Publications by authors named "Elena B Okon"

29 Publications

  • Page 1 of 1

Proteomic Portraits Reveal Evolutionarily Conserved and Divergent Responses to Spinal Cord Injury.

Mol Cell Proteomics 2021 Jun 12;20:100096. Epub 2021 Jun 12.

Division of Neurosurgery, University of British Columbia, Vancouver, British Columbia, Canada.

Despite the emergence of promising therapeutic approaches in preclinical studies, the failure of large-scale clinical trials leaves clinicians without effective treatments for acute spinal cord injury (SCI). These trials are hindered by their reliance on detailed neurological examinations to establish outcomes, which inflate the time and resources required for completion. Moreover, therapeutic development takes place in animal models whose relevance to human injury remains unclear. Here, we address these challenges through targeted proteomic analyses of cerebrospinal fluid and serum samples from 111 patients with acute SCI and, in parallel, a large animal (porcine) model of SCI. We develop protein biomarkers of injury severity and recovery, including a prognostic model of neurological improvement at 6 months with an area under the receiver operating characteristic curve of 0.91, and validate these in an independent cohort. Through cross-species proteomic analyses, we dissect evolutionarily conserved and divergent aspects of the SCI response and establish the cerebrospinal fluid abundance of glial fibrillary acidic protein as a biochemical outcome measure in both humans and pigs. Our work opens up new avenues to catalyze translation by facilitating the evaluation of novel SCI therapies, while also providing a resource from which to direct future preclinical efforts.
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http://dx.doi.org/10.1016/j.mcpro.2021.100096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260874PMC
June 2021

Duraplasty in Traumatic Thoracic Spinal Cord Injury: Impact on Spinal Cord Hemodynamics, Tissue Metabolism, Histology, and Behavioral Recovery Using a Porcine Model.

J Neurotrauma 2021 Jun 18. Epub 2021 Jun 18.

International Collaboration on Repair Discoveries, University of British Columbia (UBC), Vancouver, British Columbia, Canada.

After acute traumatic spinal cord injury (SCI), the spinal cord can swell to fill the subarachnoid space and become compressed by the surrounding dura. In a porcine model of SCI, we performed a duraplasty to expand the subarachnoid space around the injured spinal cord and evaluated how this influenced acute intraparenchymal hemodynamic and metabolic responses, in addition to histological and behavioral recovery. Female Yucatan pigs underwent a T10 SCI, with or without duraplasty. Using microsensors implanted into the spinal cord parenchyma, changes in blood flow (ΔSCBF), oxygenation (ΔPO), and spinal cord pressure (ΔSCP) during and after SCI were monitored, alongside metabolic responses. Behavioral recovery was tested weekly using the Porcine Injury Behavior Scale (PTIBS). Thereafter, spinal cords were harvested for tissue sparing analyses. In both duraplasty and non-animals, the ΔSCP increased ∼5 mm Hg in the first 6 h post-injury. After this, the SCP appeared to be slightly reduced in the duraplasty animals, although the group differences were not statistically significant after controlling for injury severity in terms of impact force. During the first seven days post-SCI, the ΔSCBF or ΔPO values were not different between the duraplasty and control animals. Over 12 weeks, there was no improvement in hindlimb locomotion as assessed by PTIBS scores and no reduction in tissue damage at the injury site in the duraplasty animals. In our porcine model of SCI, duraplasty did not provide any clear evidence of long-term behavioral or tissue sparing benefit after SCI.
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http://dx.doi.org/10.1089/neu.2021.0084DOI Listing
June 2021

Characterization of Lower Urinary Tract Dysfunction after Thoracic Spinal Cord Injury in Yucatan Minipigs.

J Neurotrauma 2021 May 2;38(9):1306-1326. Epub 2021 Mar 2.

International Collaboration on Repair Discoveries (ICORD), Departments of Department of Orthopaedics, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

There is an increasing need to develop approaches that will not only improve the clinical management of neurogenic lower urinary tract dysfunction (NLUTD) after spinal cord injury (SCI), but also advance therapeutic interventions aimed at recovering bladder function. Although pre-clinical research frequently employs rodent SCI models, large animals such as the pig may play an important translational role in facilitating the development of devices or treatments. Therefore, the objective of this study was to develop a urodynamics protocol to characterize NLUTD in a porcine model of SCI. An iterative process to develop the protocol to perform urodynamics in female Yucatan minipigs began with a group of spinally intact, anesthetized pigs. Subsequently, urodynamic studies were performed in a group of awake, lightly restrained pigs, before and after a contusion-compression SCI at the T2 or T9-T11 spinal cord level. Bladder tissue was obtained for histological analysis at the end of the study. All anesthetized pigs had bladders that were acontractile, which resulted in overflow incontinence once capacity was reached. Uninjured, conscious pigs demonstrated appropriate relaxation and contraction of the external urethral sphincter during the voiding phase. SCI pigs demonstrated neurogenic detrusor overactivity and a significantly elevated post-void residual volume. Relative to the control, SCI bladders were heavier and thicker. The developed urodynamics protocol allows for repetitive evaluation of lower urinary tract function in pigs at different time points post-SCI. This technique manifests the potential for using the pig as an intermediary, large animal model for translational studies in NLUTD.
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http://dx.doi.org/10.1089/neu.2020.7404DOI Listing
May 2021

Relationship between Early Vasopressor Administration and Spinal Cord Hemorrhage in a Porcine Model of Acute Traumatic Spinal Cord Injury.

J Neurotrauma 2020 08 8;37(15):1696-1707. Epub 2020 May 8.

International Collaboration on Repair Discoveries, Department of Orthopedics, The University of British Columbia, Vancouver, British Columbia, Canada.

