Publications by authors named "Alex Lu"

35 Publications

Single versus dual operative spine fractures in ankylosing spondylitis.

Neurosurg Focus 2021 10;51(4):E6

1Department of Neurological Surgery, University of California, San Francisco.

Objective: Ankylosing spondylitis, the most common spondyloarthritis, fuses individual spinal vertebrae into long segments. The unique biomechanics of the ankylosed spine places patients at unusually high risk for unstable fractures secondary to low-impact mechanisms. These injuries are unique within the spine trauma population and necessitate thoughtful management. Therefore, the authors aimed to present a richly annotated data set of operative AS spine fractures with a significant portion of patients with simultaneous dual noncontiguous fractures.

Methods: Patients with ankylosing spondylitis with acute fractures who received operative management between 2012 and 2020 were reviewed. Demographic, admission, surgical, and outcome parameters were retrospectively collected and reviewed.

Results: In total, 29 patients were identified across 30 different admissions. At admission, the mean age was 71.7 ± 11.8 years. The mechanism of injury in 77% of the admissions was a ground-level fall; 30% also presented with polytrauma. Of admissions, 50% were patient transfers from outside hospitals, whereas the other half presented primarily to our emergency departments. Fifty percent of patients sustained a spinal cord injury, and 35 operative fractures were identified and treated in 32 surgeries. The majority of fractures clustered around the cervicothoracic (C4-T1, 48.6%) and thoracolumbar (T8-L3, 37.11%) junctions. Five patients (17.2%) had simultaneous dual noncontiguous operative fractures; these patients were more likely to have presented with a higher-energy mechanism of injury such as a bicycle or motor vehicle accident compared with patients with a single operative fracture (60% vs 8%, p = 0.024). On preoperative MRI, 56.3% of the fractures had epidural hematomas (EDHs); 25% were compressive of the underlying neural elements, which dictated the number of laminectomy levels performed (no EDH, 2.1 ± 2.36; noncompressive EDH, 2.1 ± 1.85; and compressive EDH, 7.4 ± 4 [p = 0.003]). The mean difference in instrumented levels was 8.7 ± 2.6 with a mean estimated blood loss (EBL) of 1183 ± 1779.5 mL. Patients on a regimen of antiplatelet therapy had a significantly higher EBL (2635.7 mL vs 759.4 mL, p = 0.015). Overall, patients had a mean hospital length of stay of 15.2 ± 18.5 days; 5 patients died during the same admission or after transfer to an outside hospital. Nine of 29 patients (31%) had died by the last follow-up (the mean follow-up was 596.3 ± 878.9 days).

Conclusions: Patients with AS who have been found to have unstable spine fractures warrant a thorough diagnostic evaluation to identify secondary fractures as well as compressive EDHs. These patients experienced prolonged inpatient hospitalizations with significant morbidity and mortality.
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http://dx.doi.org/10.3171/2021.7.FOCUS21329DOI Listing
October 2021

Factors associated with seizures at initial presentation in pediatric patients with cerebral arteriovenous malformations.

J Neurosurg Pediatr 2021 Sep 24:1-6. Epub 2021 Sep 24.

1Department of Neurological Surgery, University of California San Francisco, San Francisco.

Objective: Children with cerebral arteriovenous malformations (AVMs) can present with seizures, potentially increasing morbidity and impacting clinical management. However, the factors that lead to seizures as a presenting sign are not well defined. While AVM-related seizures have been described in case series, most studies have focused on adults and have included patients who developed seizures after an AVM rupture. To address this, the authors sought to analyze demographic and morphological characteristics of AVMs in a large cohort of children.

Methods: The demographic, clinical, and AVM morphological characteristics of 189 pediatric patients from a single-center database were studied. Univariate and multivariate logistic regression models were used to test the effect of these characteristics on seizures as an initial presenting symptom in patients with unruptured brain AVMs.

Results: Overall, 28 of 189 patients initially presented with seizures (14.8%). By univariate comparison, frontal lobe location (p = 0.02), larger AVM size (p = 0.003), older patient age (p = 0.04), and the Supplemented Spetzler-Martin (Supp-SM) grade (0.0006) were associated with seizure presentation. Multivariate analysis confirmed an independent effect of frontal lobe AVM location and higher Supp-SM grade. All patients presenting with seizures had AVMs in the cortex or subcortical white matter.

Conclusions: While children and adults share some risk factors for seizure presentation, their risk factor profiles do not entirely overlap. Pediatric patients with cortical AVMs in the frontal lobe were more likely to present with seizures. Additionally, the Supp-SM grade was highly associated with seizure presentation. Future clinical research should focus on the effect of therapeutic interventions targeting AVMs on seizure control in these patients.
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http://dx.doi.org/10.3171/2021.6.PEDS21126DOI Listing
September 2021

Multiple Tumor-Associated Intracranial Aneurysms Adjacent to a Suprasellar Germ Cell Tumor: Case Report and Review of Literature.

Pediatr Neurosurg 2021 28;56(5):482-491. Epub 2021 Jul 28.

Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.

Introduction: Tumor-associated intracranial aneurysms are rare and not well understood.

Case Presentation: We describe a 4-year-old female with multiple intracranial aneurysms intimately associated with a suprasellar germ cell tumor (GCT). We provide the clinical history, medical, and surgical treatment course, as well as a comprehensive and concise synthesis of the literature on tumor-associated aneurysms.

Discussion: We discuss mechanisms for aneurysm formation with relevance to the current case, including cellular and paracrine signaling pertinent to suprasellar GCTs and possible molecular pathways involved. We review the complex multidisciplinary treatment required for complex tumor and cerebrovascular interactions.
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http://dx.doi.org/10.1159/000517890DOI Listing
July 2021

Updated SARS-CoV-2 single nucleotide variants and mortality association.

J Med Virol 2021 12 16;93(12):6525-6534. Epub 2021 Jul 16.

Department of BioHealth Informatics, Indiana University School of Informatics and Computing, Indiana University - Purdue University Indianapolis, Indianapolis, Indiana, USA.

