natural killer cells activation and function. JAK3 inhibition with CP-690,550 prevents acute allograft rejection. To provide further insight into the mechanisms of efficacy, we investigated the immunomodulatory effects of CP-690,550 in vitro and in vivo in nonhuman primates.

Methods: Pharmacodynamic assessments of lymphocyte activation, function, proliferation and phenotype were performed in three settings: in vitro in whole blood isolated from untransplanted cynomolgus monkeys (cynos), in vivo in blood from untransplanted cynos dosed with CP-690,550 for 8 days, and in vivo in blood from transplanted cynos immunosuppressed with CP-690,550. Cell surface activation markers expression, IL-2- enhanced IFN-gamma production, lymphocyte proliferation and immune cell phenotype analyzes were performed with multiparametric flow cytometry.

Results: In vitro exposure to CP-690,550 resulted in significant reduction of IL-2-enhanced IFN-gamma production by T-cells (maximum inhibition of 55-63%), T-cell surface expression of CD25 (50% inhibitory concentration (IC50); 0.18 microM) and CD71 (IC50; 1.6 microM), and T-cell proliferative capacities measured by proliferating cell nuclear antigen expression (IC50; 0.87 microM). Similar results were observed in animals dosed with CP-690,550. In addition, transplanted animals displayed significant reduction of NK cell (90% from baseline) and T-cell numbers whereas CD8 effector memory T-cell populations were unaffected.

Conclusions: Potent in vitro and in vivo immunomodulatory effects of the JAK3 inhibitor CP-690,550 likely contribute to its efficacy in the prevention of organ allograft rejection.
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http://dx.doi.org/10.1097/01.tp.0000177643.05739.cdDOI Listing
November 2005

Differential transcriptional expression profiles of juvenile and adult calvarial bone.

Plast Reconstr Surg 2005 Jun;115(7):1986-94

Department of Surgery, Stanford University School of Medicine, Stanford, Calif 94305-5148, USA.

Background: It has widely been observed that young children are capable of reossifying large calvarial defects, while adults lack this endogenous tissue-engineering capacity. The ability of juvenile animals to regenerate calvarial defects has been investigated in multiple animal models, including mice. In this study, the authors used cDNA microarrays to investigate the expression of osteogenesis-associated genes upstream and downstream of Runx2 in juvenile and adult mouse calvaria.

Methods: Nonsuture-associated parietal bone discs were harvested from 6-day-old (n = 50) and 60-day-old (n = 35) male CD-1 mice. After separation of the underlying dura mater and overlying pericranium, the calvarial discs were snap-frozen and RNA was extracted from pooled samples of calvaria for microarray analysis. Genes analyzed included cytokines, receptors, and cell-surface and matrix proteins both upstream and downstream of Runx2.

Results: Genes associated with the Runx2 pathway had notably higher levels in the juvenile versus adult calvaria. All genes except for osteocalcin were expressed at least twofold higher in the juvenile calvaria. This pattern was validated with quantitative real-time polymerase chain reaction. In addition, mRNA for potent osteoinductive growth factors was present at higher levels in the juvenile compared with the adult calvaria.

Conclusions: These findings reflect a genomic environment of active osteoblast differentiation and ossification in the juvenile calvaria compared with the adult "quiescent" calvarial tissue. These data suggest that a decreased osteogenic potential of adult calvarial osteoblasts may, in part, explain the inability of adult animals to heal calvarial defects.
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http://dx.doi.org/10.1097/01.prs.0000163323.66318.73DOI Listing
June 2005

Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover.

Tissue Eng 2005 Mar-Apr;11(3-4):645-58

Department of Surgery, Stanford University School of Medicine, CA 94305, USA.

Reconstruction of craniofacial defects presents a substantial biomedical burden, and requires complex surgery. Interestingly, children after age 2 years and adults are unable to heal large skull defects. This nonhealing paradigm provides an excellent model system for craniofacial skeletal tissueengineering strategies. Previous studies have documented the in vivo osteogenic potential of adipose-derived stromal (ADS) cells and bone marrow-derived stromal (BMS) cells. This study investigates the ability to accelerate in vivo osteogenesis on ex vivo recombinant human bone morphogenetic protein 2 (BMP-2) and retinoic acid stimulation. Mouse osteoblasts, ADS cells, and BMS cells were seeded onto apatite-coated PLGA scaffolds, stimulated with rhBMP-2 and retinoic acid ex vivo for 4 weeks, and subsequently implanted into critically sized (4 mm) calvarial defects. Samples were harvested after 2, 4, 8, and 12 weeks. Areas of complete bony bridging were noted as early as 2 weeks in vivo; however, osteoclasts were attracted to the scaffold as identified by calcitonin receptor staining and tartrate-resistant acid phosphatase activity staining. Although the optimal method of in vitro osteogenic priming for mesenchymal cells remains unknown, these results provide evidence that BMP-2 and retinoic acid stimulation of multipotent cells ex vivo can subsequently induce significant quantities of bone formation within a short time period in vivo.
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http://dx.doi.org/10.1089/ten.2005.11.645DOI Listing
August 2005

Applications of a mouse model of calvarial healing: differences in regenerative abilities of juveniles and adults.