Current practice guidelines for acute spinal cord injury (SCI) recommend augmenting mean arterial blood pressure (MAP) for the first 7 days post-injury. After SCI, the cord may be compressed by the bone/ligaments of the spinal column, limiting regional spinal cord blood flow. Following surgical decompression, blood flow may be restored, and can potentially promote a "reperfusion" injury. The effects of MAP augmentation on the injured cord during the compressed and decompressed conditions have not been previously characterized. Here, we used our porcine model of SCI to examine the impact of MAP augmentation on blood flow, oxygenation, hydrostatic pressure, metabolism, and intraparenchymal (IP) hemorrhage within the compressed and then subsequently decompressed spinal cord. Yucatan mini-pigs underwent a T10 contusion injury followed by 2 h of sustained compression. MAP augmentation of ∼20 mm Hg was achieved with norepinephrine (NE). Animals received MAP augmentation either during the period of cord compression (CP), after decompression (DCP), or during both periods (CP-DCP). Probes to monitor spinal cord blood flow (SCBF), oxygenation, pressure, and metabolic responses were inserted into the cord parenchyma adjacent to the injury site to measure these responses. The cord was harvested for histological evaluation. MAP augmentation increased SCBF and oxygenation in all groups. In the CP-DCP group, spinal cord pressure steadily increased and histological analysis showed significantly increased hemorrhage in the spinal cord at and near the injury site. MAP augmentation with vasopressors may improve blood flow and reduce ischemia in the injured cord but may also induce undesirable increases in IP pressure and hemorrhage.
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http://dx.doi.org/10.1089/neu.2019.6781DOI Listing
August 2020

Review of the UBC Porcine Model of Traumatic Spinal Cord Injury.

J Korean Neurosurg Soc 2018 Sep 31;61(5):539-547. Epub 2018 Aug 31.

International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Vancouver, Canada.

Traumatic spinal cord injury (SCI) research has recently focused on the use of rat and mouse models for in vivo SCI experiments. Such small rodent SCI models are invaluable for the field, and much has been discovered about the biologic and physiologic aspects of SCI from these models. It has been difficult, however, to reproduce the efficacy of treatments found to produce neurologic benefits in rodent SCI models when these treatments are tested in human clinical trials. A large animal model may have advantages for translational research where anatomical, physiological, or genetic similarities to humans may be more relevant for pre-clinically evaluating novel therapies. Here, we review the work carried out at the University of British Columbia (UBC) on a large animal model of SCI that utilizes Yucatan miniature pigs. The UBC porcine model of SCI may be a useful intermediary in the pre-clinical testing of novel pharmacological treatments, cell-based therapies, and the "bedside back to bench" translation of human clinical observations, which require preclinical testing in an applicable animal model.
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http://dx.doi.org/10.3340/jkns.2017.0276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129752PMC
September 2018

A Direct Comparison between Norepinephrine and Phenylephrine for Augmenting Spinal Cord Perfusion in a Porcine Model of Spinal Cord Injury.

J Neurotrauma 2018 06 28;35(12):1345-1357. Epub 2018 Mar 28.

1 International Collaboration on Repair Discoveries, University of British Columbia (UBC) , Vancouver, British Columbia, Canada .

Current clinical guidelines recommend elevating the mean arterial blood pressure (MAP) to increase spinal cord perfusion in patients with acute spinal cord injury (SCI). This is typically achieved with vasopressors such as norepinephrine (NE) and phenylephrine (PE). These drugs differ in their pharmacological properties and potentially have different effects on spinal cord blood flow (SCBF), oxygenation (PO), and downstream metabolism after injury. Using a porcine model of thoracic SCI, we evaluated how these vasopressors influenced intraparenchymal SCBF, PO, hydrostatic pressure, and metabolism within the spinal cord adjacent to the injury site. Yorkshire pigs underwent a contusion/compression SCI at T10 and were randomized to receive either NE or PE for MAP elevation of 20 mm Hg, or no MAP augmentation. Prior to injury, a combined SCBF/PO sensor, a pressure sensor, and a microdialysis probe were inserted into the spinal cord adjacent to T10 at two locations: a "proximal" site and a "distal" site, 2 mm and 22 mm from the SCI, respectively. At the proximal site, NE and PE resulted in little improvement in SCBF during cord compression. Following decompression, NE resulted in increased SCBF and PO, whereas decreased levels were observed for PE. However, both NE and PE were associated with a gradual decrease in the lactate to pyruvate (L/P) ratio after decompression. PE was associated with greater hemorrhage through the injury site than that in control animals. Combined, our results suggest that NE promotes better restoration of blood flow and oxygenation than PE in the traumatically injured spinal cord, thus providing a physiological rationale for selecting NE over PE in the hemodynamic management of acute SCI.
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http://dx.doi.org/10.1089/neu.2017.5285DOI Listing
June 2018

Changes in Pressure, Hemodynamics, and Metabolism within the Spinal Cord during the First 7 Days after Injury Using a Porcine Model.

J Neurotrauma 2017 12 14;34(24):3336-3350. Epub 2017 Sep 14.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Vancouver, British Columbia, Canada .

Traumatic spinal cord injury (SCI) triggers many perturbations within the injured cord, such as decreased perfusion, reduced tissue oxygenation, increased hydrostatic pressure, and disrupted bioenergetics. While much attention is directed to neuroprotective interventions that might alleviate these early pathophysiologic responses to traumatic injury, the temporo-spatial characteristics of these responses within the injured cord are not well documented. In this study, we utilized our Yucatan mini-pig model of traumatic SCI to characterize intraparenchymal hemodynamic and metabolic changes within the spinal cord for 1 week post-injury. Animals were subjected to a contusion/compression SCI at T10. Prior to injury, probes for microdialysis and the measurement of spinal cord blood flow (SCBF), oxygenation (in partial pressure of oxygen; PaPO), and hydrostatic pressure were inserted into the spinal cord 0.2 and 2.2 cm from the injury site. Measurements occurred under anesthesia for 4 h post-injury, after which the animals were recovered and measurements continued for 7 days. Close to the lesion (0.2 cm), SCBF levels decreased immediately after SCI, followed by an increase in the subsequent days. Similarly, PaPO plummeted, where levels remained diminished for up to 7 days post-injury. Lactate/pyruvate (L/P) ratio increased within minutes. Further away from the injury site (2.2 cm), L/P ratio also gradually increased. Hydrostatic pressure remained consistently elevated for days and negatively correlated with changes in SCBF. An imbalance between SCBF and tissue metabolism also was observed, resulting in metabolic stress and insufficient oxygen levels. Taken together, traumatic SCI resulted in an expanding area of ischemia/hypoxia, with ongoing physiological perturbations sustained out to 7 days post-injury. This suggests that our clinical practice of hemodynamically supporting patients out to 7 days post-injury may fail to address persistent ischemia within the injured cord. A detailed understanding of these pathophysiological mechanisms after SCI is essential to promote best practices for acute SCI patients.
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http://dx.doi.org/10.1089/neu.2017.5034DOI Listing
December 2017

Responses of the Acutely Injured Spinal Cord to Vibration that Simulates Transport in Helicopters or Mine-Resistant Ambush-Protected Vehicles.

