Publications by authors named "David F Cechetto"

37 Publications

Developing and implementing a novel mentorship model (4) for maternal, newborn and child health in Rwanda.

BMC Health Serv Res 2020 Oct 7;20(1):924. Epub 2020 Oct 7.

Department of Geography, University of Western Ontario, London, Ontario, N6A 5C1, Canada.

Background: There are a number of factors that may contribute to high mortality and morbidity of women and newborns in low-income countries. These include a shortage of competent health care providers (HCP) and a lack of sufficient continuous professional development (CPD) opportunities. Strengthening the skills and building the capacity of HCP involved in the provision of maternal, newborn and child health (MNCH) is essential to ensure quality care for mothers, newborns and children. To address this challenge in Rwanda, mentorship of HCPs was identified as an approach that could help build capacity, improve the provision of care and accelerate the reduction in maternal and neonatal mortality and morbidity. In this paper, we describe the development and implementation of a novel mentorship model named Four plus One (4) for MNCH in Rwanda.

Methods: The mentorship model built on the basis of inter-professional collaboration (IPC) was developed in early 2017 through consultations with different key actors. The design phase included refresher courses in specific skills and training course on mentoring. Field visits were conducted in 10 hospitals from June 2017 to February 2020. Hospital management teams (MT) were involved in the development and implementation of this mentorship model to ensure ownership of the program.

Results: Upon completion of planned visits to each hospital, a total of 218 HCPs were involved in the process. Reports prepared by mentors upon each mentorship visit and compiled by Training Support and Access Model (TSAM) for MNCH'CPD team, highlighted the mothers and newborns who were saved by both mentors and mentees. Also, different logbooks of mentees showed how the capacity of staff was strengthened, thereby suggesting effectiveness of the model. Through different mentorship coordination meetings, the model was much appreciated by the MTs of hospitals, especially the IPC component of the model and confirmed the program 'effectiveness.

Conclusion: The initiation of a mentorship model built on IPC together with the involvement of the leadership of the hospital may be the cause effect of reduction of specific mortality and improve MNCH in low resource settings even when there are a limited number of specialists in the health facilities.
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http://dx.doi.org/10.1186/s12913-020-05789-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542882PMC
October 2020

"I cannot say no when a pregnant woman needs my support to get to the health centre": involvement of community health workers in Rwanda's maternal health.

BMC Health Serv Res 2020 Jun 9;20(1):524. Epub 2020 Jun 9.

College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda.

Background: In Rwanda, maternal community health workers (M-CHWs) are involved in the country's overall health system. In maternal health, their role includes the provision of preventive and promotional health services at the community level. They provide services such as health education on maternal health wellbeing, advice and information on access and timely utilization of health facilities for prenatal, delivery and postpartum care. The contribution of M-CHWs in the health sector combined with other government initiatives led the country to achieving the fifth Millennium Development Goal (MDG) - target 5A- that aimed to improve maternal health through the reduction of maternal mortality ratio by 75% between 1990 and 2015). The objective of this study was to explore M-CHWs' perceptions and experiences on access and provision of maternal health services.

Methods: We used a case study methodology, a qualitative research approach to explore M-CHWs' experiences and perceptions on access and provision of maternal health services at the community level in Rwanda. For the period of June-August 2014, in-depth interviews were conducted with sixteen M-CHWs who had been providing maternal health services in the Eastern Province of Rwanda. Participants shared their experiences and perceptions on access and provision of maternal health service in their communities.

Results: The results of this research highlight the role of M-CHWs in promoting the use of health facilities for prenatal care and delivery and the ways they use to reach out to women. Several challenges prohibit M-CHWs to deliver adequate maternal health services and these are related to the poor resources settings in which they operate.

Conclusion: The results of this study highlight the experiences and perceptions of M-CHWs on the provision and access to maternal health services in their communities. The fact that M-CHWs are volunteers operating in limited resources settings with no formal training in maternal health and with considerable workloads translates into challenges regarding the quality and quantity of services they provide in their communities. Such challenges create an impact on M-CHWs service provision, satisfaction and retention. The voices of M-CHWs and the communities they serve are needed to explore areas that are specific to each community context that would contribute to making the M-CHW program sustainable to achieve equitable access to maternal health services.
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http://dx.doi.org/10.1186/s12913-020-05405-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285794PMC
June 2020

Pathological Changes in Microvascular Morphology, Density, Size and Responses Following Comorbid Cerebral Injury.

Front Aging Neurosci 2019 27;11:47. Epub 2019 Mar 27.

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, Canada.

Aberrations in brain microcirculation and the associated increase in blood-brain-barrier (BBB) permeability in addition to neuroinflammation and Aβ deposition observed in Alzheimer's disease (AD) and ischemia have gained considerable attention recently. However, the role of microvascular homeostasis as a pathogenic substrate to disturbed microperfusion as well as an overlapping etiologic mechanism between AD and ischemia has not been thoroughly explored. In this study, we employ temporal histopathology of cerebral vasculature in a rat model of β-amyloid (Aβ) toxicity and endothelin-1 induced-ischemia (ET1) to investigate the panorama of cerebral pathology and the protein expression on d1, d7, and d28 post-injury. The combination of Aβ and ET1 pathological states leads to an alteration in microvascular anatomy, texture, diameter, density, and protein expression, in addition to disturbed vessel-matrix-connections, inter-compartmental water exchange and basement membrane profile within the lesion epicenter localized in the striatum of Aβ+ET1 brains compared to Aβ and ET1 rats. We conclude that the neural microvascular network, in addition to the neural tissue, is not only sensitive to structural deterioration but also serves as an underlying vascular etiology between ischemia and AD pathologies. Such investigation can provide prospects to appreciate the interrelationships between structure and responses of cerebral microvasculature and to provide a venue for vascular remodeling as a new treatment strategy.
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http://dx.doi.org/10.3389/fnagi.2019.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445844PMC
March 2019

Spatio-temporal disparities in maternal health service utilization in Rwanda: What next for SDGs?

Soc Sci Med 2019 04 1;226:164-175. Epub 2019 Mar 1.

Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, N6A 5C1, Canada.