By analyzing newly collected SARS-CoV-2 genomes and comparing them with our previous study about SARS-CoV-2 single nucleotide variants (SNVs) before June 2020, we found that the SNV clustering had changed remarkably since June 2020. Apart from that the group of SNVs became dominant, which is represented by two nonsynonymous mutations A23403G (S:D614G) and C14408T (ORF1ab:P4715L), a few emerging groups of SNVs were recognized with sharply increased monthly incidence ratios of up to 70% in November 2020. Further investigation revealed sets of SNVs specific to patients' ages and/or gender, or strongly associated with mortality. Our logistic regression model explored features contributing to mortality status, including three critical SNVs, G25088T(S:V1176F), T27484C (ORF7a:L31L), and T25A (upstream of ORF1ab), ages above 40 years old, and the male gender. The protein structure analysis indicated that the emerging subgroups of nonsynonymous SNVs and the mortality-related ones were located on the protein surface area. The clashes in protein structure introduced by these mutations might in turn affect the viral pathogenesis through the alteration of protein conformation, leading to a difference in transmission and virulence. Particularly, we explored the fact that nonsynonymous SNVs tended to occur in intrinsic disordered regions of Spike and ORF1ab to significantly increase hydrophobicity, suggesting a potential role in the change of protein folding related to immune evasion.
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http://dx.doi.org/10.1002/jmv.27191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426680PMC
December 2021

Cerebrovascular complications of coccidioidomycosis meningitis: Case report and systematic review.

J Clin Neurosci 2020 Oct 2;80:282-289. Epub 2020 Oct 2.

Department of Medicine, University of California San Francisco, 505 Parnassus Avenue, Room M1498, Box 0119, San Francisco, CA 94117, USA.

Coccidioidomycosis exposure is common in the southwest United States and northern Mexico. Dissemination to the meninges is the most severe form of progression. Although ischemic strokes are well-reported in these patients, other cerebrovascular complications of coccidioidomycosis meningitis (CM), as well as their treatment options and outcomes, have not been systematically studied. We present a uniquely severe case of CM with several cerebrovascular complications. We also systematically queried PubMed and EMBASE databases, including articles published before April 2020 reporting human patients with CM-induced cerebrovascular pathology other than ischemic infarcts. Sixteen articles met inclusion criteria, which describe 6 patients with aneurysmal hemorrhage, 10 with non-aneurysmal hemorrhage, one with vasospasm, and one with transient ischemic attacks. CM-associated aneurysms invariably presented with hemorrhage. These were universally fatal until the past decade, when advances in surgical clipping and/or combined surgical and endovascular treatment have improved outcomes. We found that non-aneurysmal intracranial hemorrhages were limited to male patients, involved a diverse set of intracranial vasculature, and had a mortality rate surpassing 80%. Vasospasm was reported once, and was treated with percutaneous transluminal angioplasty. Transient ischemic attacks were reported once, and were successfully treated with fluconazole and dexamethasone. This review suggests that CM can present with a wide array of cerebrovascular complications, including ischemic infarcts, aneurysmogenesis, non-aneurysmal intracranial hemorrhage, vasospasm, and transient ischemic attacks. Mortality has improved over time due to advances in surgical and endovascular treatment modalities. The exception is non-aneurysmal intracranial hemorrhage, which remains associated with high mortality rates and few targeted therapeutic options.
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http://dx.doi.org/10.1016/j.jocn.2020.08.007DOI Listing
October 2020

Application of droplet digital PCR for the detection of vector copy number in clinical CAR/TCR T cell products.

J Transl Med 2020 05 8;18(1):191. Epub 2020 May 8.

Center for Cellular Engineering, Department of Transfusion Medicine and Cellular Engineering, NIH Clinical Center, Bethesda, MD, USA.

Background: Genetically engineered T cells have become an important therapy for B-cell malignancies. Measuring the efficiency of vector integration into the T cell genome is important for assessing the potency and safety of these cancer immunotherapies.

Methods: A digital droplet polymerase chain reaction (ddPCR) assay was developed and evaluated for assessing the average number of lenti- and retroviral vectors integrated into Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR)-engineered T cells.

Results: The ddPCR assay consistently measured the concentration of an empty vector in solution and the average number of CAR and TCR vectors integrated into T cell populations. There was a linear relationship between the average vector copy number per cell measured by ddPCR and the proportion of cells transduced as measured by flow cytometry. Similar vector copy number measurements were obtained by different staff using the ddPCR assay, highlighting the assays reproducibility among technicians. Analysis of fresh and cryopreserved CAR T and TCR engineered T cells yielded similar results.

Conclusions: ddPCR is a robust tool for accurate quantitation of average vector copy number in CAR and TCR engineered T cells. The assay is also applicable to other types of genetically engineered cells including Natural Killer cells and hematopoietic stem cells.
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http://dx.doi.org/10.1186/s12967-020-02358-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206671PMC
May 2020

Bringing high-grade arteriovenous malformations under control: clinical outcomes following multimodality treatment in children.

J Neurosurg Pediatr 2020 Apr 10:1-10. Epub 2020 Apr 10.

Departments of1Neurological Surgery.

Objective: Brain arteriovenous malformations (AVMs) consist of dysplastic blood vessels with direct arteriovenous shunts that can hemorrhage spontaneously. In children, a higher lifetime hemorrhage risk must be balanced with treatment-related morbidity. The authors describe a collaborative, multimodal strategy resulting in effective and safe treatment of pediatric AVMs.

Methods: A retrospective analysis of a prospectively maintained database was performed in children with treated and nontreated pediatric AVMs at the University of California, San Francisco, from 1998 to 2017. Inclusion criteria were age ≤ 18 years at time of diagnosis and an AVM confirmed by a catheter angiogram.