J Neurotrauma 2016 12 5;33(24):2217-2226. Epub 2016 Jul 5.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Vancouver, British Columbia, Canada .

In the military environment, injured soldiers undergoing medical evacuation via helicopter or mine-resistant ambush-protected vehicle (MRAP) are subjected to vibration and shock inherent to the transport vehicle. We conducted the present study to assess the consequences of such vibration on the acutely injured spinal cord. We used a porcine model of spinal cord injury (SCI). After a T10 contusion-compression injury, animals were subjected to 1) no vibration (n = 7-8), 2) whole body vibration at frequencies and amplitudes simulating helicopter transport (n = 8), or 3) whole body vibration simulating ground transportation in an MRAP ambulance (n = 7). Hindlimb locomotor function (using Porcine Thoracic Injury Behavior Scale [PTIBS]), Eriochrome Cyanine histochemistry and biochemical analysis of inflammatory and neural damage markers were analyzed. Cerebrospinal fluid (CSF) expression levels for monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, IL-8, and glial fibrillary acidic protein (GFAP) were similar between the helicopter or MRAP group and the unvibrated controls. Spared white/gray matter tended to be lower in the MRAP-vibrated animals than in the unvibrated controls, especially rostral to the epicenter. However, spared white/gray matter in the helicopter-vibrated group appeared normal. Although there was a relationship between the extent of sparing and the extent of locomotor recovery, no significant differences were found in PTIBS scores between the groups. In summary, exposures to vibration in the context of ground (MRAP) or aeromedical (helicopter) transportation did not significantly impair functional outcome in our large animal model of SCI. However, MRAP vibration was associated with increased tissue damage around the injury site, warranting caution around exposure to vehicle vibration acutely after SCI.
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http://dx.doi.org/10.1089/neu.2016.4456DOI Listing
December 2016

The Evaluation of Magnesium Chloride within a Polyethylene Glycol Formulation in a Porcine Model of Acute Spinal Cord Injury.

J Neurotrauma 2016 12 1;33(24):2202-2216. Epub 2016 Jun 1.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Blusson Spinal Cord Center, Vancouver, British Columbia, Canada .

A porcine model of spinal cord injury (SCI) was used to evaluate the neuroprotective effects of magnesium chloride (MgCl) within a polyethylene glycol (PEG) formulation, called "AC105" (Acorda Therapeutics Inc., Ardsley, NY). Specifically, we tested the hypothesis that AC105 would lead to greater tissue sparing at the injury site and improved behavioral outcome when delivered in a clinically realistic time window post-injury. Four hours after contusion/compression injury, Yucatan minipigs were randomized to receive a 30-min intravenous infusion of AC105, magnesium sulfate (MgSO), or saline. Animals received 4 additional infusions of the same dose at 6-h intervals. Behavioral recovery was tested for 12 weeks using two-dimensional (2D) kinematics during weight-supported treadmill walking and the Porcine Injury Behavior Scale (PTIBS), a 10-point locomotion scale. Spinal cords were evaluated ex vivo by diffusion-weighted magnetic resonance imaging (MRI) and subjected to histological analysis. Treatment with AC105 or MgSO did not result in improvements in locomotor recovery on the PTIBS or in 2D kinematics on weight-supported treadmill walking. Diffusion weighted imaging (DWI) showed severe loss of tissue integrity at the impact site, with decreased fractional anisotropy and increased mean diffusivity; this was not improved with AC105 or MgSO treatment. Histological analysis revealed no significant increase in gray or white matter sparing with AC105 or MgSO treatment. Finally, AC105 did not result in higher Mg levels in CSF than with the use of standard MgSO. In summary, when testing AC105 in a porcine model of SCI, we were unable to reproduce the promising therapeutic benefits observed previously in less-severe rodent models of SCI.
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http://dx.doi.org/10.1089/neu.2016.4439DOI Listing
December 2016

The effect of whole-body resonance vibration in a porcine model of spinal cord injury.

J Neurotrauma 2015 Jun 9;32(12):908-21. Epub 2015 Apr 9.

1 International Collaboration on Repair Discoveries (ICORD), University of British Columbia , Vancouver, British Columbia, Canada .

Whole-body vibration has been identified as a potential stressor to spinal cord injury (SCI) patients during pre-hospital transportation. However, the effect that such vibration has on the acutely injured spinal cord is largely unknown, particularly in the frequency domain of 5 Hz in which resonance of the spine occurs. The objective of the study was to investigate the consequences of resonance vibration on the injured spinal cord. Using our previously characterized porcine model of SCI, we subjected animals to resonance vibration (5.7±0.46 Hz) or no vibration for a period of 1.5 or 3.0 h. Locomotor function was assessed weekly and cerebrospinal fluid (CSF) samples were collected to assess different inflammatory and injury severity markers. Spinal cords were evaluated histologically to quantify preserved white and gray matter. No significant differences were found between groups for CSF levels of monocyte chemotactic protein-1, interleukin 6 (IL-6) and lL-8. Glial fibrillary acidic protein levels were lower in the resonance vibration group, compared with the non-vibrated control group. Spared white matter tissue was increased within the vibrated group at 7 d post-injury but this difference was not apparent at the 12-week time-point. No significant difference was observed in locomotor recovery following resonance vibration of the spine. Here, we demonstrate that exposure to resonance vibration for 1.5 or 3 h following SCI in our porcine model is not detrimental to the functional or histological outcomes. Our observation that a 3.0-h period of vibration at resonance frequency induces modest histological improvement at one week post-injury warrants further study.
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http://dx.doi.org/10.1089/neu.2014.3707DOI Listing
June 2015

Cerebrospinal fluid pressures resulting from experimental traumatic spinal cord injuries in a pig model.