Plast Reconstr Surg 2004 Sep;114(3):713-20

Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305-5148, USA.

Young children are capable of healing large calvarial defects, whereas adults lack this endogenous osseous tissue-engineering capacity. Despite the important clinical implications, little is known about the molecular and cell biology underlying this differential ability. Traditionally, guinea pig, rabbit, and rat models have been used to study the orchestration of calvarial healing. To harness the research potential of knockout and transgenic mice, the authors developed a mouse model for calvarial healing. Nonsuture-associated parietal defects 3, 4, and 5 mm in diameter were made in both juvenile (6-day-old, n = 15) and adult (60-day-old, n = 15) mice. Calvariae were harvested after 8 weeks and analyzed radiographically and histologically. Percentage of healing was quantified using Scion Image software analysis of calvarial radiographs. A significant difference in the ability to heal calvarial defects was seen between 6-day-old and 60-day-old mice when 3-, 4-, or 5-mm defects were created. The authors' analysis revealed that juvenile mice healed a significantly greater percentage of their calvarial defects than adult mice (juvenile mean percentage of healing: 3-mm defects, 59 percent; 4-mm defects, 65 percent; 5-mm defects, 44 percent; adult mean percentage of healing: <5 percent in all groups; p < 0.05). All three defect sizes were found to be critical in the adult, whereas significant healing was seen regardless of the size of the defect in juvenile mice. The establishment of this model will facilitate further, detailed evaluation of the molecular biology underlying the different regenerative abilities of juvenile versus adult mice and enhance research into membranous bone induction by making available powerful tools such as knockout and transgenic animals.
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http://dx.doi.org/10.1097/01.prs.0000131016.12754.30DOI Listing
September 2004

Mechanisms of murine cranial suture patency mediated by a dominant negative transforming growth factor-beta receptor adenovirus.

Plast Reconstr Surg 2004 May;113(6):1685-97

Department of Surgery, Stanford University School of Medicine, 257 Campus Drive, Stanford, CA 94305-5148, USA.

Using a physiologic model of mouse cranial suture fusion, the authors' laboratory has previously demonstrated that transforming growth factor (TGF)-betas appear to be more abundantly expressed in the suture complex of the fusing posterior frontal compared with the patent sagittal suture. Furthermore, the authors have shown that by blocking TGF-beta signaling with a replication-deficient adenovirus encoding a defective, dominant negative type II TGF-beta receptor (AdDN-TbetaRII), posterior frontal suture fusion was inhibited. In this study, the authors attempt to further elucidate the role of TGF-beta in cranial suture fusion by investigating possible mechanisms of AdDN-TbetaRII-mediated cranial suture patency using both an established organ culture model and a novel in vitro co-culture system that recapitulates the in vivo anatomic dura mater/cranial suture relationship. In this article, the authors demonstrate that blocking TGF-beta signaling with the AdDN-TbetaRII construct led to inhibition of cellular proliferation in the suture mesenchyme and subjacent dura mater during the early period of predicted posterior frontal suture fusion. Interestingly, co-culture experiments revealed that transfecting osteoblasts with AdDN-TbetaRII led to alterations in the gene expression levels of two important bone-related molecules (Msx2 and osteopontin). Inhibiting TGF-beta signaling prevented time-dependent suppression of Msx2 and prevented induction of osteopontin, thereby retarding osteoblast differentiation. Furthermore, the authors demonstrated that the AdDN-TbetaRII construct was capable of blocking TGF-beta -mediated up-regulation of collagen IalphaI, an extracellular matrix molecule important for bone formation. Collectively, these data strongly suggest that AdDN-TbetaRII maintains posterior frontal patency, in part by altering early events in de novo bone formation, including cellular proliferation and early extracellular matrix production.
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http://dx.doi.org/10.1097/01.prs.0000117363.43699.5bDOI Listing
May 2004

In vitro murine posterior frontal suture fate is age-dependent: implications for cranial suture biology.