Results: The authors evaluated 189 pediatric patients with AVMs over the study period, including 119 ruptured (63%) and 70 unruptured (37%) AVMs. The mean age at diagnosis was 11.6 ± 4.3 years. With respect to Spetzler-Martin (SM) grade, there were 38 (20.1%) grade I, 40 (21.2%) grade II, 62 (32.8%) grade III, 40 (21.2%) grade IV, and 9 (4.8%) grade V lesions. Six patients were managed conservatively, and 183 patients underwent treatment, including 120 resections, 82 stereotactic radiosurgery (SRS), and 37 endovascular embolizations. Forty-four of 49 (89.8%) high-grade AVMs (SM grade IV or V) were treated. Multiple treatment modalities were used in 29.5% of low-grade and 27.3% of high-grade AVMs. Complete angiographic obliteration was obtained in 73.4% of low-grade lesions (SM grade I-III) and in 45.2% of high-grade lesions. A periprocedural stroke occurred in a single patient (0.5%), and there was 1 treatment-related death. The mean clinical follow-up for the cohort was 4.1 ± 4.6 years, and 96.6% and 84.3% of patients neurologically improved or remained unchanged in the ruptured and unruptured AVM groups following treatment, respectively. There were 16 bleeding events following initiation of AVM treatment (annual rate: 0.02 events per person-year).

Conclusions: Coordinated multidisciplinary evaluation and individualized planning can result in safe and effective treatment of children with AVMs. In particular, it is possible to treat the majority of high-grade AVMs with an acceptable safety profile. Judicious use of multimodality therapy should be limited to appropriately selected patients after thorough team-based discussions to avoid additive morbidity. Future multicenter studies are required to better design predictive models to aid with patient selection for multimodal pediatric care, especially with high-grade AVMs.
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http://dx.doi.org/10.3171/2020.1.PEDS19487DOI Listing
April 2020

Priapism associated with lumbar stenosis: case report and literature review.

J Spine Surg 2019 Dec;5(4):596-600

Department of Neurosurgery, UCSF Medical Center, San Francisco, CA, USA.

Lumbar spinal stenosis (LSS) is characterized by narrowing of the central canal, lateral recesses, or foramina leading to compression of neural tissue. The clinical syndrome associated with LSS is usually neurogenic claudication, which often presents as lower back and extremity pain, numbness, and tingling upon ambulation. Autonomic dysfunction is rarely observed in patients with LSS; however, a subset of male patients has been reported to experience intermittent priapism associated with the onset of neurogenic claudication symptoms. We present the case of a 33-year-old male who was diagnosed with LSS associated with neurogenic claudication and priapism who underwent minimally invasive decompressive surgery. Complete resolution of claudication and priapism was observed at the 6-week follow-up visit. This case report highlights minimally invasive lumbar decompression as an effective treatment for the rarely observed presentation of priapism associated with LSS.
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http://dx.doi.org/10.21037/jss.2019.09.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989923PMC
December 2019

Cost determinants in management of brain arteriovenous malformations.

Acta Neurochir (Wien) 2020 01 23;162(1):169-173. Epub 2019 Nov 23.

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.

Introduction: There is little data on the cost of treating brain arteriovenous malformations (AVMs). The goal of this study then is to identify cost determinants in multimodal management of brain AVMs.

Methods: One hundred forty patients with brain AVMs prospectively enrolled in the UCSF brain AVM registry and treated between 2012 and 2015 were included in the study. Patient and AVM characteristics, treatment type, and length of stay and radiographic evidence of obliteration were collected from the registry. We then calculated the cost of all inpatient and outpatient encounters, interventions, and imaging attributable to the AVM. We used generalized linear models to test whether there was an association between patient and AVM characteristics, treatment type, and cost and length of stay. We tested whether the proportion of patients with radiographic evidence of obliteration differed between treatment modalities using Fisher's exact test.

Results: The overall median cost of treatment and interquartile range was $77,865 (49,566-107,448). Surgery with preoperative embolization was the costliest treatment at $91,948 (79,914-140,600), while radiosurgery was the least at $20,917 (13,915-35,583). In multi-predictor analyses, hemorrhage, Spetzler-Martin grade, and treatment type were significant predictors of cost. Patients who had surgery had significantly higher rates of obliteration compared with radiosurgery patients.

Conclusions: Hemorrhage, AVM grade, and treatment modality are significant cost determinants in AVM management. Surgery with preoperative embolization was the costliest treatment and radiosurgery the least; however, surgical cases had significantly higher rates of obliteration.
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http://dx.doi.org/10.1007/s00701-019-04134-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197935PMC
January 2020

Detecting substance-related problems in narrative investigation summaries of child abuse and neglect using text mining and machine learning.

Child Abuse Negl 2019 12 12;98:104180. Epub 2019 Sep 12.

Child and Adolescent Data Lab, University of Michigan, School of Social Work, 1080 S University Ave, Ann Arbor, MI, 48109, United States.

Background: State child welfare agencies collect, store, and manage vast amounts of data. However, they often do not have the right data, or the data is problematic or difficult to inform strategies to improve services and system processes. Considerable resources are required to read and code these text data. Data science and text mining offer potentially efficient and cost-effective strategies for maximizing the value of these data.

Objective: The current study tests the feasibility of using text mining for extracting information from unstructured text to better understand substance-related problems among families investigated for abuse or neglect.

Method: A state child welfare agency provided written summaries from investigations of child abuse and neglect. Expert human reviewers coded 2956 investigation summaries based on whether the caseworker observed a substance-related problem. These coded documents were used to develop, train, and validate computer models that could perform the coding on an automated basis.

Results: A set of computer models achieved greater than 90% accuracy when judged against expert human reviewers. Fleiss kappa estimates among computer models and expert human reviewers exceeded .80, indicating that expert human reviewer ratings are exchangeable with the computer models.

Conclusion: These results provide compelling evidence that text mining procedures can be a cost-effective and efficient solution for extracting meaningful insights from unstructured text data. Additional research is necessary to understand how to extract the actionable insights from these under-utilized stores of data in child welfare.
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http://dx.doi.org/10.1016/j.chiabu.2019.104180DOI Listing
December 2019

Learning unsupervised feature representations for single cell microscopy images with paired cell inpainting.

PLoS Comput Biol 2019 09 3;15(9):e1007348. Epub 2019 Sep 3.