J Biomech Eng 2013 Oct;135(10):101005

Despite considerable effort over the last four decades, research has failed to translate into consistently effective treatment options for spinal cord injury (SCI). This is partly attributed to differences between the injury response of humans and rodent models. Some of this difference could be because the cerebrospinal fluid (CSF) layer of the human spine is relatively large, while that of the rodents is extremely thin. We sought to characterize the fluid impulse induced in the CSF by experimental SCIs of moderate and high human-like severity, and to compare this with previous studies in which fluid impulse has been associated with neural tissue injury. We used a new in vivo pig model (n = 6 per injury group, mean age 124.5 days, 20.9 kg) incorporating four miniature pressure transducers that were implanted in pairs in the subarachnoid space, cranial, and caudal to the injury at 30 mm and 100 mm. Tissue sparing was assessed with Eriochrome Cyanine and Neutral Red staining. The median peak pressures near the injury were 522.5 and 868.8 mmHg (range 96.7-1430.0) and far from the injury were 7.6 and 36.3 mmHg (range 3.8-83.7), for the moderate and high injury severities, respectively. Pressure impulse (mmHg.ms), apparent wave speed, and apparent attenuation factor were also evaluated. The data indicates that the fluid pressure wave may be sufficient to affect the severity and extent of primary tissue damage close to the injury site. However, the CSF pressure was close to normal physiologic values at 100 mm from the injury. The high injury severity animals had less tissue sparing than the moderate injury severity animals; this difference was statistically significant only within 1.6 mm of the epicenter. These results indicate that future research seeking to elucidate the mechanical origins of primary tissue damage in SCI should consider the effects of CSF. This pig model provides advantages for basic and preclinical SCI research due to its similarities to human scale, including the existence of a human-like CSF fluid layer.
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http://dx.doi.org/10.1115/1.4025100DOI Listing
October 2013

Intraparenchymal microdialysis after acute spinal cord injury reveals differential metabolic responses to contusive versus compressive mechanisms of injury.

J Neurotrauma 2013 Sep 9;30(18):1564-76. Epub 2013 Aug 9.

International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, Canada.

In animal models, spinal cord injury (SCI) is typically imparted by contusion alone (e.g., weight drop) or by compression alone (e.g., clip compression). In humans, however, the cord is typically injured by a combination of violent contusion followed by varying degrees of ongoing mechanical compression. Understanding how the combination of contusion and compression influences the early pathophysiology of SCI is important for the pre-clinical development of neuroprotective therapies that are applicable to the human condition. Disturbances in the metabolism of energy-related substrates such as lactate, pyruvate, and glucose are important aspects of secondary damage. In this study, we used a porcine model of traumatic SCI to determine the extent to which these metabolites were influenced by contusion followed by sustained compression, using the microdialysis technique. Following contusion injury, lactate and pyruvate levels near the epicenter both increased, while glucose remained quite stable. When the contusion injury was followed by sustained compression, we observed a transient rise in lactate, while pyruvate and glucose levels dropped rapidly, which may reflect decreased regional spinal cord blood flow. Furthermore, contusion with sustained compression produced a prolonged and dramatic increase in the lactate-pyruvate (L/P) ratio as a marker of tissue hypoxia, whereas after contusion injury alone, a transient and less significant elevation of the L/P ratio was observed. In this study, we demonstrate that disturbances in energy metabolism within the injured spinal cord vary greatly depending upon the biomechanical nature of the injury. Such differences are likely to be relevant to the applicability of novel therapies targeting specific aspects of the early secondary injury cascade after acute human SCI.
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http://dx.doi.org/10.1089/neu.2013.2956DOI Listing
September 2013

A novel porcine model of traumatic thoracic spinal cord injury.

J Neurotrauma 2013 Feb 14;30(3):142-59. Epub 2013 Jan 14.

International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, British Columbia, Canada .

Spinal cord injury (SCI) researchers have predominately utilized rodents and mice for in vivo SCI modeling and experimentation. From these small animal models have come many insights into the biology of SCI, and a growing number of novel treatments that promote behavioral recovery. It has, however, been difficult to demonstrate the efficacy of such treatments in human clinical trials. A large animal SCI model that is an intermediary between rodent and human SCI may be a valuable translational research resource for pre-clinically evaluating novel therapies, prior to embarking upon lengthy and expensive clinical trials. Here, we describe the development of such a large animal model. A thoracic spinal cord injury at T10/11 was induced in Yucatan miniature pigs (20-25 kg) using a weight drop device. Varying degrees of injury severity were induced by altering the height of the weight drop (5, 10, 20, 30, 40, and 50 cm). Behavioral recovery over 12 weeks was measured using a newly developed Porcine Thoracic Injury Behavior Scale (PTIBS). This scale distinguished locomotor recovery among animals of different injury severities, with strong intra-observer and inter-observer reliability. Histological analysis of the spinal cords 12 weeks post-injury revealed that animals with the more biomechanically severe injuries had less spared white matter and gray matter and less neurofilament immunoreactivity. Additionally, the PTIBS scores correlated strongly with the extent of tissue sparing through the epicenter of injury. This large animal model of SCI may represent a useful intermediary in the testing of novel pharmacological treatments and cell transplantation strategies.
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http://dx.doi.org/10.1089/neu.2012.2386DOI Listing
February 2013

A grading system to evaluate objectively the strength of pre-clinical data of acute neuroprotective therapies for clinical translation in spinal cord injury.

J Neurotrauma 2011 Aug 18;28(8):1525-43. Epub 2010 Oct 18.

Combined Neurosurgical and Orthopaedic Spine Program, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada.

The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the "robustness" of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials.
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http://dx.doi.org/10.1089/neu.2010.1296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143387PMC
August 2011

A systematic review of cellular transplantation therapies for spinal cord injury.

J Neurotrauma 2011 Aug 20;28(8):1611-82. Epub 2010 Apr 20.

University of British Columbia, ICORD, Vancouver, British Columbia, Canada.

Cell transplantation therapies have become a major focus in pre-clinical research as a promising strategy for the treatment of spinal cord injury (SCI). In this article, we systematically review the available pre-clinical literature on the most commonly used cell types in order to assess the body of evidence that may support their translation to human SCI patients. These cell types include Schwann cells, olfactory ensheathing glial cells, embryonic and adult neural stem/progenitor cells, fate-restricted neural/glial precursor cells, and bone-marrow stromal cells. Studies were included for review only if they described the transplantation of the cell substrate into an in-vivo model of traumatic SCI, induced either bluntly or sharply. Using these inclusion criteria, 162 studies were identified and reviewed in detail, emphasizing their behavioral effects (although not limiting the scope of the discussion to behavioral effects alone). Significant differences between cells of the same "type" exist based on the species and age of donor, as well as culture conditions and mode of delivery. Many of these studies used cell transplantations in combination with other strategies. The systematic review makes it very apparent that cells derived from rodent sources have been the most extensively studied, while only 19 studies reported the transplantation of human cells, nine of which utilized bone-marrow stromal cells. Similarly, the vast majority of studies have been conducted in rodent models of injury, and few studies have investigated cell transplantation in larger mammals or primates. With respect to the timing of intervention, nearly all of the studies reviewed were conducted with transplantations occurring subacutely and acutely, while chronic treatments were rare and often failed to yield functional benefits.
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http://dx.doi.org/10.1089/neu.2009.1177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143488PMC
August 2011

A systematic review of directly applied biologic therapies for acute spinal cord injury.

