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1.
Am J Otolaryngol ; 43(5): 103598, 2022.
Article in English | MEDLINE | ID: mdl-35981429

ABSTRACT

BACKGROUND: The time and cost of data collection via chart review of the electronic medical record (EMR) is a research barrier. This study describes the development of a digital dashboard conjoining EMR and finance data and its application in a pediatric otolaryngology practice. METHODS: The dashboard creates a common language crosswalk between surgeries via the EMR, financial data, and national Vizient database. First, all Otolaryngology procedures billed via ICD-10 or CPT codes were categorized into Procedure Groups, which constitute the common language that links all data sources. The joined dataset was inputted into a Tableau workbook supporting dynamic filtering and custom real-time analysis. RESULTS: The dashboard includes 84 Procedure Groups within Otolaryngology. Examples for pediatrics include Sistrunk procedure and supraglottoplasty. User-friendly dynamic filtering by Procedure Group, surgery date range, age, insurance, hospital, surgeon, and discharge status were developed. Outcomes include length of stay, telephone callbacks, postoperative hemorrhage, reoperations, return to Emergency Department, readmissions, and mortality. National comparisons can be analyzed via embedded Vizient data. The usability of the dashboard was tested by evaluating pediatric tonsillectomy outcomes, which revealed a significantly higher rate of postoperative hemorrhages and reoperations during the COVID-19 pandemic. CONCLUSION: The hybrid finance/EMR dashboard creates a crosswalk between data sources and shows utility for use in evaluating patient outcomes via real-time data analysis and dynamic filtering. This innovative dashboard expedites data extraction, promoting efficient implementation of quality improvement initiatives and surgical outcomes research.


Subject(s)
COVID-19 , Otolaryngology , Pediatrics , COVID-19/epidemiology , Child , Electronic Health Records , Humans , Pandemics
3.
Appl Clin Inform ; 11(4): 564-569, 2020 08.
Article in English | MEDLINE | ID: mdl-32851617

ABSTRACT

BACKGROUND: Performing high-quality surveillance for influenza-associated hospitalization (IAH) is challenging, time-consuming, and essential. OBJECTIVES: Our objectives were to develop a fully automated surveillance system for laboratory-confirmed IAH at our multihospital health system, to evaluate the performance of the automated system during the 2018 to 2019 influenza season at eight hospitals by comparing its sensitivity and positive predictive value to that of manual surveillance, and to estimate the time and cost savings associated with reliance on the automated surveillance system. METHODS: Infection preventionists (IPs) perform manual surveillance for IAH by reviewing laboratory records and making a determination about each result. For automated surveillance, we programmed a query against our Enterprise Data Vault (EDV) for cases of IAH. The EDV query was established as a dynamic data source to feed our data visualization software, automatically updating every 24 hours.To establish a gold standard of cases of IAH against which to evaluate the performance of manual and automated surveillance systems, we generated a master list of possible IAH by querying four independent information systems. We reviewed medical records and adjudicated whether each possible case represented a true case of IAH. RESULTS: We found 844 true cases of IAH, 577 (68.4%) of which were detected by the manual system and 774 (91.7%) of which were detected by the automated system. The positive predictive values of the manual and automated systems were 89.3 and 88.3%, respectively.Relying on the automated surveillance system for IAH resulted in an average recoup of 82 minutes per day for each IP and an estimated system-wide payroll redirection of $32,880 over the four heaviest weeks of influenza activity. CONCLUSION: Surveillance for IAH can be entirely automated at multihospital health systems, saving time, and money while improving case detection.


Subject(s)
Electronic Health Records , Epidemiological Monitoring , Hospitalization/statistics & numerical data , Influenza, Human/epidemiology , Influenza, Human/therapy , Automation , Data Mining , Humans , Laboratories , Ohio/epidemiology , Software
4.
Surgery ; 166(4): 691-697, 2019 10.
Article in English | MEDLINE | ID: mdl-31402128