Department of Computer Science, University of Toronto, Toronto, Canada.

Cellular microscopy images contain rich insights about biology. To extract this information, researchers use features, or measurements of the patterns of interest in the images. Here, we introduce a convolutional neural network (CNN) to automatically design features for fluorescence microscopy. We use a self-supervised method to learn feature representations of single cells in microscopy images without labelled training data. We train CNNs on a simple task that leverages the inherent structure of microscopy images and controls for variation in cell morphology and imaging: given one cell from an image, the CNN is asked to predict the fluorescence pattern in a second different cell from the same image. We show that our method learns high-quality features that describe protein expression patterns in single cells both yeast and human microscopy datasets. Moreover, we demonstrate that our features are useful for exploratory biological analysis, by capturing high-resolution cellular components in a proteome-wide cluster analysis of human proteins, and by quantifying multi-localized proteins and single-cell variability. We believe paired cell inpainting is a generalizable method to obtain feature representations of single cells in multichannel microscopy images.
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http://dx.doi.org/10.1371/journal.pcbi.1007348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6743779PMC
September 2019

YeastSpotter: accurate and parameter-free web segmentation for microscopy images of yeast cells.

Bioinformatics 2019 11;35(21):4525-4527

Department of Computer Science, University of Toronto, Toronto, ON, Canada.

Summary: We introduce YeastSpotter, a web application for the segmentation of yeast microscopy images into single cells. YeastSpotter is user-friendly and generalizable, reducing the computational expertise required for this critical preprocessing step in many image analysis pipelines.

Availability And Implementation: YeastSpotter is available at http://yeastspotter.csb.utoronto.ca/. Code is available at https://github.com/alexxijielu/yeast_segmentation.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821424PMC
November 2019

Microsurgical Clipping of Anterior Choroidal Artery Aneurysms: A Systematic Approach to Reducing Ischemic Complications in an Experience with 146 Patients.

Oper Neurosurg (Hagerstown) 2019 10;17(4):413-423

Department of Neurological Surgery, University of California - San Francisco, San Francisco, California.

Background: Aneurysms of the anterior choroidal artery (AChA) have been associated with high treatment-associated morbidity due to ischemic complications.

Objective: To report a large clinical experience of microsurgically treated AChA aneurysms and describe a systematic approach to reduce ischemic complications.

Methods: One hundred forty-six patients with AChA aneurysms were retrospectively reviewed from a prospectively maintained database. Clinical characteristics, surgical techniques, clinical outcomes, arterial infarction, and use of intraoperative adjuncts (ie, ultrasonography, indocyanine green videoangiography, and neuromonitoring) were analyzed.

Results: In total, one hundred forty-three aneurysms (97.9%) were clipped. Temporary clipping was utilized in 47 cases (32.2%) with mean occlusion time of 5.6 min. Arterial infarction occurred in 12 patients (8.2%). In clipped aneurysms, 90.5% were completely obliterated, 8.8% had minimal residual (<5% of original), and 0.7% were incompletely occluded (>5% of original). Mortality (2.7%) was limited to patients with high-grade subarachnoid hemorrhage. Indocyanine green videoangiography and neuromonitoring altered operative technique in ∼20% of cases. Multivariate logistic regression identified intraoperative rupture as the sole predictor for arterial infarction.

Conclusion: Open microsurgical clipping remains a safe, effective treatment for AChA aneurysms. Microsurgical technique is paramount in preserving AChA patency and reducing ischemic complications. Despite increasing reliance on qualitative measures of AChA blood flow (videoangiography and ultrasonography) and neurophysiological monitoring, these technologies aid us infrequently. However, these adjuncts provide important safety checks for AChA patency. Temporary clipping must be used judiciously to lower the risk of intraoperative rupture while limiting possible ischemia in the AChA territory.
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http://dx.doi.org/10.1093/ons/opz007DOI Listing
October 2019

Local in situ fibrinolysis for recanalization of an occluded extracranial-intracranial bypass: Technical note.

J Clin Neurosci 2019 Jun 15;64:287-291. Epub 2019 Mar 15.

University of California San Francisco, Department of Neurological Surgery, San Francisco, CA, USA. Electronic address:

Extracranial-intracranial (EC-IC) bypass is a versatile technique to augment or preserve blood flow when treating cerebrovascular pathologies to prevent ischemic complications. Technical success and good patient outcomes rely on the successful establishment and maintenance of a patent bypass graft. Multiple modalities have been developed to confirm intraoperative graft patency. However, techniques and strategies to manage an occluded bypass are sparsely reported. The authors describe a novel technique for the in situ fibrinolysis utilizing recombinant tissue plasminogen activator (r-tPA) to recanalize an occluded EC-IC bypass following thrombus formation. This technique is feasible and effective in restoring long term EC-IC graft patency without requirement of additional vessel harvest or added ischemia time which may be tailored for use with other pharmacologic agents based on the acuity of an in-graft thrombosis.
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http://dx.doi.org/10.1016/j.jocn.2019.03.012DOI Listing
June 2019

Defective vascular signaling & prospective therapeutic targets in brain arteriovenous malformations.

Neurochem Int 2019 06 8;126:126-138. Epub 2019 Mar 8.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.

The neurovascular unit is composed of endothelial cells, vascular smooth muscle cells, pericytes, astrocytes and neurons. Through tightly regulated multi-directional cell signaling, the neurovascular unit is responsible for the numerous functionalities of the cerebrovasculature - including the regulation of molecular and cellular transport across the blood-brain barrier, angiogenesis, blood flow responses to brain activation and neuroinflammation. Historically, the study of the brain vasculature focused on endothelial cells; however, recent work has demonstrated that pericytes and vascular smooth muscle cells - collectively known as mural cells - play critical roles in many of these functions. Given this emerging data, a more complete mechanistic understanding of the cellular basis of brain vascular malformations is needed. In this review, we examine the integrated functions and signaling within the neurovascular unit necessary for normal cerebrovascular structure and function. We then describe the role of aberrant cell signaling within the neurovascular unit in brain arteriovenous malformations and identify how these pathways may be targeted therapeutically to eradicate or stabilize these lesions.
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http://dx.doi.org/10.1016/j.neuint.2019.03.002DOI Listing
June 2019

National trends in cerebral bypass surgery in the United States, 2002-2014.