J Neurotrauma 2011 Aug 16;28(8):1589-610. Epub 2010 Jun 16.

Combined Neurosurgical and Orthopaedic Spine Program, Department of Orthopaedics, University of British Columbia, Vancouver, British Columbia, Canada.

An increasing number of therapies for spinal cord injury (SCI) are emerging from the laboratory and seeking translation into human clinical trials. Many of these are administered as soon as possible after injury with the hope of attenuating secondary damage and maximizing the extent of spared neurologic tissue. In this article, we systematically reviewed the available preclinical research on such neuroprotective therapies that are administered in a non-invasive manner for acute SCI. Specifically, we reviewed treatments that have a relatively high potential for translation due to the fact that they are already used in human clinical applications or are available in a form that could be administered to humans. These included: erythropoietin, NSAIDs, anti-CD11d antibodies, minocycline, progesterone, estrogen, magnesium, riluzole, polyethylene glycol, atorvastatin, inosine, and pioglitazone. The literature was systematically reviewed to examine studies in which an in vivo animal model was utilized to assess the efficacy of the therapy in a traumatic spinal cord injury paradigm. Using these criteria, 122 studies were identified and reviewed in detail. Wide variations exist in the animal species, injury models, and experimental designs reported in the preclinical literature on the therapies reviewed. The review highlights the extent of investigation that has occurred in these specific therapies, and points out gaps in our knowledge that would be potentially valuable prior to human translation.
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http://dx.doi.org/10.1089/neu.2009.1150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3143411PMC
August 2011

Diabetes modulates capacitative calcium entry and expression of transient receptor potential canonical channels in human saphenous vein.

Eur J Pharmacol 2009 Jun 23;613(1-3):114-8. Epub 2009 Apr 23.

The James Hogg iCAPTURE Center for the Cardiovascular and Pulmonary Research, St Paul's Hospital, Vancouver, British Columbia, Canada.

Diabetes is associated with a perturbation of signaling pathways in vascular tissue, which causes vasomotor dysfunction such as hypertension. We have previously demonstrated that vessels from diabetic patients were more contractile than those from non-diabetic. However, in human vessels, the receptor-stimulated contraction is mainly due to enzymatic, rather than calcium signaling pathway. In this study, we hypothesized that the differential contractile response between diabetic and non-diabetic human vessels could be due to the receptor signaling to sarcoplasmic reticulum and the regulation of capacitative calcium entry. In saphenous vein samples (n=20) collected from diabetic patients undergoing bypass surgery, the contraction initiated by the addition of the sarco-endoplasmatic reticulum calcium ATPase blocker, cyclopiazonic acid, was significantly higher than that in the vessels from non-diabetic patients (n=26) (84.0+/-14.9% vs 44.2+/-9.2%), and this contraction was inhibited by SKF-96365, an inhibitor of store-operated calcium channels. Pre-incubation with indomethacin reduced the cyclopiazonic acid-induced contraction in the non-diabetic veins, but had no effect on the diabetic ones. The gene expression of transient receptor potential canonical channels (TRPC)4 was upregulated by 22% in the diabetic vessels compared with the non-diabetic ones. However, the protein expression of TRPC1 and TRPC6 was downregulated in the diabetic group by 50%. We concluded that diabetes would modulate the capacitative calcium entry likely through the store-operated calcium channel specifically via the regulation of TRPC.
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http://dx.doi.org/10.1016/j.ejphar.2009.04.029DOI Listing
June 2009

Arterialization of a vein graft promotes cell cycle progression through Akt and p38 mitogen-activated protein kinase pathways: impact of the preparation procedure.

Can J Cardiol 2007 Dec;23(14):1147-54

James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, Canada.

Background: Vein arterialization following bypass surgery often leads to graft occlusion, but the underlying cellular mechanisms have been poorly studied.

Objectives: Cell cycle progression and the activation of proliferation signalling were compared in arterialized grafts prepared either according to the conventional procedure or using pharmacological relaxation with the native vein.

Methods: Using the porcine carotid-jugular bilateral interposition graft model on one side, a segment of porcine jugular vein was prepared for grafting using the conventional procedure, with pressure distention at 300 mmHg; the segment grafted on the other side was treated with a combination of pharmacological vasodilators. Both veins were grafted into the carotid artery for two weeks.

Results: On the immunolabelling of proliferation cell nuclear antigen, a greater number of proliferating cells was found in the conventionally prepared grafts compared with pharmacologically prepared grafts. Cyclin D1 expression and phosphorylation of retinoblastoma increased after implantation, coinciding with nuclear accumulation of beta-catenin, activation of the Akt and mitogen-activated protein kinase cascades, and upregulated phosphatase and tensin homologue phosphorylation. Replacement of distention with pharmacological relaxation reduced the increase in cyclin D1 expression, phosphorylation of retinoblastoma, Akt-Thr(308), glycogen synthase kinase 3 beta and p38, but not extracellular signal-regulated kinases. This technique preserved the active phosphatase and tensin homologue, as well as the expression of cyclin-dependent kinase inhibitor p21(Cip1), while elevating the expression of p27(Kip1).

Conclusions: It was concluded that two-week arterial implantation stimulates proliferation signalling and promotes the cell cycle in vein grafts. Replacement of the conventional preparation procedures with pharmacological vasorelaxation restricts the activation of proliferation and cell cycle progression, and can be beneficial for improving vein graft patency.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652006PMC
http://dx.doi.org/10.1016/s0828-282x(07)70886-3DOI Listing
December 2007

Hyperglycemia and hyperlipidemia are associated with endothelial dysfunction during the development of type 2 diabetes.

Can J Physiol Pharmacol 2007 May;85(5):562-7

James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, 1081 Burrard Street, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada.