The Sustainable Development Goals (SDGs) in part aim to further improve maternal health outcomes by reducing spatial disparities in utilization of critical services such as antenatal and assisted delivery, with emphasis on decentralization and integration of strategies. Yet, our understanding of within country spatial disparities in maternal health services (MHS) utilization over time has been scant. By fitting multiple regression models to a pooled dataset of the 2010/11 and 2014/15 Rwanda Demographic and Health Surveys (n = 12,273), and employing post-estimation margins analysis, we examined spatial differentiation of MHS trends prior to the SDGs in Rwanda. Our study found that women in 2014/15 were more likely to utilize antenatal services and assisted delivery (OR = 1.757, p ≤ 0.001) compared with 2010/11, but with nuanced spatial variations. Compared with Nyarugenge, women in nineteen out of the twenty-nine remaining districts were more likely to report utilization of antenatal services and skilled birth delivery, while the probability of accessing four or more antenatal services in seven districts declined between 2010/11 and 2014/15. Physical, financial and socio-cultural factors were associated with maternal health service utilization over the period. Based on our findings, we present policy suggestions for improving utilization of MHS in Rwanda and in similar contexts in the SDGs period.
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http://dx.doi.org/10.1016/j.socscimed.2019.02.040DOI Listing
April 2019

Fluctuation of primary motor cortex excitability during cataplexy in narcolepsy.

Ann Clin Transl Neurol 2019 02 20;6(2):210-221. Epub 2019 Jan 20.

Department of Neurology Changzheng Hospital The Second Military Medical University Shanghai China.

Objective: Cataplexy is a complicated and dynamic process in narcolepsy type 1 (NT1) patients. This study aimed to clarify the distinct stages during a cataplectic attack and identify the changes of the primary motor cortex (PMC) excitability during these stages.

Methods: Thirty-five patients with NT1 and 29 healthy controls were recruited to this study. Cataplectic stages were distinguished from a cataplectic attack by video-polysomnogram monitoring. Transcranial magnetic stimulation motor-evoked potential (TMS-MEP) was performed to measure the excitability of PMC during quiet wakefulness, laughter without cataplexy, and each cataplectic stage.

Results: Based on the video and electromyogram observations, a typical cataplectic attack (CA) process is divided into four stages: triggering (CA1), resisting (CA2), atonic (CA3), and recovering stages (CA4). Compared with healthy controls, NT1 patients showed significantly decreased intracortical facilitation during quiet wakefulness. During the laughter stage, both patients and controls showed increased MEP amplitude compared with quiet wakefulness. The MEP amplitude significantly increased even higher in CA1 and 2, and then dramatically decreased in CA3 accompanied with prolonged MEP latency compared with the laughter stage and quiet wakefulness. The MEP amplitude and latency gradually recovered during CA4.

Interpretation: This study identifies four stages during cataplectic attack and reveals the existence of a resisting stage that might change the process of cataplexy. The fluctuation of MEP amplitude and MEP latency shows a potential participation of PMC and motor control pathway during cataplexy, and the increased MEP amplitude during CA1 and 2 strongly implies a compensatory mechanism in motor control that may resist or avoid cataplectic attack.
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http://dx.doi.org/10.1002/acn3.670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389735PMC
February 2019

Chloroquine Restores Ganglioside Homeostasis and Improves Pathological and Behavioral Outcomes Post-stroke in the Rat.

Mol Neurobiol 2019 May 25;56(5):3552-3562. Epub 2018 Aug 25.

Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, N6A 5C1, Canada.

Perturbations of ganglioside homeostasis have been observed following stroke whereby toxic simple gangliosides GM2 and GM3 accumulate, while protective complex species GM1 and GD1 are reduced. Thus, there is a need for therapeutic interventions which can prevent ganglioside dysregulation after stroke. A pharmacological intervention using chloroquine was selected for its transient lysosomotropic properties which disrupt the activity of catabolic ganglioside enzymes. Chloroquine was administered both in vitro (0.1 μM), to primary cortical neurons exposed to GM3 toxicity, and in vivo (45 mg/kg i.p.), to 3-month-old male Wistar rats that underwent a severe stroke injury. Chloroquine was administered for seven consecutive days beginning 3 days prior to the stroke injury. Gangliosides were examined using MALDI imaging mass spectrometry at 3 and 21 days after the injury, and motor deficits were examined using the ladder task. Chloroquine treatment prevented ganglioside dysregulation 3 days post-stroke and partially prevented complex ganglioside depletion 21 days post-stroke. Exogenous GM3 was found to be toxic to primary cortical neurons which was protected by chloroquine treatment. Motor deficits were prevented in the forelimbs of stroke-injured rats with chloroquine treatment and was associated with decreased inflammation, neurodegeneration, and an increase in cell survival at the site of injury. Chloroquine administration prevents ganglioside dysregulation acutely, protects against GM3 toxicity in neurons, and is associated with long-term functional and pathological improvements after stroke in the rat. Therefore, targeting lipid dysregulation using lysosomotropic agents such as chloroquine may represent a novel therapeutic avenue for stroke injuries.
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http://dx.doi.org/10.1007/s12035-018-1317-0DOI Listing
May 2019

Altered Insulin/Insulin-Like Growth Factor Signaling in a Comorbid Rat model of Ischemia and β-Amyloid Toxicity.

Sci Rep 2018 03 23;8(1):5136. Epub 2018 Mar 23.

Department of Anatomy and Cell Biology, University of Western Ontario, London, N6A 5C1, Canada.

Ischemic stroke and diabetes are vascular risk factors for the development of impaired memory such as dementia and/or Alzheimer's disease. Clinical studies have demonstrated that minor striatal ischemic lesions in combination with β-amyloid (Aβ) load are critical in generating cognitive deficits. These cognitive deficits are likely to be associated with impaired insulin signaling. In this study, we examined the histological presence of insulin-like growth factor-I (IGF-1) and insulin receptor substrate (IRS-1) in anatomically distinct brain circuits compared with morphological brain damage in a co-morbid rat model of striatal ischemia (ET1) and Aβ toxicity. The results demonstrated a rapid increase in the presence of IGF-1 and IRS-1 immunoreactive cells in Aβ + ET1 rats, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion. These regions included subcortical white matter, motor cortex, thalamus, dentate gyrus, septohippocampal nucleus, periventricular region and horizontal diagonal band of Broca in the basal forebrain. The alteration in IGF-1 and IRS-1 presence induced by ET1 or Aβ rats alone was not severe enough to affect the entire brain circuit. Understanding the causal or etiologic interaction between insulin and IGF signaling and co-morbidity after ischemia and Aβ toxicity will help design more effective therapeutics.
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http://dx.doi.org/10.1038/s41598-018-22985-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865153PMC
March 2018

Membrane-lipid homeostasis in a prodromal rat model of Alzheimer's disease: Characteristic profiles in ganglioside distributions during aging detected using MALDI imaging mass spectrometry.