Neurosurg Focus 2019 02;46(2):E4

1Department of Neurological Surgery, University of California, San Francisco, California; and.

OBJECTIVECerebral bypass procedures are microsurgical techniques to augment or restore cerebral blood flow when treating a number of brain vascular diseases including moyamoya disease, occlusive vascular disease, and cerebral aneurysms. With advances in endovascular therapy and evolving evidence-based guidelines, it has been suggested that cerebral bypass procedures are in a state of decline. Here, the authors characterize the national trends in cerebral bypass surgery in the United States from 2002 to 2014.METHODSUsing the National (Nationwide) Inpatient Sample, the authors extracted for analysis the data on all adult patients who had undergone cerebral bypass as indicated by ICD-9-CM procedure code 34.28. Indications for bypass procedures, patient demographics, healthcare costs, and regional variations are described. Results were stratified by indication for cerebral bypass including moyamoya disease, occlusive vascular disease, and cerebral aneurysms. Predictors of inpatient complications and death were evaluated using multivariable logistic regression analysis.RESULTSFrom 2002 to 2014, there was an increase in the annual number of cerebral bypass surgeries performed in the United States. This increase reflected a growth in the number of cerebral bypass procedures performed for adult moyamoya disease, whereas cases performed for occlusive vascular disease or cerebral aneurysms declined. Inpatient complication rates for cerebral bypass performed for moyamoya disease, vascular occlusive disease, and cerebral aneurysm were 13.2%, 25.1%, and 56.3%, respectively. Rates of iatrogenic stroke ranged from 3.8% to 20.4%, and mortality rates were 0.3%, 1.4%, and 7.8% for moyamoya disease, occlusive vascular disease, and cerebral aneurysms, respectively. Multivariate logistic regression confirmed that cerebral bypass for vascular occlusive disease or cerebral aneurysm is a statistically significant predictor of inpatient complications and death. Mean healthcare costs of cerebral bypass remained unchanged from 2002 to 20014 and varied with treatment indication: moyamoya disease $38,406 ± $483, vascular occlusive disease $46,618 ± $774, and aneurysm $111,753 ± $2381.CONCLUSIONSThe number of cerebral bypass surgeries performed for adult revascularization has increased in the United States from 2002 to 2014. Rising rates of surgical bypass reflect a greater proportion of surgeries performed for moyamoya disease, whereas bypasses performed for vascular occlusive disease and aneurysms are decreasing. Despite evolving indications, cerebral bypass remains an important surgical tool in the modern endovascular era and may be increasing in use. Stagnant complication rates highlight the need for continued interest in advancing available bypass techniques or technologies to improve patient outcomes.
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http://dx.doi.org/10.3171/2018.11.FOCUS18530DOI Listing
February 2019

Cerebrospinal fluid untargeted metabolomic profiling of aneurysmal subarachnoid hemorrhage: an exploratory study.

Br J Neurosurg 2018 Dec 26;32(6):637-641. Epub 2018 Dec 26.

d Division of Neurosurgery , University of Connecticut Health Center , Farmington , CT , USA.

Introduction: Despite advancements in medical and surgical therapies, clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH) continue to be poor. Currently, aSAH pathophysiology remains poorly understood. No aSAH biomarkers are commonly used in the clinical setting. This exploratory study used metabolomics profiling to identify global metabolic changes and metabolite predictors of long-term outcome using cerebrospinal fluid (CSF) samples of aSAH patients.

Methods And Methods: Gas chromatography time-of-flight mass spectrometry was applied to CSF samples collected from 15 consecutive high-grade aSAH patients (modified Fisher grade 3 or 4). Collected CSF samples were analyzed at two time points (admission and the anticipated vasospasm timeframe). Metabolite levels at both time points were compared and correlated with vasospasm status and Glasgow Outcome Scale (GOS) of patients at 1 year post-aSAH. Significance level was defined as p < 0.05 with false discovery rate correction for multiple comparisons.

Results: Of 97 metabolites identified, 16 metabolites, primarily free amino acids, significantly changed between the two time points. These changes were magnified in modified Fisher grade 4 compared with grade 3. Six metabolites (2-hydroxyglutarate, tryptophan, glycine, proline, isoleucine, and alanine) correlated with GOS at 1 year post-aSAH independent of vasospasm status. When predicting patients who had low disability (GOS 5 vs. GOS ≤4), 2-hydroxyglutarate had a sensitivity and specificity of 0.89 and 0.83 respectively.

Conclusions: Our preliminary study suggests that specific metabolite changes occur in the brain during the course of aSAH and that quantification of specific CSF metabolites may be used to predict long-term outcome in patients with aSAH. This is the first study to implicate 2-hydroxyglutarate, a known marker of tissue hypoxia, in aSAH pathogenesis.
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http://dx.doi.org/10.1080/02688697.2018.1519107DOI Listing
December 2018

A mini-open transspinous approach for resection of intramedullary spinal cavernous malformations.

J Clin Neurosci 2018 Dec 13;58:210-212. Epub 2018 Oct 13.

University of California San Francisco, Department of Neurological Surgery, San Francisco, CA, USA. Electronic address:

Background And Importance: Advances in minimally invasive (MIS) and mini-open surgical approaches have led to reductions in perioperative morbidity without compromising rates of resection of non-degenerative intradural spinal pathologies. Whether these approaches may be adapted for the surgical resection for intramedullary vascular malformations - such as cavernous malformations (CMs) - has yet to be reported. The authors describe a mini-open transspinous approach to resect a ruptured intramedullary CM of the conus medullaris.

Clinical Presentation: A 28-year-old man presented with sudden onset of bilateral lower extremity weakness, urinary retention and saddle anesthesia. Magnetic resonance imaging demonstrated a ruptured CM within the conus medullaris with pronounced extralesional hemorrhage. A mini-open transspinous approach with an expandable tubular retractor was successfully applied to facilitate microsurgical resection of the CM and evacuation of the associated hematoma. The patient made a good neurologic recovery, and postoperative imaging confirmed a gross total resection of the CM.