Diabetes mellitus impairs endothelial function, which can be considered as the hallmark in the development of cardiovascular diseases. Hyperglycemia, hyperinsulinemia, and hyperlipidemia are believed to contribute to endothelial dysfunction. In the present study, we investigated the possible links among these plasma metabolic markers and endothelial function in a mouse model during the development of type 2 diabetes. C57BL/6J-Lepob/ob mice at 8, 12, and 16 weeks were used to study endothelial function during the establishment of type 2 diabetes. Endothelial function was accessed in vitro in the thoracic aorta by measuring acetylcholine (ACh)-stimulated vasodilatation. Blood plasma was obtained for the measurements of glucose, insulin, triglycerides, and cholesterol levels. Correlation and multiple regression analysis revealed strong negative associations between the ACh responsiveness and the plasma levels of glucose, insulin, and lipid profiles at the age of 8 weeks. Associations were observed at neither older age nor in C57BL/6J mice. In conclusion, the increase in plasma levels of glucose, insulin, and lipids is associated with the impairment of the endothelial function during the early stage of the development of type 2 diabetes. The loss of correlation at an older age suggests multifactorial regulation of endothelial function and cardiovascular complications at later stages of the disease.
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http://dx.doi.org/10.1139/y07-026DOI Listing
May 2007

Enhanced cell cycle entry and mitogen-activated protein kinase-signaling and downregulation of matrix metalloproteinase-1 and -3 in human diabetic arterial vasculature.

Atherosclerosis 2007 Nov 20;195(1):e1-8. Epub 2007 Feb 20.

The James Hogg iCAPTURE Center for the Cardiovascular and Pulmonary Research, St. Paul's Hospital, Canada.

Diabetic patients have a strong predilection for atherosclerosis and postangioplasty restenosis. Accelerated cell proliferation and excessive extracellular matrix deposition are believed to contribute to the development of atherosclerotic plaques and neointima. We investigated the effect of diabetes on cell cycle, proliferation signaling, and the activation of matrix metalloproteinases (MMPs). Segments of internal mammary arteries from 26 type 2 diabetic and 26 non-diabetic patients undergoing coronary artery bypass grafting surgery were compared. Increased levels of cyclin D1 mRNA (by 135+/-14%) and protein expression (by 93.8+/-7.0%), retinoblastoma protein phosphorylation (by 45.9+/-4.8%), and beta-catenin nuclear localization (by 176+/-16%) indicated the enhanced cell cycle entry in the diabetic arteries. Diabetes increased phosphorylation of extracellular signal-regulated kinase-1/2 and p-38-mitogen-activated protein kinase (MAPK) by 76.0+/-6.8 and 62.3+/-4.3%. Increased collagen deposition was evidenced in the diabetic arteries. mRNA levels of MMP-1 and MMP-3 were decreased in the diabetic tissue to 55 and 82%, respectively, compared to the non-diabetic group; protein levels were also decreased accompanied with decreased enzymatic activities by 21 and 50%, respectively. In conclusion, enhanced cell cycle entry, increased MAPK signaling, and downregulated MMP-1 and MMP-3 were characteristic of diabetic arterial vasculature, and could contribute to the progressive atherosclerosis and postangioplasty restenosis in diabetic patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2007.01.011DOI Listing
November 2007

Fast, cheap and out of control: a zero curation model for ontology development.

Pac Symp Biocomput 2006 :128-39

James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia V6Z1 Y6, Canada.

During two days at a conference focused on circulatory and respiratory health, 68 volunteers untrained in knowledge engineering participated in an experimental knowledge capture exercise. These volunteers created a shared vocabulary of 661 terms, linking these terms to each other and to a pre-existing upper ontology by adding 245 hyponym relationships and 340 synonym relationships. While ontology-building has proved to be an expensive and labor-intensive process using most existing methodologies, the rudimentary ontology constructed in this study was composed in only two days at a cost of only 3 t-shirts, 4 coffee mugs, and one chocolate moose. The protocol used to create and evaluate this ontology involved a targeted, web-based interface. The design and implementation of this protocol is discussed along with quantitative and qualitative assessments of the constructed ontology.
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January 2007

Pharmacologic relaxation of vein grafts is beneficial compared with pressure distention caused by upregulation of endothelial nitric oxide synthase and nitric oxide production.

J Thorac Cardiovasc Surg 2006 Oct;132(4):925-32

James Hogg iCAPTURE Center for the Cardiovascular and Pulmonary Research, St Paul's Hospital, Vancouver, British Columbia, Canada.

Objective: Pressure distention of veins during preparation for bypass surgery is believed to impair vascular integrity and reduce graft patency. We previously suggested a combination of pharmacologic vasodilatators as an alternative to distention. Vascular homeostasis is largely regulated by nitric oxide. We investigated the role of distention in comparison with pharmacologic vasorelaxation in the regulation of nitric oxide synthases, nitric oxide bioavailability, and vascular reactivity in vein grafts.

Methods: In a porcine model the internal jugular vein from either side received pressure distention or the combination of vasodilators (alpha-adrenergic antagonist, phenoxybenzamine, 10 micromol/L; Rho-kinase inhibitor, HA-1077 [fasudil], 50 mumol/L; calcium blocker, nicardipine, 1 micromol/L) and then was grafted into the carotid artery. Regulation of nitric oxide synthase, as well as nitrate and nitrite levels, were examined in vein grafts after 2 weeks of implantation.

Results: Distention of jugular veins resulted in reduction of vasoconstriction in response to depolarization and agonist stimulation. Arterial grafting doubled inducible nitric oxide synthase expression in both grafts but caused a pronounced upregulation of endothelial nitric oxide synthase protein (by 57.3% +/- 5%) only in drug-treated grafts, whereas in distended grafts the endothelial nitric oxide synthase level was decreased by 27.5% +/- 2.7%. The downregulated endothelial nitric oxide synthase level in the distended grafts was accompanied by a 45.2% +/- 3.1% reduction of phospho-endothelial nitric oxide synthase Ser1177 levels and by a significant reduction in nitric oxide synthase activity (12.1% +/- 1.2%) and nitrate production (48.9% +/- 5.6%) in comparison with that seen in drug-treated grafts.

Conclusions: Pharmacologic preparation of the vein grafts results in upregulation of endothelial nitric oxide synthase and increased nitric oxide production in the vein grafts after arterial implantation. This might provide greater clinical benefit than conventional pressure-distention methods.
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http://dx.doi.org/10.1016/j.jtcvs.2006.04.033DOI Listing
October 2006

Reduced expression of vascular endothelial growth factor paralleled with the increased angiostatin expression resulting from the upregulated activities of matrix metalloproteinase-2 and -9 in human type 2 diabetic arterial vasculature.

Circ Res 2006 Jul 15;99(2):140-8. Epub 2006 Jun 15.

The James Hogg iCAPTURE Center for the Cardiovascular and Pulmonary Research, St. Paul's Hospital, University of British Columbia, Vancouver, Canada.