Biochim Biophys Acta Gen Subj 2018 06 13;1862(6):1327-1338. Epub 2018 Mar 13.

Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada. Electronic address:

Background: Accumulation of simple gangliosides GM2 and GM3, and gangliosides with longer long-chain bases (d20:1) have been linked to toxicity and the pathogenesis of Alzheimer's disease (AD). Conversely, complex gangliosides, such as GM1, have been shown to be neuroprotective. Recent evidence using matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) has demonstrated that a-series gangliosides are differentially altered during normal aging, yet it remains unclear how simple species are shifting relative to complex gangliosides in the prodromal stages of AD.

Methods: Ganglioside profiles in wild-type (Wt) and transgenic APP21 Fischer rats were detected and quantified using MALDI-IMS at P0 (birth), 3, 12, and 20 months of age and each species quantified to allow for individual species comparisons.

Results: Tg APP21 rats were found to have a decreased level of complex gangliosides in a number of brain regions as compared to Wt rats and showed higher levels of simple gangliosides. A unique pattern of expression was observed in the white matter as compared to gray matter regions, with an age-dependent decrease in GD1 d18:1 species observed and significantly elevated levels of GM3 in Tg APP21 rats.

Conclusions: These results are indicative of a pathological shift in ganglioside homeostasis during aging that is exacerbated in Tg APP21 rats.

General Significance: Ganglioside dysregulation may occur in the prodromal stages of neurodegenerative diseases like AD.
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http://dx.doi.org/10.1016/j.bbagen.2018.03.011DOI Listing
June 2018

The Dynamics of Impaired Blood-Brain Barrier Restoration in a Rat Model of Co-morbid Injury.

Mol Neurobiol 2018 Oct 5;55(10):8071-8083. Epub 2018 Mar 5.

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, N6A 5C1, Canada.

Defect in brain microperfusion is increasingly recognized as an antecedent event to Alzheimer's disease (AD) and ischemia. Nevertheless, studies on the role of impaired microperfusion as a pathological trigger to neuroinflammation, Aβ deposition as well as blood-brain barrier (BBB) disruption, and the etiological link between AD and ischemia are lacking. In this study, we employ in vivo sequential magnetic resonance imaging (MRI) and computed tomography (CT) imaging in a co-morbid rat model of β-amyloid toxicity (Aβ) and ischemia (ET1) with subsequent histopathology of striatal lesion core and penumbra at 1, 7, and 28 days post injury. Within 24 h, cerebral injury resulted in increased BBB permeability due to the dissolution of β-dystroglycan (β-DG) and basement membrane laminin by active matrix metalloproteinase9 (MMP9). As a result, net flow of circulating IgG down a hydrostatic gradient into the parenchyma led to vasogenic edema and impaired perfusion, thus increasing the apparent hyperintensity in true fast imaging with steady-state free precession (true FISP) imaging and acute hypoperfusion in CT. This was followed by a slow recruitment of reactive astroglia to the affected brain and depolarization of aquaporin4 (AQP4) expression resulting in cytotoxic edema-in an attempt to resolve vasogenic edema. On d28, functional BBB was restored in ET1 rats as observed by astrocytic MMP9 release, β-DG stabilization, and new vessel formation. This was confirmed by reduced hyperintensity on true FISP imaging and normalized cerebral blood flow in CT. While, Aβ toxicity alone was not detrimental enough, Aβ+ET1 rats showed delayed differential expression of MMP9, late recruitment of astroglial cells, protracted loss of AQP4 depolarization, and thus delayed BBB restoration and cerebral perfusion.
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http://dx.doi.org/10.1007/s12035-018-0904-4DOI Listing
October 2018

Dipyridamole plus Triflusal versus Triflusal Alone in Infarct Reduction after Middle Cerebral Artery Occlusion.

J Stroke Cerebrovasc Dis 2018 May 12;27(5):1283-1287. Epub 2018 Jan 12.

Anatomy and Cell Biology Department, The University of Western Ontario, London, Ontario, Canada.

Background And Purpose: The objective of this work is to study the dose-dependent effect of combination therapy with dipyridamole and triflusal over that of triflusal alone on infarct size after middle cerebral artery occlusion (MCAO) ischemia.

Materials And Methods: Male Wistar rats were subjected to a permanent MCAO in the right hemisphere. Rats received triflusal alone and with dipyridamole via oral route. Three days after surgery, infarct volumes were measured.

Results: The lower dose regime of triflusal (10 mg/kg) and dipyridamole (200 mg/kg) caused the greatest decrease in infarct size compared with higher dose regime of triflusal (30 mg/kg) and dipyridamole (200 mg/kg) (P <.01), triflusal (30 mg/kg) alone (P <.07), and vehicle-treated controls.

Conclusions: The lower dose combination of dipyridamole and triflusal appears to be more effective than triflusal alone after MCAO-induced cerebral ischemia. Therefore, there is a strong rationale to continue to examine the protective effects of triflusal and dipyridamole after cerebral ischemia.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.12.013DOI Listing
May 2018

Sublimation of DAN Matrix for the Detection and Visualization of Gangliosides in Rat Brain Tissue for MALDI Imaging Mass Spectrometry.

J Vis Exp 2017 03 23(121). Epub 2017 Mar 23.

Department of Anatomy and Cell Biology, The University of Western Ontario;

Sample preparation is key for optimal detection and visualization of analytes in Matrix-assisted Laser Desorption/Ionization (MALDI) Imaging Mass Spectrometry (IMS) experiments. Determining the appropriate protocol to follow throughout the sample preparation process can be difficult as each step must be optimized to comply with the unique characteristics of the analytes of interest. This process involves not only finding a compatible matrix that can desorb and ionize the molecules of interest efficiently, but also selecting the appropriate matrix deposition technique. For example, a wet matrix deposition technique, which entails dissolving a matrix in solvent, is superior for desorption of most proteins and peptides, whereas dry matrix deposition techniques are particularly effective for ionization of lipids. Sublimation has been reported as a highly efficient method of dry matrix deposition for the detection of lipids in tissue by MALDI IMS due to the homogeneity of matrix crystal deposition and minimal analyte delocalization as compared to many wet deposition methods . Broadly, it involves placing a sample and powdered matrix in a vacuum-sealed chamber with the samples pressed against a cold surface. The apparatus is then lowered into a heated bath (sand or oil), resulting in sublimation of the powdered matrix onto the cooled tissue sample surface. Here we describe a sublimation protocol using 1,5-diaminonaphthalene (DAN) matrix for the detection and visualization of gangliosides in the rat brain using MALDI IMS.
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http://dx.doi.org/10.3791/55254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408897PMC
March 2017

Pediatric emergency care capacity in a low-resource setting: An assessment of district hospitals in Rwanda.