Conclusion: A mini-open transspinous approach utilizing an expandable tubular retractor offers feasible less invasive alternative to provide dorsal midline access for the microsurgical resection of intramedullary spinal CMs. Larger case series or future randomized prospective trials are warranted to fully explore suitability of MIS techniques for the surgical management of intradural spinal cord vascular pathologies - such as CMs.
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http://dx.doi.org/10.1016/j.jocn.2018.10.028DOI Listing
December 2018

Extracting and Integrating Protein Localization Changes from Multiple Image Screens of Yeast Cells.

Bio Protoc 2018 Sep 20;8(18):e3022. Epub 2018 Sep 20.

Department of Computer Science, University of Toronto, Toronto, Canada.

The evaluation of protein localization changes in cells under diverse chemical and genetic perturbations is now possible due to the increasing quantity of screens that systematically image thousands of proteins in an organism. Integrating information from different screens provides valuable contextual information about the protein function. For example, proteins that change localization in response to many different stressful environmental perturbations may have different roles than those that only change in response to a few. We developed, to our knowledge, the first protocol that permits the quantitative comparison and clustering of protein localization changes across multiple screens. Our analysis allows for the exploratory analysis of proteins according to their pattern of localization changes across many different perturbations, potentially discovering new roles by association.
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http://dx.doi.org/10.21769/BioProtoc.3022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328619PMC
September 2018

Current treatment of congenital pseudarthrosis of the tibia: a systematic review and meta-analysis.

J Pediatr Orthop B 2018 Nov;27(6):541-550

Department of Orthopaedic Surgery, University of Toledo Medical Center, Toledo, Ohio, USA.

To compare the current treatments for congenital pseudarthrosis of tibia, a total of 33 studies were reviewed. Vascularized fibular graft with external fixation or combined fixation had the fastest time till initial union (P<0.05). Bone morphogenetic protein had no advantage in terms of initial union, time till union, and refracture rates. This meta-analysis supports that fixation methods with corticocancellous bone autograft utilizing the combined technique of Ilizarov external fixation and intramedullary rod stabilization ensure a statistically significant reduction in the number of refractures compared with standalone fixation methods and would be the preferred method for preventing long-term complications in patients with congenital pseudarthrosis of tibia.
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http://dx.doi.org/10.1097/BPB.0000000000000524DOI Listing
November 2018

Integrating images from multiple microscopy screens reveals diverse patterns of change in the subcellular localization of proteins.

Elife 2018 04 5;7. Epub 2018 Apr 5.

Department of Computer Science, University of Toronto, Toronto, Canada.

The evaluation of protein localization changes on a systematic level is a powerful tool for understanding how cells respond to environmental, chemical, or genetic perturbations. To date, work in understanding these proteomic responses through high-throughput imaging has catalogued localization changes independently for each perturbation. To distinguish changes that are targeted responses to the specific perturbation or more generalized programs, we developed a scalable approach to visualize the localization behavior of proteins across multiple experiments as a quantitative pattern. By applying this approach to 24 experimental screens consisting of nearly 400,000 images, we differentiated specific responses from more generalized ones, discovered nuance in the localization behavior of stress-responsive proteins, and formed hypotheses by clustering proteins that have similar patterns. Previous approaches aim to capture all localization changes for a single screen as accurately as possible, whereas our work aims to integrate large amounts of imaging data to find unexpected new cell biology.
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http://dx.doi.org/10.7554/eLife.31872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935485PMC
April 2018

Review: Medial collateral ligament injuries.

J Orthop 2017 Dec 15;14(4):550-554. Epub 2017 Aug 15.

Department of Orthopaedics, University of Toledo Medical Center, Toledo, OH, United States.

The medial collateral ligament (MCL) is a major stabilizer of the knee joint. It is the most common ligament injured in the knee, particularly in athletes, and has been reported to be torn in 7.9% of all knee injuries. The MCL has a complex, layered anatomy with multiple insertions and functions. Minor trauma can cause tearing of the superficial portion whereas higher energy mechanisms can disrupt both the deep and superficial layers. History and physical are often adequate, but the gold standard for diagnosis is MRI. Lesser injuries to the MCL can often be treated conservatively with early rehabilitation, but more significant tears often necessitate surgery. A thorough understanding of the MCL and associated injuries is essential for proper diagnosis and treatment.
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http://dx.doi.org/10.1016/j.jor.2017.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581380PMC
December 2017

Novel biomarker identification using metabolomic profiling to differentiate radiation necrosis and recurrent tumor following Gamma Knife radiosurgery.

J Neurosurg 2017 Aug 25;127(2):388-396. Epub 2016 Nov 25.

Departments of 1 Neurosurgery.

OBJECTIVE Following an initial response of brain metastases to Gamma Knife radiosurgery, regrowth of the enhancing lesion as detected on MRI may represent either radiation necrosis (a treatment-related inflammatory change) or recurrent tumor. Differentiation of radiation necrosis from tumor is vital for management decision making but remains difficult by imaging alone. In this study, gas chromatography with time-of-flight mass spectrometry (GC-TOF) was used to identify differential metabolite profiles of the 2 tissue types obtained by surgical biopsy to find potential targets for noninvasive imaging. METHODS Specimens of pure radiation necrosis and pure tumor obtained from patient brain biopsies were flash-frozen and validated histologically. These formalin-free tissue samples were then analyzed using GC-TOF. The metabolite profiles of radiation necrosis and tumor samples were compared using multivariate and univariate statistical analysis. Statistical significance was defined as p ≤ 0.05. RESULTS For the metabolic profiling, GC-TOF was performed on 7 samples of radiation necrosis and 7 samples of tumor. Of the 141 metabolites identified, 17 (12.1%) were found to be statistically significantly different between comparison groups. Of these metabolites, 6 were increased in tumor, and 11 were increased in radiation necrosis. An unsupervised hierarchical clustering analysis found that tumor had elevated levels of metabolites associated with energy metabolism, whereas radiation necrosis had elevated levels of metabolites that were fatty acids and antioxidants/cofactors. CONCLUSIONS To the authors' knowledge, this is the first tissue-based metabolomics study of radiation necrosis and tumor. Radiation necrosis and recurrent tumor following Gamma Knife radiosurgery for brain metastases have unique metabolite profiles that may be targeted in the future to develop noninvasive metabolic imaging techniques.
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http://dx.doi.org/10.3171/2016.8.JNS161395DOI Listing
August 2017

An Unsupervised kNN Method to Systematically Detect Changes in Protein Localization in High-Throughput Microscopy Images.