Plast Reconstr Surg 2004 Apr;113(4):1192-204

Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA.

In CD-1 mice, the posterior frontal suture (analogous to the human metopic suture) fuses while all other cranial sutures remain patent. In an in vitro organ culture model, the authors previously demonstrated that posterior frontal sutures explanted immediately before the onset of suture fusion (at 25 days old) mimic in vivo physiologic fusion. In the first portion of this study, the authors defined how early in development the posterior frontal suture fuses in their tension-free, serum-free organ culture system by serially analyzing posterior frontal suture fusion from calvariae explanted at different stages of postnatal development. Their results revealed a divergence of suture fate leading to abnormal patency or physiologic fusion between the first and second weeks of life, respectively, despite viability and continued growth of the calvarial explants in vitro. From these data, the authors postulated that the gene expression patterns present in the suture complex at the time of explant may determine whether the posterior frontal suture fuses or remains patent in organ culture. Therefore, to elucidate potentially important differences in gene expression within this "window of opportunity," they performed a cDNA microarray analysis on 5-day-old and 15-day-old posterior frontal and sagittal whole suture complexes corresponding to the age ranges for unsuccessful (1 to 7 days old) and successful (14 to 21 days old) in vitro posterior frontal suture fusion. Overall, their microarray results reveal interesting differential expression patterns of candidate genes in different categories, including angiogenic cytokines and mechanosensitive genes potentially important in cranial suture biology.
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http://dx.doi.org/10.1097/01.prs.0000110203.90911.63DOI Listing
April 2004

Adipose-derived adult stromal cells heal critical-size mouse calvarial defects.

Nat Biotechnol 2004 May 11;22(5):560-7. Epub 2004 Apr 11.

The Department of Surgery, Stanford University School of Medicine, Stanford University, 257 Campus Drive, Stanford, California 94305, USA.

In adults and children over two years of age, large cranial defects do not reossify successfully, posing a substantial biomedical burden. The osteogenic potential of bone marrow stromal (BMS) cells has been documented. This study investigates the in vivo osteogenic capability of adipose-derived adult stromal (ADAS) cells, BMS cells, calvarial-derived osteoblasts and dura mater cells to heal critical-size mouse calvarial defects. Implanted, apatite-coated, PLGA scaffolds seeded with ADAS or BMS cells produced significant intramembranous bone formation by 2 weeks and areas of complete bony bridging by 12 weeks as shown by X-ray analysis, histology and live micromolecular imaging. The contribution of implanted cells to new bone formation was 84-99% by chromosomal detection. These data show that ADAS cells heal critical-size skeletal defects without genetic manipulation or the addition of exogenous growth factors.
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http://dx.doi.org/10.1038/nbt958DOI Listing
May 2004

Postoperative rhabdomyolysis following laparoscopic gastric bypass in the morbidly obese.

Arch Surg 2004 Jan;139(1):73-6

Departments of Medicine, California Pacific Medical Center, San Francisco, USA.

Hypothesis: Laparoscopic approaches for weight reduction in the morbidly obese have become common with more than 50,000 bariatric surgical procedures being performed in 2001. The objective of this article is to raise awareness among surgeons of a new complication of rhabdomyolysis from this frequent procedure.

Design: Case series extracted from surgical database from January 2, 2001, through December 31, 2002.

Patients And Methods: We identified 5 cases of postoperative rhabdomyolysis in morbidly obese patients who underwent laparoscopic duodenal switch procedures with parietal gastrectomy. The cause, pathogenesis, and clinical features are reviewed and discussed.

Results: Postoperative rhabdomyolysis developed in 5 of 353 morbidly obese patients who underwent consecutive laparoscopic duodenal switch procedures, an incidence of 1.4%. All 5 patients were male, had a mean peak serum creatine kinase level of 19 680 U/L, and reported muscle pain in either the buttock, hip, or shoulder regions during the early postoperative period.

Conclusions: We hypothesized that morbidly obese patients develop critical surface and deep tissue pressures during bariatric surgery, increasing their risk for tissue injury and rhabdomyolysis. Unexplained elevations in the serum creatinine level or reports of buttock, hip, or shoulder pain in the postoperative period should raise the possibility of rhabdomyolysis and prompt clinical investigation. We recommend routine preoperative and postoperative measurements of the serum creatine kinase and serum creatinine levels to aid detection. Surgeons need to keep a low index of suspicion because early diagnosis and treatment are the cornerstones of successful management of rhabdomyolysis.
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http://dx.doi.org/10.1001/archsurg.139.1.73DOI Listing
January 2004
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