PLoS One 2017 3;12(3):e0173233. Epub 2017 Mar 3.

Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Health system strengthening is crucial to improving infant and child health outcomes in low-resource countries. While the knowledge related to improving newborn and child survival has advanced remarkably over the past few decades, many healthcare systems in such settings remain unable to effectively deliver pediatric advance life support management. With the introduction of the Emergency Triage, Assessment and Treatment plus Admission care (ETAT+)-a locally adapted pediatric advanced life support management program-in Rwandan district hospitals, we undertook this study to assess the extent to which these hospitals are prepared to provide this pediatric advanced life support management. The results of the study will shed light on the resources and support that are currently available to implement ETAT+, which aims to improve care for severely ill infants and children.

Methods: A cross-sectional survey was undertaken in eight district hospitals across Rwanda focusing on the availability of physical and human resources, as well as hospital services organizations to provide emergency triage, assessment and treatment plus admission care for severely ill infants and children.

Results: Many of essential resources deemed necessary for the provision of emergency care for severely ill infants and children were readily available (e.g. drugs and laboratory services). However, only 4/8 hospitals had BVM for newborns; while nebulizer and MDI were not available in 2/8 hospitals. Only 3/8 hospitals had F-75 and ReSoMal. Moreover, there was no adequate triage system across any of the hospitals evaluated. Further, guidelines for neonatal resuscitation and management of malaria were available in 5/8 and in 7/8 hospitals, respectively; while those for child resuscitation and management of sepsis, pneumonia, dehydration and severe malnutrition were available in less than half of the hospitals evaluated.

Conclusions: Our assessment provides evidence to inform new strategies to enhance the capacity of Rwandan district hospitals to provide pediatric advanced life support management. Identifying key gaps in the health care system is required in order to facilitate the implementation and scale up of ETAT+ in Rwanda. These findings also highlight a need to establish an outreach/mentoring program, embedded within the ongoing ETAT+ program, to promote cross-hospital learning exchanges.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173233PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336272PMC
August 2017

Assessing the Effects of Acute Amyloid β Oligomer Exposure in the Rat.

Int J Mol Sci 2016 Aug 24;17(9). Epub 2016 Aug 24.

Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, 1151 Richmond St, London, ON N6A 5C1, Canada.

Alzheimer's disease (AD) is the most common form of dementia, yet there are no therapeutic treatments that can either cure or delay its onset. Currently, the pathogenesis of AD is still uncertain, especially with respect to how the disease develops from a normal healthy brain. Amyloid β oligomers (AβO) are highly neurotoxic proteins and are considered potential initiators to the pathogenesis of AD. Rat brains were exposed to AβO via bilateral intracerebroventricular injections. Rats were then euthanized at either 1, 3, 7 or 21-days post surgery. Rat behavioural testing was performed using the Morris water maze and open field tests. Post-mortem brain tissue was immunolabelled for Aβ, microglia, and cholinergic neurons. Rats exposed to AβO showed deficits in spatial learning and anxiety-like behaviour. Acute positive staining for Aβ was only observed in the corpus callosum surrounding the lateral ventricles. AβO exposed rat brains also showed a delayed increase in activated microglia within the corpus callosum and a decreased number of cholinergic neurons within the basal forebrain. Acute exposure to AβO resulted in mild learning and memory impairments with co-concomitant white matter pathology within the corpus callosum and cholinergic cell loss within the basal forebrain. Results suggest that acute exposure to AβO in the rat may be a useful tool in assessing the early phases for the pathogenesis of AD.
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http://dx.doi.org/10.3390/ijms17091390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037670PMC
August 2016

Correlates of Performance of Healthcare Workers in Emergency, Triage, Assessment and Treatment plus Admission Care (ETAT+) Course in Rwanda: Context Matters.

PLoS One 2016 31;11(3):e0152882. Epub 2016 Mar 31.

Collaboration for Outcomes Research and Evaluation, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.

Background: The Emergency, Triage, Assessment and Treatment plus Admission care (ETAT+) course, a comprehensive advanced pediatric life support course, was introduced in Rwanda in 2010 to facilitate the achievement of the fourth Millennium Development Goal. The impact of the course on improving healthcare workers (HCWs) knowledge and practical skills related to providing emergency care to severely ill newborns and children in Rwanda has not been studied.

Objective: To evaluate the impact of the ETAT+ course on HCWs knowledge and practical skills, and to identify factors associated with greater improvement in knowledge and skills.

Methods: We used a one group, pre-post test study using data collected during ETAT+ course implementation from 2010 to 2013. The paired t-test was used to assess the effect of ETAT+ course on knowledge improvement in participating HCWs. Mixed effects linear and logistic regression models were fitted to explore factors associated with HCWs performance in ETAT+ course knowledge and practical skills assessments, while accounting for clustering of HCWs in hospitals.

Results: 374 HCWs were included in the analysis. On average, knowledge scores improved by 22.8/100 (95% confidence interval (CI) 20.5, 25.1). In adjusted models, bilingual (French & English) participants had a greater improvement in knowledge 7.3 (95% CI 4.3, 10.2) and higher odds of passing the practical skills assessment (adjusted odds ratio (aOR) = 2.60; 95% CI 1.25, 5.40) than those who were solely proficient in French. Participants who attended a course outside of their health facility had higher odds of passing the skills assessment (aOR = 2.11; 95% CI 1.01, 4.44) than those who attended one within their health facility.

Conclusions: The current study shows a positive impact of ETAT+ course on improving participants' knowledge and skills related to managing emergency pediatric and neonatal care conditions. The findings regarding key factors influencing ETAT+ course outcomes demonstrate the importance of considering key contextual factors (e.g., language barriers) that might affect HCWs performance in this type of continuous medical education.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152882PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816404PMC
August 2016

Motor and Hippocampal Dependent Spatial Learning and Reference Memory Assessment in a Transgenic Rat Model of Alzheimer's Disease with Stroke.