ABSTRACT

BACKGROUND: Care pathways facilitate standardized, evidence-based treatment to improve outcomes and value of care. Care pathways consist of multiple nodes representing decision points. Few studies investigate care pathway compliance. We demonstrate nodal care pathway analysis by reviewing compliance with our institutional multidisciplinary, evidence-based care pathways on the treatment of thyroid nodule to generate strategies to increase care pathway adherence and value of care. METHODS: Patients undergoing workup and treatment of structural thyroid disease between January 2018 and June 2018 were included in a retrospective analysis of enterprise-wide compliance with the following 3 care pathway nodes: (1) laboratory testing: only patients with abnormal results from thyroid-stimulating hormone testing should have T3/T4 measured. (2) imaging: neck computed tomography, magnetic resonance imaging, and positron emission tomography ordered for the workup of nodules were reviewed to determine clinical appropriateness. (3) operative treatment: the first 200 thyroid resections conducted in 2018 were reviewed to determine whether the indication and extent of the operation complied with the care pathway. Medicare fee schedules were used for financial calculations. RESULTS: Care pathway nonadherence occurred in 48% of the thyroid-stimulating hormone studies and 38% of the imaging studies obtained, with annual costs exceeding $120,000. Substantial care pathway nonadherence occurred in 3% of nodule-related operations. CONCLUSION: Care pathway nodal analysis can identify areas of care pathway nonadherence. Nodal analysis should be considered for care pathway maintenance and generation of strategies of quality improvement.


Subject(s)
Critical Pathways , Thyroid Diseases/diagnostic imaging , Thyroid Nodule/diagnostic imaging , Thyroidectomy/methods , Treatment Adherence and Compliance , Academic Medical Centers , Adult , Cohort Studies , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Positron-Emission Tomography/methods , Quality of Health Care , Retrospective Studies , Thyroid Diseases/pathology , Thyroid Diseases/surgery , Thyroid Function Tests , Thyroid Nodule/pathology , Thyroid Nodule/surgery , Tomography, X-Ray Computed/methods
5.
Cancer Causes Control ; 26(12): 1813-24, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26407955

ABSTRACT

PURPOSE: We investigated the breast cancer survival disparity between Indigenous Maori and non-Indigenous European women in New Zealand, and quantified the relative contributions of patient, tumor and healthcare system factors toward this disparity. METHODS: All women diagnosed with breast cancer in Waikato, New Zealand, during 1999-2012 were identified from the Waikato Breast Cancer Register. Cancer-specific survivals were compared using Kaplan-Meier survival curves, while contributions of different factors toward the survival disparity were quantified with serial Cox proportional hazard modeling. RESULTS: Of the 2,679 women included in this study, 2,260 (84.4%) were NZ European and 419 (15.6%) were Maori. Compared with NZ European women, Maori women had a significantly higher age-adjusted cancer-specific mortality (HR 2.02, 95% CI 1.59-2.58) with significantly lower 5-year (86.8 vs. 76.1%, p < 0.001) and 10-year (79.9 vs. 66.9%, p < 0.001%) crude cancer-specific survivals. Stage at diagnosis made the greatest contribution (approximately 25-40%), while screening, treatment and patient factors (i.e., comorbidity, obesity and smoking) contributed by approximately 15% each toward the survival disparity. The final model accounted for almost all of the cancer survival disparity (HR 1.07, 95% CI 0.80-1.44). CONCLUSIONS: Maori women experience an age-adjusted risk of death from breast cancer, which is more than twice that for NZ European women. Equity-focussed improvements in health care, including increasing mammographic screening coverage and providing equitable quality and timely cancer care, may improve the survival disparity between Maori and NZ European women.


Subject(s)
Breast Neoplasms/epidemiology , Mammography , Native Hawaiian or Other Pacific Islander/statistics & numerical data , White People/statistics & numerical data , Adult , Aged , Breast Neoplasms/diagnosis , Breast Neoplasms/ethnology , Comorbidity , Early Detection of Cancer , Female , Humans , Kaplan-Meier Estimate , Middle Aged , New Zealand , Risk
6.
PLoS One ; 10(4): e0123523, 2015.
Article in English | MEDLINE | ID: mdl-25849101