Impaired angiogenesis could contribute to the increased incidence of coronary and peripheral artery disease in diabetic patients. Angiogenesis is initiated by vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, and suppressed by angiostatin, which is generated by matrix metalloproteinase (MMP)-2 and -9 through proteolytic cleavage of plasminogen. We hypothesized that MMP-2 and -9 were upregulated in the diabetic vasculature, resulting in increased angiostatin production and reduced blood vessel formation. In diabetic internal mammary artery samples (n=32) collected from patients undergoing coronary artery bypass grafting surgery, capillary density was only 30% of that in the nondiabetic vessels (n=32), whereas VEGF expression was reduced by 48%. Diabetes upregulated the expression and the gelatinolytic activity of MMP-2 and -9. Active MMP-2 and -9 were released from diabetic arteries, but not from nondiabetic vessels, during phenylephrine-induced vasoconstriction. Diabetes enhanced transcription and protein expression of tissue inhibitor of MMP (TIMP)-1 but had an opposite effect on TIMP-2. In diabetic vessels angiostatin was increased by 62% and was positively correlated with the activities of MMP-2 and -9 (r2=0.806 and 0.742, respectively). This report indicated a strong correlation between the upregulation of MMP-2 and MMP-9 and the increased angiostatin expression in the human diabetic arterial vasculature. The enhanced angiostatin production with a reduced VEGF formation may explain the pathogenesis of impaired angiogenesis in diabetes mellitus.
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http://dx.doi.org/10.1161/01.RES.0000232352.90786.faDOI Listing
July 2006

Pressure distention compared with pharmacologic relaxation in vein grafting upregulates matrix metalloproteinase-2 and -9.

J Vasc Surg 2005 Oct;42(4):747-56

James Hogg iCAPTURE Center, St. Paul's Hospital, Vancouver, British Columbia, Canada.

Objective: Autogenous vein bypasses are a common and effective method to treat occlusive disease. During surgical preparation, veins are routinely pressure distended to overcome vasospasm and twists. Distention, however, is believed to promote vascular remodeling and contribute to decreased graft patency. Pharmacologic vasorelaxation with a combination of effective vasodilators has been suggested as an alternative to pressure distention. The extracellular matrix (ECM)-degrading matrix metalloproteinases (MMPs) have been implicated in vascular remodeling and neointima formation. The purpose of the present study was to compare the effects of pressure distention with pharmacologic vasorelaxation on graft remodeling and regulation of MMP-2 and MMP-9 in porcine vein grafts.

Methods: Carotid artery bypass utilizing internal jugular veins was performed in eight female white pigs. Jugular veins were randomized to receive pressure distention (300 mm Hg for 2 minutes) or a combination of vasodilators (the alpha-adrenergic antagonist phenoxybenzamine, 10 micromol/L; the Rho-kinase inhibitor HA-1077 [fasudil], 50 micromol/L; and the calcium-channel blocker nicardipine, 1 micromol/L) for 30 minutes and then were grafted into the carotid arteries. Two weeks after surgery, vein graft samples were analyzed for vessel intimal and medial area, lumen diameter, and ECM composition. Molecular analysis using reverse transcription-polymerase chain reaction, Western immunoblotting, gelatin zymography, and reverse zymography were performed to study the expression and activation of MMP-2 and MMP-9, and tissue inhibitors of MMP (TIMP)-1 and TIMP-2.

Results: Pressure distention irreversibly overstretched the porcine jugular vein and increased MMP-2 and MMP-9 proteolytic activity by 40% and 77%, respectively. Two weeks of vein grafting in the carotid arterial bed induced vessel wall thickening, ECM modification, and neointima formation, which were more pronounced in the distended grafts (P < .05) and accompanied by an increase in MMP expression and activity. Distended grafts demonstrated higher percentages of active MMP-9 (17.8% +/- 1.0%) and higher activities of latent (35.5% +/- 3.3%) and active MMP-2 (69.6% +/- 8.8%) than the pharmacologically treated grafts. Protein expression of TIMP-1 and TIMP-2 was downregulated after arterial grafting, but the pharmacologically treated grafts expressed significantly more TIMP-1 protein (by 36.8% +/- 4.1%) than the distended ones. The activities of TIMPs were markedly decreased after grafting, contributing to the upregulated MMP activity.

Conclusions: Pressure distention of vein grafts before implantation, compared with pharmacologic vasodilatation, stimulates neointima formation and augments MMP activities. Pharmacologic vasorelaxation may be clinically superior to distention in attenuating graft remodeling and possibly improving graft patency.

Clinical Relevance: Autogenous vein bypasses are a common and effective method to treat occlusive disease. This study demonstrated that pressure distention, a common preparatory procedure in bypass surgery, upregulates extracellular matrix-degrading matrix metalloproteinases, which predisposes vein grafts to extensive remodeling and contributes to neointima formation and graft occlusion. The topical application of a combination of vasodilators to the vein graft before implantation may be clinically superior to pressure distention in attenuating graft remodeling and may possibly improve graft patency and reduce secondary surgical interventions.
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http://dx.doi.org/10.1016/j.jvs.2005.05.037DOI Listing
October 2005

Compromised arterial function in human type 2 diabetic patients.

Diabetes 2005 Aug;54(8):2415-23

James Hogg iCAPTURE Center, St. Paul's Hospital, Room 166, 1081 Burrard St., Vancouver, BC, Canada V6Z 1Y6.

Diabetes is associated with a perturbation of signaling pathways in vascular tissue, which causes vasomotor dysfunction such as hypertension and accelerated atherosclerosis. In the present study, the mechanisms of vasomotor dysfunction, Akt (Thr308 and Ser473) phosphorylation and expression of endothelial NO (nitric oxide) synthase, and inducible NO synthase were investigated in human diabetic internal mammary arteries. The phospho-Akt (Thr308) level in arteries from diabetic patients was reduced to about one-half of the level in nondiabetic patients, suggesting impaired insulin signaling in human diabetic vascular tissue. Augmented vasoconstriction was observed in diabetic arteries, due in part to deficiency of basal and stimulated NO production. This correlated with decreased endothelial NO synthase expression and activity in diabetic vessels. The sensitivity of diabetic vessels to the NO donor, sodium nitroprusside, was reduced as well, suggesting that NO breakdown and/or decreased sensitivity of smooth muscle to NO are also responsible for abnormal vasoconstriction. In addition, the abnormal vasoconstriction in diabetic vessels was not completely abolished in the presence of Nomega-nitro-L-arginine methyl ester, revealing that NO-independent mechanisms also contribute to vasomotor dysfunction in diabetes. In conclusion, diabetes downregulates the Akt-signaling pathway and compromises human arterial function through a decrease in NO availability as well as through NO-independent mechanisms.
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http://dx.doi.org/10.2337/diabetes.54.8.2415DOI Listing
August 2005

Effect of moderate pressure distention on the human saphenous vein vasomotor function.