J Vis Exp 2016 Mar 22(109). Epub 2016 Mar 22.

Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University;

Alzheimer's disease (AD) is a debilitating neurodegenerative disease that results in neurodegeneration and memory loss. While age is a major risk factor for AD, stroke has also been implicated as a risk factor and an exacerbating factor. The co-morbidity of stroke and AD results in worsened stroke-related motor control and AD-related cognitive deficits when compared to each condition alone. To model the combined condition of stroke and AD, a novel transgenic rat model of AD, with a mutated form of amyloid precursor protein (a key protein involved in the development of AD) incorporated into its DNA, is given a small unilateral striatal stroke. For a model with the combination of both stroke and AD, behavioral tests that assess stroke-related motor control, locomotion and AD-related cognitive function must be implemented. The cylinder task involves a cost-efficient, multipurpose apparatus that assesses spontaneous forelimb motor use. In this task, a rat is placed in a cylindrical apparatus, where the rat will spontaneously rear and contact the wall of the cylinder with its forelimbs. These contacts are considered forelimb motor use and quantified during video analysis after testing. Another cost-efficient motor task implemented is the beam-walk task, which assesses forelimb control, hindlimb control and locomotion. This task involves a rat walking across a wooden beam allowing for the assessment of limb motor control through analysis of forelimb slips, hindlimb slips and falls. Assessment of learning and memory is completed with Morris water maze for this behavioral paradigm. The protocol starts with spatial learning, whereby the rat locates a stationary hidden platform. After spatial learning, the platform is removed and both short-term and long-term spatial reference memory is assessed. All three of these tasks are sensitive to behavioral differences and completed within 28 days for this model, making this paradigm time-efficient and cost-efficient.
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http://dx.doi.org/10.3791/53089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829052PMC
March 2016

Targeted Antioxidant, Catalase-SKL, Reduces Beta-Amyloid Toxicity in the Rat Brain.

Brain Pathol 2017 01 13;27(1):86-94. Epub 2016 Jun 13.

Department of Anatomy and Cell Biology, University of Western Ontario, London, ON, N6A 5C1, Canada.

Accumulation of beta-amyloid (Aβ) in the brain has been implicated as a major contributor to the cellular pathology and cognitive impairment observed in Alzheimer's disease. Beta-amyloid may exert its toxic effects by increasing reactive oxygen species and neuroinflammation in the brain. This study set out to investigate whether a genetically engineered derivative of the peroxisomal antioxidant enzyme catalase (CAT-SKL), is able to reduce the toxicity induced by intracerebroventricular injection of Aβ in the mature rat brain. Histopathological and immunohistochemical analyses were used to evaluate neuroinflammation, and neuronal loss. Spatial learning and reference memory was assessed using the Morris water maze. CAT-SKL treatment was able to reduce the pathology induced by Aβ toxicity by significantly decreasing microglia activation in the basal forebrain and thalamus, and reducing cholinergic loss in the basal forebrain. Aβ animals showed deficits in long-term reference memory in the Morris water maze, while Aβ animals treated with CAT-SKL did not demonstrate long-term memory impairments. This preclinical data provides support for the use of CAT-SKL in reducing neuroinflammation and long-term reference memory deficits induced by Aβ
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http://dx.doi.org/10.1111/bpa.12368DOI Listing
January 2017

Increased Expression of Simple Ganglioside Species GM2 and GM3 Detected by MALDI Imaging Mass Spectrometry in a Combined Rat Model of Aβ Toxicity and Stroke.

PLoS One 2015 18;10(6):e0130364. Epub 2015 Jun 18.

Dept. Anatomy and Cell Biology, Western University, London, ON, N6A 5C1, Canada; Dept. Clinical Neurological Sciences, London Health Sciences Centre, University of Western Ontario, London, ON, N6A 5A5, Canada.

The aging brain is often characterized by the presence of multiple comorbidities resulting in synergistic damaging effects in the brain as demonstrated through the interaction of Alzheimer's disease (AD) and stroke. Gangliosides, a family of membrane lipids enriched in the central nervous system, may have a mechanistic role in mediating the brain's response to injury as their expression is altered in a number of disease and injury states. Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) was used to study the expression of A-series ganglioside species GD1a, GM1, GM2, and GM3 to determine alteration of their expression profiles in the presence of beta-amyloid (Aβ) toxicity in addition to ischemic injury. To model a stroke, rats received a unilateral striatal injection of endothelin-1 (ET-1) (stroke alone group). To model Aβ toxicity, rats received intracerebralventricular (i.c.v.) injections of the toxic 25-35 fragment of the Aβ peptide (Aβ alone group). To model the combination of Aβ toxicity with stroke, rats received both the unilateral ET-1 injection and the bilateral icv injections of Aβ25-35 (combined Aβ/ET-1 group). By 3 d, a significant increase in the simple ganglioside species GM2 was observed in the ischemic brain region of rats who received a stroke (ET-1), with or without Aβ. By 21 d, GM2 levels only remained elevated in the combined Aβ/ET-1 group. GM3 levels however demonstrated a different pattern of expression. By 3 d GM3 was elevated in the ischemic brain region only in the combined Aβ/ET-1 group. By 21 d, GM3 was elevated in the ischemic brain region in both stroke alone and Aβ/ET-1 groups. Overall, results indicate that the accumulation of simple ganglioside species GM2 and GM3 may be indicative of a mechanism of interaction between AD and stroke.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130364PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4473074PMC
April 2016

Amyloid burden, neuroinflammation, and links to cognitive decline after ischemic stroke.

Stroke 2014 Sep 8;45(9):2825-9. Epub 2014 Jul 8.

From the Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada (A.T.); Vulnerable Brain Laboratory, Department of Anatomy and Cell Biology (D.F.C., S.N.W.), and Department of Clinical Neurological Sciences, London Health Sciences Centre (V.H., S.N.W.), Western University, London, Ontario, Canada; and Max Planck Institute for Neurological Research, Cologne, Germany (W.-D.H.).

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http://dx.doi.org/10.1161/STROKEAHA.114.004285DOI Listing
September 2014

Hemodynamic effects of combined focal cerebral ischemia and amyloid protein toxicity in a rat model: a functional CT study.