ABSTRACT

INTRODUCTION: Indigenous Maori women have a 60% higher breast cancer mortality rate compared with European women in New Zealand. We investigated differences in cancer biological characteristics and their impact on breast cancer mortality disparity between Maori and NZ European women. MATERIALS AND METHODS: Data on 2849 women with primary invasive breast cancers diagnosed between 1999 and 2012 were extracted from the Waikato Breast Cancer Register. Differences in distribution of cancer biological characteristics between Maori and NZ European women were explored adjusting for age and socioeconomic deprivation in logistic regression models. Impacts of socioeconomic deprivation, stage and cancer biological characteristics on breast cancer mortality disparity between Maori and NZ European women were explored in Cox regression models. RESULTS: Compared with NZ European women (n=2304), Maori women (n=429) had significantly higher rates of advanced and higher grade cancers. Maori women also had non-significantly higher rates of ER/PR negative and HER-2 positive breast cancers. Higher odds of advanced stage and higher grade remained significant for Maori after adjusting for age and deprivation. Maori women had almost a 100% higher age and deprivation adjusted breast cancer mortality hazard compared with NZ European women (HR=1.98, 1.55-2.54). Advanced stage and lower proportion of screen detected cancer in Maori explained a greater portion of the excess breast cancer mortality (HR reduction from 1.98 to 1.38), while the additional contribution through biological differences were minimal (HR reduction from 1.38 to 1.35). CONCLUSIONS: More advanced cancer stage at diagnosis has the greatest impact while differences in biological characteristics appear to be a minor contributor for inequities in breast cancer mortality between Maori and NZ European women. Strategies aimed at reducing breast cancer mortality in Maori should focus on earlier diagnosis, which will likely have a greater impact on reducing breast cancer mortality inequity between Maori and NZ European women.


Subject(s)
Breast Neoplasms/mortality , Carcinoma, Ductal, Breast/mortality , Carcinoma, Lobular/mortality , Ethnicity/statistics & numerical data , Healthcare Disparities , Biomarkers, Tumor/metabolism , Breast Neoplasms/epidemiology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/epidemiology , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/epidemiology , Carcinoma, Lobular/metabolism , Carcinoma, Lobular/pathology , Cohort Studies , Early Detection of Cancer , Female , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Staging , New Zealand/epidemiology , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Registries , Risk Factors , Survival Rate
7.
BMC Public Health ; 15: 46, 2015 Jan 31.
Article in English | MEDLINE | ID: mdl-25637343

ABSTRACT

BACKGROUND: Indigenous Maori women experience a 60% higher breast cancer mortality rate compared with European women in New Zealand. We explored the impact of differences in rates of screen detected breast cancer on inequities in cancer stage at diagnosis and survival between Maori and NZ European women. METHODS: All primary breast cancers diagnosed in screening age women (as defined by the New Zealand National Breast Cancer Screening Programme) during 1999-2012 in the Waikato area (n = 1846) were identified from the Waikato Breast Cancer Register and the National Screening Database. Stage at diagnosis and survival were compared for screen detected (n = 1106) and non-screen detected (n = 740) breast cancer by ethnicity and socioeconomic status. RESULTS: Indigenous Maori women were significantly more likely to be diagnosed with more advanced cancer compared with NZ European women (OR = 1.51), and approximately a half of this difference was explained by lower rate of screen detected cancer for Maori women. For non-screen detected cancer, Maori had significantly lower 10-year breast cancer survival compared with NZ European (46.5% vs. 73.2%) as did most deprived compared with most affluent socioeconomic quintiles (64.8% vs. 81.1%). No significant survival differences were observed for screen detected cancer by ethnicity or socioeconomic deprivation. CONCLUSIONS: The lower rate of screen detected breast cancer appears to be a key contributor towards the higher rate of advanced cancer at diagnosis and lower breast cancer survival for Maori compared with NZ European women. Among women with screen-detected breast cancer, Maori women do just as well as NZ European women, demonstrating the success of breast screening for Maori women who are able to access screening. Increasing breast cancer screening rates has the potential to improve survival for Maori women and reduce breast cancer survival inequity between Maori and NZ European women.


Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/mortality , Ethnicity/statistics & numerical data , Mammography/statistics & numerical data , Mass Screening/statistics & numerical data , Aged , Breast Neoplasms/pathology , Cohort Studies , Early Detection of Cancer/statistics & numerical data , Female , Humans , Middle Aged , New Zealand/epidemiology , Severity of Illness Index , Social Class , Socioeconomic Factors , Survival Analysis
8.
ANZ J Surg ; 85(5): 353-7, 2015 May.
Article in English | MEDLINE | ID: mdl-24754798