PLoS One 2016 21;11(7):e0158712. Epub 2016 Jul 21.

Department of Computer Science, University of Toronto, Toronto, ON M5S3E1, Canada.

Despite the importance of characterizing genes that exhibit subcellular localization changes between conditions in proteome-wide imaging experiments, many recent studies still rely upon manual evaluation to assess the results of high-throughput imaging experiments. We describe and demonstrate an unsupervised k-nearest neighbours method for the detection of localization changes. Compared to previous classification-based supervised change detection methods, our method is much simpler and faster, and operates directly on the feature space to overcome limitations in needing to manually curate training sets that may not generalize well between screens. In addition, the output of our method is flexible in its utility, generating both a quantitatively ranked list of localization changes that permit user-defined cut-offs, and a vector for each gene describing feature-wise direction and magnitude of localization changes. We demonstrate that our method is effective at the detection of localization changes using the Δrpd3 perturbation in Saccharomyces cerevisiae, where we capture 71.4% of previously known changes within the top 10% of ranked genes, and find at least four new localization changes within the top 1% of ranked genes. The results of our analysis indicate that simple unsupervised methods may be able to identify localization changes in images without laborious manual image labelling steps.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158712PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956220PMC
July 2017

Hybrid anisotropic nanostructures for dual-modal cancer imaging and image-guided chemo-thermo therapies.

Biomaterials 2016 10 2;103:265-277. Epub 2016 Jul 2.

Molecular Imaging Program at Stanford (MIPS), Canary Center at Stanford for Cancer Early Detection, Department of Radiology and Bio-X Program, School of Medicine, Stanford University, 1201 Welch Road, Lucas P095, Stanford, CA 94305-5484, USA. Electronic address:

The multimodality theranostic system, which can integrate two or more different therapeutic modalities and multimodal imaging agents into a nanoentity, shows great promising prospects for the cancer treatment. Herein, we developed an efficient and novel strategy to synthesize hybrid anisotropic nanoparticles (HANs) with intrinsic multimodal theranostic capability [chemotherapy, photothermal therapy, magnetic resonance imaging (MRI), and photoacoustic imaging (PAI)]. For the first time, under the guidance of MRI and PAI, the chemotherapy and thermotherapy induced by administration of multifunctional hybrid nanoprobes were applied simultaneously to the treatment of colon cancer-bearing mice in vivo.
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http://dx.doi.org/10.1016/j.biomaterials.2016.06.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970737PMC
October 2016

Influence of repetitive mechanical loading on MMP2 activity in tendon fibroblasts.

J Orthop Res 2016 11 7;34(11):1991-2000. Epub 2016 Apr 7.

Department of Physical Therapy, University of British Columbia, Vancouver, Canada.

Matrix metalloproteinase2 has been implicated in tendon pathology caused by repetitive movements. However, its activity in the early stages of the tendon's response to overuse, and its presence in the circulation as a possible indicator of tendon degradation, remain unknown. Human tendon cells were repetitively stretched for 5 days, and the rabbit Achilles tendon complex underwent repetitive motion 3× per week for 2 weeks. Quantitative polymer chain reaction analysis was performed to detect matrix metalloproteinase2/14 and tissue inhibitor of matrix metalloproteinase2 messenger ribonucleic acid of cells and rabbit tissue, and matrix metalloproteinase2 protein levels were determined with an enzyme linked immunoassay. Matrix metalloproteinase2 activity was examined using zymography of the conditioned media, tendon and serum. Immunohistochemistry was used to localize matrix metalloproteinase2 in tendon tissue, and the density of fibrillar collagen in tendons was examined using second harmonic generation microscopy. Tendon cells stretched with high strain or high frequency demonstrated increased matrix metalloproteinase2 messenger ribonucleic acid and protein levels. Matrix metalloproteinase2 activity was increased in the rabbit Achilles tendon tissue at weeks 1 and 2; however, serum activity was only increased at week 1. After 2 weeks of exercise, the collagen density was lower in specific regions of the exercised rabbit Achilles tendon complex. Matrix metalloproteinase2 expression in exercised rabbit Achilles tendons was detected surrounding tendon fibroblasts. Repetitive mechanical stimulation of tendon cells results in a small increase in matrix metalloproteinase2 levels, but it appears unlikely that serum matrix metalloproteinase2 will be a useful indicator of tendon overuse injury. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1991-2000, 2016.
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http://dx.doi.org/10.1002/jor.23207DOI Listing
November 2016

Demonstration of differential radiosensitivity based upon mutation profile in metastatic melanoma treated with stereotactic radiosurgery.

J Radiosurg SBRT 2016 ;4(2):97-106

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06510, USA.

Background: Metastatic melanoma often involves the brain. Radiotherapy is an important treatment of melanoma brain metastases, although melanoma radiosensitivity is considered heterogeneous. Thus, identifying subsets with differential radiosensitivity is essential.

Materials And Methods: Patients with metastatic melanoma were identified in a prospective stereotactic radiosurgery (SRS) database. Tumor were tested for alterations in B-RAF, N-RAS, and c-KIT. Standardized imaging following SRS was reviewed for recurrence. Differences in local and distant failure were determined using modified Cox proportional hazards models.