PLoS One 2014 27;9(6):e100575. Epub 2014 Jun 27.

Imaging Laboratories, Robarts Research Institute, Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada; Imaging Division, Lawson Health Research Institute, London, Ontario, Canada.

Background/objective: Clinical evidence indicates that cerebral ischemia (CI) and a pathological factor of Alzheimer's disease, the β-amyloid (Aβ) protein, can increase the rate of cognitive impairment in the ageing population. Using the CT Perfusion (CTP) functional imaging, we sought to investigate the interaction between CI and the Aβ protein on cerebral hemodynamics.

Methods: A previously established rat model of CI and Aβ was used for the CTP study. Iodinated contrast was given intravenously, while serial CT images of sixteen axial slices were acquired. Cerebral blood flow (CBF) and blood volume (CBV) parametric maps were co-registered to a rat brain atlas and regions of interest were drawn on the maps. Microvascular alteration was investigated with histopathology.

Results: CTP results revealed that ipsilateral striatum of Aβ+CI and CI groups showed significantly lower CBF and CBV than control at the acute phase. Striatal CBF and CBV increased significantly at week 1 in the CI and Aβ+CI groups, but not in the Aβ alone or control group. Histopathology showed that average density of dilated microvessels in the ipsilateral striatum in CI and Aβ+CI groups was significantly higher than control at week 1, indicating this could be associated with hyperperfusion and hypervolemia observed from CTP results.

Conclusion: These results demonstrate that CTP can quantitatively measure the hemodynamic disturbance on CBF and CBV functional maps in a rat model of CI interacting with Aβ.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100575PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074060PMC
October 2015

Comorbid rat model of ischemia and β-amyloid toxicity: striatal and cortical degeneration.

Brain Pathol 2015 Jan 19;25(1):24-32. Epub 2014 May 19.

CIHR Group on Vascular Cognitive Impairment, Department of Anatomy and Cell Biology, Western University, London, ON, Canada.

Levels of cerebral amyloid, presumably β-amyloid (Abeta), toxicity and the incidence of cortical and subcortical ischemia increases with age. However, little is known about the severe pathological condition and dementia that occur as a result of the comorbid occurrence of this vascular risk factor and Abeta toxicity. Clinical studies have indicated that small ischemic lesions in the striatum are particularly important in generating dementia in combination with minor amyloid lesions. These cognitive deficits are highly likely to be caused by changes in the cortex. In this study, we examined the viability and morphological changes in microglial and neuronal cells, gap junction proteins (connexin43) and neuritic/axonal retraction (Fer Kinase) in the striatum and cerebral cortex using a comorbid rat model of striatal injections of endothelin-1 (ET1) and Abeta toxicity. The results demonstrated ventricular enlargement, striatal atrophy, substantial increases in β-amyloid, ramified microglia and increases in neuritic retraction in the combined models of stroke and Abeta toxicity. Changes in connexin43 occurred equally in both groups of Abeta-treated rats, with and without focal ischemia. Although previous behavioral tests demonstrated impairment in memory and learning, the visual discrimination radial maze task did not show significant difference, suggesting the cognitive impairment in these models is not related to damage to the dorsolateral striatum. These results suggest an insight into the relationship between cortical/striatal atrophy, pathology and functional impairment.
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http://dx.doi.org/10.1111/bpa.12149DOI Listing
January 2015

Comorbid Aβ toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit.

Neurobiol Aging 2014 Jul 8;35(7):1605-14. Epub 2014 Jan 8.

Department of Anatomy and Cell Biology, Canadian Institutes of Health Research Group on Vascular Cognitive Impairment, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.

Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and β-amyloid (Aβ) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Aβ toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Aβ. Gross morphologic changes in comorbid Aβ and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of Aβ precursor protein fragments, and cellular degeneration. In addition, there was bilateral induction of connexin43, reduced neuronal survival, and impaired dendritic development of adult-born immature neurons in the dentate gyrus of these rats compared with either rats alone. Behaviorally, there was impairment in the hippocampal-based discriminative fear-conditioning to context task indicating learning and memory deficit. These results suggest an insight into the relationship between hippocampal atrophy, pathology, and functional impairment. Our work not only highlights the exacerbated pathology that emerges when Aβ toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.005DOI Listing
July 2014

Cortical control of the autonomic nervous system.

Authors:
David F Cechetto

Exp Physiol 2014 Feb 11;99(2):326-31. Epub 2013 Oct 11.

* University of Western Ontario, Department of Anatomy & Cell Biology, 1151 Richmond Street, London, Ontario, Canada N6A 5C1.

New Findings: What is the topic of this review? The pathways in the brain by which visceral information, in particular cardiopulmonary afferents, ascend to the cerebral cortex have been delineated in animal models. Studies using functional magnetic resonance imaging in humans have confirmed what was known from the animal studies and established the critical sites in the cerebral cortex of humans for autonomic control and the significance of these sites for cognitive emotional function. What advances does it highlight? Stimulation of cardiopulmonary afferents in humans has consistently resulted in activation in the insular cortex and the anterior cingulate cortex. It has been shown that individuals who are characterized as cardiovascular responders to mental stress have a different pattern of activity in the cortex related to the cardiac changes. A number of animal studies in the rat and cat have been particularly useful for determining the pathways and the sites in the forebrain and cortex that are responsible for autonomic control. For example, these experiments have demonstrated that there is a viscerotopically organized pathway, with the first site of termination in the nucleus of the solitary tract and with subsequent relays in the parabrachial nucleus and the ventroposterior parvocellular nucleus of the thalamus before final visceral afferent inputs in the insular cortex. Several neuroimaging studies in humans, using cardiopulmonary manipulations, have confirmed the importance of the insular cortex as a site of for visceral afferent inputs. The anterior cingulate cortex has also been implicated in cardiopulmonary control. Both the insular cortex and the infralimbic cortex have been shown to be involved in descending control of the cardiovascular system. Neuroimaging with functional magnetic resonance imaging has demonstrated that the cortical autonomic control pathways are different in individuals who are characterized as cardiovascular reactors to mental stress. There is evidence that this alteration in pathways in the cortex may be due to past experiences, including childhood trauma.
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http://dx.doi.org/10.1113/expphysiol.2013.075192DOI Listing
February 2014

Cortical circuitry associated with reflex cardiovascular control in humans: does the cortical autonomic network "speak" or "listen" during cardiovascular arousal.