ABSTRACT

BACKGROUND: There is limited evidence to support use of local anaesthetic (LA) wound infiltration in breast surgery. This study seeks to examine whether wound infiltration of bupivacaine (0.25%) decreases post-operative pain and analgesic use, without increasing post-operative complications. METHODS: A prospective single-blind study was undertaken of 90 patients undergoing breast lump excision, wide local excision and mastectomy with or without axillary surgery. Patients were randomized to receive infiltration with bupivacaine (0.25%) into the surgical wound (Group LA) or no infiltration (Group No LA). Data on post-operative analgesia use was collected. Pain scores were assessed at 1, 24, 48 h and 1 week with a visual analogue scale. Complications associated with wound healing were documented at the first post-operative visit. RESULTS: Forty-five patients received infiltration and 34 patients received none. There were no significant differences in baseline characteristics between patient groups or surgical details. Analysis revealed Group LA used significantly less opioids than Group No LA during the first 48 h post-op (3.42 mg versus 7.33 mg; P = 0.02). Overall, Group LA used half the total average opioid equivalent amount (5.04 mg versus 10.08 mg; P = 0.069). There were no significant differences in post-operative pain scores or complications. Overall pain scores were low, suggesting effective analgesic use by nursing staff. DISCUSSION: LA infiltration during breast surgery has a marked opioid sparing effect, which has significant patient benefits as well as reducing nursing workload and drug costs.


Subject(s)
Anesthesia, Local , Anesthetics, Local/therapeutic use , Bupivacaine/therapeutic use , Intraoperative Care/methods , Mastectomy , Pain, Postoperative/prevention & control , Adult , Aged , Aged, 80 and over , Analgesics, Opioid/therapeutic use , Female , Follow-Up Studies , Humans , Middle Aged , Pain Measurement , Pain, Postoperative/diagnosis , Pain, Postoperative/drug therapy , Prospective Studies , Single-Blind Method , Treatment Outcome
9.
Nature ; 515(7527): 431-435, 2014 Nov 20.
Article in English | MEDLINE | ID: mdl-25383517

ABSTRACT

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies.


Subject(s)
Ischemia/metabolism , Mitochondria/metabolism , Reactive Oxygen Species/metabolism , Reperfusion Injury/metabolism , Succinic Acid/metabolism , Adenosine Monophosphate/metabolism , Animals , Aspartic Acid/metabolism , Citric Acid Cycle , Disease Models, Animal , Electron Transport , Electron Transport Complex I/metabolism , Fumarates/metabolism , Ischemia/enzymology , Malates/metabolism , Male , Metabolomics , Mice , Mitochondria/enzymology , Myocardial Infarction/enzymology , Myocardial Infarction/metabolism , Myocardium/cytology , Myocardium/enzymology , Myocardium/metabolism , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/metabolism , NAD/metabolism , Reperfusion Injury/enzymology , Stroke/enzymology , Stroke/metabolism , Succinate Dehydrogenase/metabolism
10.
Cancer Epidemiol ; 38(5): 638-44, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25037979

ABSTRACT

PURPOSE: Population based cancer registries are an invaluable resource for monitoring incidence and mortality for many types of cancer. Research and healthcare decisions based on cancer registry data rely on the case completeness and accuracy of recorded data. This study was aimed at assessing completeness and accuracy of breast cancer staging data in the New Zealand Cancer Registry (NZCR) against a regional breast cancer register. METHODOLOGY: Data from 2562 women diagnosed with invasive primary breast cancer between 1999 and 2011 included in the Waikato Breast Cancer Register (WBCR) were used to audit data held on the same individuals by the NZCR. WBCR data were treated as the benchmark. RESULTS: Of 2562 cancers, 315(12.3%) were unstaged in the NZCR. For cancers with a known stage in the NZCR, staging accuracy was 94.4%. Lower staging accuracies of 74% and 84% were noted for metastatic and locally invasive (involving skin or chest wall) cancers, respectively, compared with localized (97%) and lymph node positive (94%) cancers. Older age (>80 years), not undergoing therapeutic surgery and higher comorbidity score were significantly (p<0.01) associated with unstaged cancer. The high proportion of unstaged cancer in the NZCR was noted to have led to an underestimation of the true incidence of metastatic breast cancer by 21%. Underestimation of metastatic cancer was greater for Maori (29.5%) than for NZ European (20.6%) women. Overall 5-year survival rate for unstaged cancer (NZCR) was 55.9%, which was worse than the 5-year survival rate for regional (77.3%), but better than metastatic (12.9%) disease. CONCLUSIONS: Unstaged cancer and accuracy of cancer staging in the NZCR are major sources of bias for the NZCR based research. Improving completeness and accuracy of staging data and increasing the rate of TNM cancer stage recording are identified as priorities for strengthening the usefulness of the NZCR.