Results: 102 patients and 1,028 brain metastases were included. N-RAS mutated patients were significantly less likely to develop local recurrence after SRS than wild type patients (HR 0.17, 95% CI 0.04-0.72, p=0.017). B-RAF and c-KIT mutations were not associated with altered rates of local recurrence. Lower local recurrence rates for N-RAS mutated tumors persisted on multivariate analysis (HR 0.18, 95% CI 0.04-0.84p=0.029).

Conclusions: N-RAS mutation is associated with improved local control following SRS. Local recurrence is more common in wild type patients and those with B-RAF or c-KIT mutations. Further research is needed to validate these findings and integrate into practice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658871PMC
January 2016

Angiopoietin-like 4 promotes angiogenesis in the tendon and is increased in cyclically loaded tendon fibroblasts.

J Physiol 2016 06 18;594(11):2971-83. Epub 2016 Jan 18.

Jack Bell Research Centre, Department of Medicine, University of British Columbia, Vancouver, Canada.

Key Points: Angiopoietin-like 4 (ANGPTL4) modulates tendon neovascularization. Cyclic loading stimulates the activity of transforming growth factor-β and hypoxia-inducible factor 1α and thereby increases the expression and release of ANGPTL4 from human tendon cells. Targeting ANGPTL4 and its regulatory pathways is a potential avenue for regulating tendon vascularization to improve tendon healing or adaptation.

Abstract: The mechanisms that regulate angiogenic activity in injured or mechanically loaded tendons are poorly understood. The present study examined the potential role of angiopoietin-like 4 (ANGPTL4) in the angiogenic response of tendons subjected to repetitive mechanical loading or injury. Cyclic stretching of human tendon fibroblasts stimulated the expression and release of ANGPTL4 protein via transforming growth factor-β (TGF-β) and hypoxia-inducible factor 1α (HIF-1α) signalling, and the released ANGPTL4 was pro-angiogenic. Angiogenic activity was increased following ANGPTL4 injection into mouse patellar tendons, whereas the patellar tendons of ANGPTL4 knockout mice displayed reduced angiogenesis following injury. In human rotator cuff tendons, the expression of ANGPTL4 was correlated with the density of tendon endothelial cells. To our knowledge, this is the first study characterizing a role of ANGPTL4 in the tendon. ANGPTL4 may assist in the regulation of vascularity in the injured or mechanically loaded tendon. TGF-β and HIF-1α comprise two signalling pathways that modulate the expression of ANGPTL4 by mechanically stimulated tendon fibroblasts and, in the future, these could be manipulated to influence tendon healing or adaptation.
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http://dx.doi.org/10.1113/JP271752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887665PMC
June 2016

Dragon fruit-like biocage as an iron trapping nanoplatform for high efficiency targeted cancer multimodality imaging.

Biomaterials 2015 Nov 5;69:30-7. Epub 2015 Aug 5.

Molecular Imaging Program at Stanford (MIPS), Canary Center at Stanford for Cancer Early Detection, Department of Radiology and Bio-X Program, School of Medicine, Stanford University, CA 94305-5484, USA. Electronic address:

Natural biopolymer based multifunctional nanomaterials are perfect candidates for multimodality imaging and therapeutic applications. Conventional methods of building multimodal imaging probe require either cross-linking manners to increase its in vivo stability or attach a target module to realize targeted imaging. In this study, the intrinsic photoacoustic signals and the native strong chelating properties with metal ions of melanin nanoparticle (MNP), and transferrin receptor 1 (TfR1) targeting ability of apoferritin (APF) was employed to construct an efficient nanoplatform (AMF) without tedious assembling process. Smart APF shell significantly increased metal ions loading (molar ratio of 1:800, APF/Fe(3+)) and therefore improved magnetic resonance imaging (MRI) sensitivity. Moreover, synergistic use of Fe(3+) and APF contributed to high photoacounstic imaging (PAI) sensitivity. AMF showed excellent bio-stability and presented good in vivo multimodality imaging (PET/MRI/PAI) properties (good tumor uptake, high specificity and high tumor contrast) in HT29 tumor because of its targeting property combined with the enhanced permeability and retention (EPR) effect, making it promising in theranostics and translational nanomedicine.
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http://dx.doi.org/10.1016/j.biomaterials.2015.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586283PMC
November 2015

Accumulation of oxidized LDL in the tendon tissues of C57BL/6 or apolipoprotein E knock-out mice that consume a high fat diet: potential impact on tendon health.

PLoS One 2014 12;9(12):e114214. Epub 2014 Dec 12.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; Centre for Hip Health and Mobility, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.

Objective: Clinical studies have suggested an association between dyslipidemia and tendon injuries or chronic tendon pain; the mechanisms underlying this association are not yet known. The objectives of this study were (1) to evaluate the impact of a high fat diet on the function of load-bearing tendons and on the distribution in tendons of oxidized low density lipoprotein (oxLDL), and (2) to examine the effect of oxLDL on tendon fibroblast proliferation and gene expression.

Methods: Gene expression (Mmp2, Tgfb1, Col1a1, Col3a1), fat content (Oil Red O staining), oxLDL levels (immunohistochemistry) and tendon biomechanical properties were examined in mice (C57Bl/6 or ApoE -/-) receiving a standard or a high fat diet. Human tendon fibroblast proliferation and gene expression (COL1A1, COL3A1, MMP2) were examined following oxLDL exposure.

Results: In both types of mice (C57Bl/6 or ApoE -/-), consumption of a high fat diet led to a marked increase in oxLDL deposition in the load-bearing extracellular matrix of the tendon. The consumption of a high fat diet also reduced the failure stress and load of the patellar tendon in both mouse types, and increased Mmp2 expression. ApoE -/- mice exhibited more pronounced reductions in tendon function than wild-type mice, and decreased expression of Col1a1 compared to wild type mice. Human tendon fibroblasts responded to oxLDL by increasing their proliferation and their mRNA levels of MMP2, while decreasing their mRNA levels for COL1A1 and COL3A1.

Conclusion: The consumption of a high fat diet resulted in deleterious changes in tendon function, and these changes may be explained in part by the effects of oxLDL, which induced a proliferative, matrix-degrading phenotype in human tenocytes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264764PMC
October 2015
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