Anat Rec (Hoboken) 2012 Sep 31;295(9):1375-84. Epub 2012 Jul 31.

School of Kinesiology, Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada N6A 3K7.

Beginning with clinical evidence of fatal cardiac arrhythmias in response to severe stress, in epileptic patients, and following stroke, the role of the cerebral cortex in autonomic control of the cardiovascular system has gained both academic and clinical interest. Studies in anesthetized rodents have exposed the role of several forebrain regions involved in cardiovascular control. The introduction of functional neuroimaging techniques has enabled investigations into the conscious human brain to illuminate the temporal and spatial activation patterns of cortical regions that are involved with cardiovascular control through the autonomic nervous system. This symposia report emphasizes the research performed by the authors to understand the functional organization of the human forebrain in cardiovascular control during physical stressors of baroreceptor unloading and handgrip exercise. The studies have exposed important associations between activation patterns of the insula cortex, dorsal anterior cingulate, and the medial prefrontal cortex and cardiovascular adjustments to physical stressors. Furthermore, these studies provide functional anatomic evidence that sensory signals arising from baroreceptors and skeletal muscle are represented within the insula cortex and the medial prefrontal cortex, in addition to the sensory cortex. Thus, the cortical pathways subserving reflex cardiovascular control integrate viscerosensory inputs with outgoing traffic that modulates the autonomic nervous system.
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http://dx.doi.org/10.1002/ar.22528DOI Listing
September 2012

Oleic acid ameliorates amyloidosis in cellular and mouse models of Alzheimer's disease.

Brain Pathol 2011 May 11;21(3):321-9. Epub 2010 Nov 11.

Department of Biochemistry, University of Western Ontario, London, ON, Canada.

Several lines of evidence support protective as well as deleterious effects of oleic acid (OA) on Alzheimer's disease (AD) and other neurological disorders; however, the bases of these effects are unclear. Our investigation demonstrates that amyloid precursor protein (APP) 695 transfected Cos-7 cells supplemented with OA have reduced secreted amyloid-beta (Aβ) levels. An early-onset AD transgenic mouse model expressing the double-mutant form of human APP, Swedish (K670N/M671L) and Indiana (V717F), corroborated our in vitro findings when they were fed a high-protein, low-fat (18% reduction), cholesterol-free diet enriched with OA. These mice exhibited an increase in Aβ40/Aβ42 ratio, reduced levels of beta-site APP cleaving enzyme (BACE) and reduced presenilin levels along with reduced amyloid plaques in the brain. The decrease in BACE levels was accompanied by increased levels of a non-amyloidogenic soluble form of APP (sAPPα). Furthermore, the low-fat/+OA diet resulted in an augmentation of insulin-degrading enzyme and insulin-like growth factor-II. These results suggest that OA supplementation and cholesterol intake restriction in a mouse model of AD reduce AD-type neuropathology.
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http://dx.doi.org/10.1111/j.1750-3639.2010.00449.xDOI Listing
May 2011

Triflusal reduces cerebral ischemia induced inflammation in a combined mouse model of Alzheimer's disease and stroke.

Brain Res 2010 Dec 8;1366:246-56. Epub 2010 Oct 8.

Institute for Biological Sciences, National Research Council of Canada, 1200 Montreal Rd, M54 Ottawa, Canada.

Clinical data has shown that stroke exacerbates dementia in Alzheimer's disease (AD) patients. Previous work, combining rat models of AD and stroke have shown that neuroinflammation may be the common mediator between AD and stroke toxicity. This study examined the effects of triflusal (2-acetoxy-4-trifluoromethylbenzoic acid) in APP(23) transgenic mice receiving strokes. Six month-old APP(23) mice over-expressing mutant human amyloid precursor protein (APP) were used to model AD in this study. Unilateral injections of a potent vasoconstrictor, endothelin-1, into the striatum were used to mimic small lacunar infarcts. Immunohistochemical analysis was performed to examine AD-like pathology and inflammatory correlates of stroke and AD. APP(23) mice showed increases in AD-like pathology and inflammatory markers of AD in the cortex and hippocampus. Endothelin-induced ischemia triggered an inflammatory response along with increases in AD pathological markers in the region of the infarct. Triflusal reduced inflammation surrounding the endothelin-induced infarct only. At the dose used, anti-inflammatory treatment may be beneficial in reducing the AD and inflammatory correlates of stroke in a combined AD-stroke mouse model.
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http://dx.doi.org/10.1016/j.brainres.2010.10.008DOI Listing
December 2010

Functional neuroanatomy of autonomic regulation.

Neuroimage 2009 Sep 14;47(3):795-803. Epub 2009 May 14.

Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.

Considerable effort has been put into animal studies establishing the sites in the brain that are responsible for control of the autonomic nervous system. These studies relied on an electrophysiological or neurochemical response to the activation of peripheral autonomic receptors or chemical or electrical stimulation of central sites. A large number of excellent reviews summarize the results of these studies. More recently, functional imaging has been used to not only confirm the electrophysiological and anatomical studies in animals, but has allowed a more complete understanding of how the brain responds as a whole for effecting autonomic control. The earliest studies to examine forebrain control during functional imaging utilized tests that involved active participation of the subjects and included maximal inspiration, Valsalva manoeuvre, isometric handgrip and cold compress application. There were a few issues that arose from these studies. First, they involved areas of the brain that included active decision making, they were more prone to inducing movement artefact, and some of these tests could activate noxious regions in the brain in addition to autonomic sites. In fact, this dual modality activation represented a more severe complication for investigators determining nociceptive sites in the brain, since virtually all of their stimuli had concomitant autonomic responses. More recent investigations attempted to resolve these issues with more selective passive and active stimuli. In spite of the very different approaches taken to visceral activation in functional imaging studies, a consistent picture of the key areas involved in autonomic control has emerged.
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http://dx.doi.org/10.1016/j.neuroimage.2009.05.024DOI Listing
September 2009

Vascular risk factors and Alzheimer's disease.

Expert Rev Neurother 2008 May;8(5):743-50

Department of Anatomy & Cell Biology, University of Western Ontario, London, ON, Canada.