Subject(s)
Breast Neoplasms/pathology , Population Surveillance/methods , Registries/standards , Adult , Age Factors , Aged , Aged, 80 and over , Bias , Breast Neoplasms/epidemiology , Female , Humans , Incidence , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Staging , New Zealand/epidemiology , Survival Rate
11.
Antioxidants (Basel) ; 3(3): 472-501, 2014 Jul 03.
Article in English | MEDLINE | ID: mdl-26785066

ABSTRACT

Transient or permanent interruption of cerebral blood flow by occlusion of a cerebral artery gives rise to an ischaemic stroke leading to irreversible damage or dysfunction to the cells within the affected tissue along with permanent or reversible neurological deficit. Extensive research has identified excitotoxicity, oxidative stress, inflammation and cell death as key contributory pathways underlying lesion progression. The cornerstone of treatment for acute ischaemic stroke remains reperfusion therapy with recombinant tissue plasminogen activator (rt-PA). The downstream sequelae of events resulting from spontaneous or pharmacological reperfusion lead to an imbalance in the production of harmful reactive oxygen species (ROS) over endogenous anti-oxidant protection strategies. As such, anti-oxidant therapy has long been investigated as a means to reduce the extent of injury resulting from ischaemic stroke with varying degrees of success. Here we discuss the production and source of these ROS and the various strategies employed to modulate levels. These strategies broadly attempt to inhibit ROS production or increase scavenging or degradation of ROS. While early clinical studies have failed to translate success from bench to bedside, the combination of anti-oxidants with existing thrombolytics or novel neuroprotectants may represent an avenue worthy of clinical investigation. Clearly, there is a pressing need to identify new therapeutic alternatives for the vast majority of patients who are not eligible to receive rt-PA for this debilitating and devastating disease.

12.
J Cereb Blood Flow Metab ; 33(8): 1215-24, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23632970

ABSTRACT

We hypothesized that targeting key points in the ischemic cascade with combined neuroglobin (Ngb) overexpression and c-jun N-terminal kinase (JNK) inhibition (SP600125) would offer greater neuroprotection than single treatment after in vitro hypoxia/reoxygenation and in a randomized, blinded in vivo experimental stroke study using a clinically relevant rat strain. Male spontaneously hypertensive stroke-prone rats underwent transient middle cerebral artery occlusion (tMCAO) and were divided into the following groups: tMCAO; tMCAO+control GFP-expressing canine adenovirus-2, CAVGFP; tMCAO+Ngb-expressing CAV-2, CAVNgb; tMCAO+SP600125; tMCAO+CAVNgb+SP600125; or sham procedure. Rats were assessed till day 14 for neurologic outcome before infarct determination. In vitro, combined lentivirus-mediated Ngb overexpression+SP600125 significantly reduced oxidative stress and apoptosis compared with single treatment(s) after hypoxia/reoxygenation in B50 cells. In vivo, infarct volume was significantly reduced by CAVNgb, SP600125, and further by CAVNgb+SP600125. The number of Ngb-positive cells in the peri-infarct cortex and striatum was significantly increased 14 days after tMCAO in animals receiving CAVNgb. Neurologic outcome, measured using a 32-point neurologic score, significantly improved with CAVNgb+SP600125 compared with single treatments at 14 days after tMCAO. Combined Ngb overexpression with JNK inhibition reduced hypoxia/reoxygenation-induced oxidative stress and apoptosis in cultured neurons and reduced infarct and improved neurologic outcome more than single therapy after in vivo experimental stroke in hypertensive rats.


Subject(s)
Antioxidants/pharmacology , Apoptosis/drug effects , Hypertension/drug therapy , Neuroprotective Agents/pharmacology , Stroke/prevention & control , Animals , Anthracenes/pharmacology , Dependovirus/genetics , Enzyme Inhibitors/pharmacology , Genetic Vectors , Globins/biosynthesis , Globins/genetics , Green Fluorescent Proteins/metabolism , Hypertension/complications , Hypoxia, Brain/pathology , Immunohistochemistry , Infarction, Middle Cerebral Artery/pathology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Lentivirus/genetics , Male , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neuroglobin , Oxidative Stress/drug effects , Plethysmography , Rats , Rats, Inbred SHR , Real-Time Polymerase Chain Reaction , Stroke/etiology , Transduction, Genetic
13.
J Neurosci Methods ; 211(2): 305-8, 2012 Nov 15.
Article in English | MEDLINE | ID: mdl-22975473