Ann Thorac Surg 2004 Jan;77(1):108-14; discussion 114-5

Department of Pathology and Laboratory Medicine, University of British Columbia and St Paul Hospital, Vancouver, British Columbia, Canada.

Background: Manual pressure distension, which is commonly applied to the human saphenous vein graft for coronary artery bypass, is believed to have detrimental consequences for the graft patency. The vasomotor function of the vein after distention during surgical preparation for grafting and after distention in laboratory conditions at pressure of 50 to 600 mm Hg was studied. The effect of a combination of vasodilative agents to prevent vasospasm was also tested.

Methods: The contractile and dilatory responses of distended and undistended human saphenous veins and those after drug treatment were examined in organ baths under isometric conditions.

Results: Distention at the pressure range 100 to 300 mm Hg resulted in an increased contractile response of the saphenous vein to both alpha-adrenergic activation with 50 micromol/L phenylephrine (153.73% +/- 15.69%) and depolarization with 80 mmol/L K(+) (141.03% +/- 15.13%) in comparison with the undistended vein and did not impair the relaxation. In contrast manual distention during surgical preparation abolished the contractile response and impaired the relaxation. The application of a combination of vasodilative drugs (alpha-adrenergic antagonist phenoxybenzamine, 10 micromol/L, Rho-kinase inhibitor HA-1077, 50 micromol/L, and calcium blocker nicardipine, 1 micromol/L) eliminated the contractile response of the vein to phenylephrine and 80 mmol/L K(+). This effect was sustained more than 20 hours after the washout of the drugs.

Conclusions: The distention of the human saphenous vein at moderate pressure combined with the application of the effective combination of vasodilative drugs before grafting into the arterial circulation could be a beneficial alternative to the current practice of uncontrolled pressure distension.
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http://dx.doi.org/10.1016/j.athoracsur.2003.06.007DOI Listing
January 2004

Augmented contractile response of vascular smooth muscle in a diabetic mouse model.

J Vasc Res 2003 Nov-Dec;40(6):520-30. Epub 2003 Nov 27.

iCAPTUR(4)E Centre and Department of Pathology, University of British Columbia, Vancouver, Canada.

The vasomotor properties of isolated aortae and mesenteric arteries of insulin-resistant ob/ob and 57CBL/6J mice were compared in organ bath studies. Vessels from ob/ob mice were more sensitive to phenylephrine. Pretreatment with L-NAME caused similar leftward shifts of the phenylephrine concentration response curves in diabetic and non-diabetic vessels. The ob/ob aortae contracted in response to phenylephrine with roughly twice the force while they were not stiffer than control aortae. L-NAME caused a greater percentage increase in maximal force in the control than in the ob/ob tissue. Denudation potentiated force in the control aortae, but not in the ob/ob aortae. Endothelium-dependent relaxation in the ob/ob aortae and mesenteric arteries was impaired as manifested by a decreased sensitivity and maximal relaxation to acetylcholine, while the aortic basal eNOS mRNA levels did not differ between the two strains. In addition, ob/ob aortae were less sensitive to the nitric oxide donor sodium nitroprusside. Inhibition of endogenous prostaglandin synthesis with indomethacin (10 microM) partly normalized the contractile response of the ob/ob aortae and enhanced their endothelium-dependent relaxation. Neither blockade of endothelin-1 receptors (bosentan, 10 microM) nor PKC inhibition (calphostin, 1 microM) affected the contractile response to phenylephrine in the mouse aortae of either strain. In conclusion, vascular dysfunction in the aorta and mesenteric artery of ob/ob mice are due to increased smooth muscle contractility and impaired dilation but not to changes in elasticity of the vascular wall. Endothelium-produced prostaglandins contribute to the increased vasoconstriction.
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http://dx.doi.org/10.1159/000075238DOI Listing
February 2004

In the presence of L-NAME SERCA blockade induces endothelium-dependent contraction of mouse aorta through activation of smooth muscle prostaglandin H2/thromboxane A2 receptors.

Br J Pharmacol 2002 Oct;137(4):545-53

iCAPTUR E Center, University of British Columbia and St. Paul's Hospital, Vancouver, British Columbia, Canada.

1. The mechanism of transient contractions induced by the sarcoplasmic-endoplasmic reticulum calcium ATPase (SERCA) blocker cyclopiazonic acid (CPA) in the presence of L-NAME was investigated in mouse aorta. 2. The contractions elicited by 10 micro M CPA required an intact endothelium, were dependent upon external Ca(2+) and were prevented by 10 micro M indomethacin, the inhibitor of prostaglandin synthesis, or 1 micro M SQ29548, the specific prostaglandin H2/thromboxane A2 (PGH2/TXA2) receptor blocker. 3. A blocker of receptor/store operated Ca(2+) channels and voltage gated calcium channels (VGCC), SK&F 96365 (10 micro M), completely abolished the contractions, while a specific blocker of VGCC nifedipine (1 micro M) inhibited them by one third. 4. Dichlorobenzamyl hydrochloride, a blocker of Na(+)/Ca(2+) exchange effectively prevented return of tension to baseline value. 5. At higher concentrations (30-100 micro M) CPA induced indomethacin-resistant tonic contractions of mouse aorta. The CPA dose response curve for tonic contractions is shifted to the right compared to the transient contractions suggesting that smooth muscle is less sensitive to CPA than endothelium. 6. PGH2/TXA2 receptors in mouse aorta are highly sensitive to the thromboxane analogue U46619 (EC(50) : 1.93 nM). This compound stimulates contractions even in the absence of external Ca(2+), which are abolished by the Rho-kinase inhibitor HA-1077. 7. The results suggest that 10 micro M CPA induced capacitive Ca(2+) entry in endothelial cells stimulating the release of PGH2/TXA2, which subsequently caused smooth muscle contraction dependent on Ca(2+) influx and myofilament sensitization by Rho-kinase. Higher concentrations of CPA (30-100 micro M) directly induced contraction of mouse aortic smooth muscle.
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http://dx.doi.org/10.1038/sj.bjp.0704884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573510PMC
October 2002
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