Vascular cognitive impairment risk factors include stroke, hypertension, diabetes and atherosclerosis. In the elderly, vascular risk factors occur in the presence of high levels of amyloid in the aging brain. Stroke alters the clinical expression of a given load of Alzheimer's disease (AD) pathology. Experimentally, large vessel infarcts or small striatal infarcts are larger in the presence of amyloid. Patients with minor cerebral infarcts and moderate AD lesions will develop the clinical manifestations of dementia. Moreover, there is also an association between other vascular risk factors and the clinical expression of cognitive decline and dementia. The risk of AD is increased in subjects with adult-onset diabetes mellitus, hypertension, atherosclerotic disease and atrial fibrillation. Experimentally, small striatal infarcts in the presence of high levels of amyloid in the brain exhibit a progression in infarct size over time with enhanced degree of cognitive impairment, AD-type pathology and neuroinflammation compared with striatal infarcts or high amyloid levels alone.
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http://dx.doi.org/10.1586/14737175.8.5.743DOI Listing
May 2008

Progressive increase in infarct size, neuroinflammation, and cognitive deficits in the presence of high levels of amyloid.

Stroke 2007 Dec 25;38(12):3245-50. Epub 2007 Oct 25.

Department of Anatomy and Cell Biology, Medical Sciences Bldg, University of Western Ontario, London, Ontario, Canada.

Background And Purpose: In the elderly, cerebral ischemia (CI) occurs in the presence of high levels of amyloid. Neuroinflammation plays a critical role in the pathophysiology of Alzheimer's disease and CI. This study examined infarct size, neuroinflammation, and cognitive deficits over time in rat models of Alzheimer's disease and CI.

Methods: beta-amyloid toxicity was modeled using bilateral intracerebroventricular injections of beta-amyloid 25 to 35 peptides. CI was modeled using unilateral injections of the potent vasoconstrictor, endothelin-1, into the striatum.

Results: Infarct volumes were higher in the presence of amyloid and compared with the CI model alone. In the CI model alone, the infarct volume was significantly smaller 28 days after surgery compared with 7 days after surgery. However, when Alzheimer's disease and CI models were combined, the infarct volume was significantly larger 28 days after surgery compared with 7 days after surgery. The neuroinflammation in the region of the infarct was also significantly increased. The Barnes circular platform test showed time-dependent increases in memory and learning deficits in the beta-amyloid-treated rats that were even greater when beta-amyloid treatment was combined with CI.

Conclusions: CI in the presence of high levels of amyloid results in progressive increases in infarct size, neuroinflammation, and cognitive deficits.
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http://dx.doi.org/10.1161/STROKEAHA.107.492660DOI Listing
December 2007

Sex differences in forebrain and cardiovagal responses at the onset of isometric handgrip exercise: a retrospective fMRI study.

J Appl Physiol (1985) 2007 Oct 5;103(4):1402-11. Epub 2007 Jul 5.

Neurovascular Research Laboratory, School of Kinesiology, The University of Western Ontario, London, Ontario, Canada N6A 3K7.

In general, cardiac regulation is dominated by the sympathetic and parasympathetic nervous systems in men and women, respectively. Our recent study had revealed sex differences in the forebrain network associated with sympathoexcitatory response to baroreceptor unloading. The present study further examined the sex differences in forebrain modulation of cardiovagal response at the onset of isometric exercise. Forebrain activity in healthy men (n = 8) and women (n = 9) was measured using functional magnetic resonance imaging during 5 and 35% maximal voluntary contraction handgrip exercise. Heart rate (HR), mean arterial pressure (MAP), and muscle sympathetic nerve activity (MSNA) were collected in a separate recording session. During the exercise, HR and MAP increased progressively, while MSNA was suppressed (P < 0.05). Relative to men, women demonstrated smaller HR (8 +/- 2 vs. 18 +/- 3 beats/min) and MAP (3 +/- 2 vs. 11 +/- 2 mmHg) responses to the 35% maximal voluntary contraction trials (P < 0.05). Although a similar forebrain network was activated in both groups, the smaller cardiovascular response in women was reflected in a weaker insular cortex activation. Nevertheless, men did not show a stronger deactivation at the ventral medial prefrontal cortex, which has been associated with modulating cardiovagal activity. In contrast, the smaller cardiovascular response in women related to their stronger suppression of the dorsal anterior cingulate cortex activity, which has been associated with sympathetic control of the heart. Our findings revealed sex differences in both the physiological and forebrain responses to isometric exercise.
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http://dx.doi.org/10.1152/japplphysiol.00171.2007DOI Listing
October 2007

Effects of triflusal and aspirin in a rat model of cerebral ischemia.

Stroke 2007 Feb 28;38(2):381-7. Epub 2006 Dec 28.

Department of Anatomy and Cell Biology, University of Western Ontario, London, Canada.

Background And Purpose: Neuroinflammation plays a critical role in the pathogenesis of cerebral ischemia. Triflusal, a selective cyclooxygenase-2, and its active metabolite 3-hydroxy-4-trifluoromethylbenzoic acid may inhibit apoptosis and inflammation after cerebral ischemia. An in vivo model of cerebral ischemia was used to investigate the effects of triflusal and aspirin treatment on infarct volume, and inflammation after cerebral ischemia in the rat.

Methods: Male Wistar rats were subjected to a permanent right-sided middle cerebral artery occlusion. Rats received oral administration of either triflusal or aspirin. After 3 days after surgery, immunostaining was used to detect neuroinflammatory cells and molecules, and infarct volumes were measured.

Results: Both triflusal and aspirin at a dose of 30 mg/kg but not 10 mg/kg significantly reduced infarct volume compared with vehicle treatment. Middle cerebral artery occlusion resulted in increased astrocyte and heat shock protein-27 (Hsp27) immunostaining in the ipsilateral cortex. Triflusal (30 mg/kg) or aspirin treatment (30 mg/kg) did not reduce the levels of GFAP or Hsp27 immunostaining. Triflusal (30 mg/kg) also significantly decreased the protein levels of IL-Ibeta but not nuclear factor kappa B or tumor necrosis factor-alpha in the cortex ipsilateral to the middle cerebral artery occlusion.

Conclusions: The results suggest that triflusal and aspirin appear to be equally neuroprotective against middle cerebral artery occlusion-induced cerebral ischemia. Therefore, strong rationale exists to continue the neuroprotective examination of triflusal in brain injury.
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http://dx.doi.org/10.1161/01.STR.0000254464.05561.72DOI Listing
February 2007