ABSTRACT

We describe a positive influence of pre-stroke surgery on recovery and survival in a commonly used experimental stroke model. Two groups of male, stroke-prone spontaneously hypertensive rats (SHRSPs) underwent transient middle cerebral artery occlusion (tMCAO). Group 1 underwent the procedure without any prior intervention whilst group 2 had an additional general anaesthetic 6 days prior to tMCAO for a cranial burrhole and durotomy. Post-stroke recovery was assessed using a 32 point neurological deficit score and tapered beam walk and infarct volume determined from haematoxylin-eosin stained sections. In group 2 survival was 92% (n=12) versus 67% in group 1 (n=18). In addition, post-tMCAO associated weight loss was significantly reduced in group 2. There was no significant difference between the two groups in experimental outcomes: infarct volume (Group 1 317±18.6 mm³ versus Group 2 332±20.4 mm³), and serial (day 0-14 post-tMCAO) neurological deficit scores and tapered-beam walk test. Drilling a cranial burrhole under general anaesthesia prior to tMCAO in SHRSP reduced mortality and gave rise to infarct volumes and neurological deficits similar to those recorded in surviving Group 1 animals. This methodological refinement has significant implications for animal welfare and group sizes required for intervention studies.


Subject(s)
Disease Models, Animal , Hypertension/complications , Ischemic Attack, Transient , Stroke , Animals , Ischemic Attack, Transient/pathology , Ischemic Attack, Transient/physiopathology , Male , Rats , Rats, Inbred SHR , Stroke/pathology , Stroke/physiopathology , Trephining
14.
J Cardiovasc Pharmacol ; 56(6): 642-50, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20838228

ABSTRACT

Oxidative stress is implicated in the pathogenesis of hypertension and stroke. Superoxide is produced by NAD(P)H oxidase in the vasculature and reduces nitric oxide bioavailability, which leads to increased blood pressure. The objective of this study was to determine whether targeting an antioxidant peptide to the vasculature would increase the antioxidant effect and reduce systolic blood pressure (SBP) in a model of genetic hypertension, the stroke-prone spontaneously hypertensive rat. Vascular-targeting peptides CRPPR and CSGMARTKC were identified by phage display in mice. These peptides retain their selectivity across species and target the aorta (CRPPR) and cardiac vasculature (CSGMARTKC) in the stroke-prone spontaneously hypertensive rat. These vascular-targeting peptides were linked to the antioxidant peptide gp91ds, which selectively inhibits assembly of NAD(P)H oxidase, thereby reducing superoxide production. SBP was determined for 1 week before treatment followed by 3 weeks of study duration before euthanasia. SBP in the control animals increased from 178.1 ± 4.1 mmHg to 201.6 ± 9.0 mmHg. The SBP of the animals treated with gp91ds alone, HIV-tat-gp91ds, and CSGMARTKC-gp91ds increased from 177.8 ± 3.5 mmHg, 179.8 ± 4.7 mmHg, and 177.9 ± 5.2 mmHg, respectively, to 201.6 ± 10.8 mmHg, 200.3 ± 11.7 mmHg and 205.7 ± 10.9 mmHg, respectively. This increase in SBP was significantly attenuated in animals receiving CRPPR-gp91ds (maximum SBP 187.5 mmHg ± 5.2, *P , 0.001 versus other treatment groups and control group). Additionally, animals treated with CRPPR-gp91ds, CSGMARTKC-gp91ds, and gp91ds alone showed significantly improved nitric oxide bioavailability determined by large vessel myography. Therefore, targeting an antioxidant to the aortic vasculature in vivo using peptides can significantly improve nitric oxide bioavailability and attenuate the time-dependent and progressive increase in SBP in the stroke-prone spontaneously hypertensive rat. This study has demonstrated the importance and potential benefit of targeting a biologically active peptide in the context of a preclinical model of endothelial dysfunction and hypertension.


Subject(s)
Antioxidants/administration & dosage , Drug Delivery Systems/methods , Endothelium, Vascular/drug effects , Hypertension/drug therapy , Stroke/drug therapy , Animals , Disease Models, Animal , Endothelium, Vascular/metabolism , Hypertension/metabolism , Male , Mice , Peptide Fragments/administration & dosage , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Stroke/metabolism
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