Methods in 'Stroke Prevention in the Wisconsin Native American Population'.

Native American individuals are more frequently affected by cerebrovascular diseases including stroke and vascular cognitive decline. The aim of this study is to determine stroke risk factors that are most prevalent in Wisconsin Native Americans and to examine how education at the community and individual level as well as intensive health wellness coaching may influence modification of stroke risk factors. Additionally, we will investigate the role novel stroke biomarkers may play in stroke risk in this population. This paper details the aims and methods employed in the "Stroke Prevention in the Wisconsin Native American Population" (clinicaltrials.gov identifier: NCT04382963) study including participant health assessments, clinical ultrasound exam of the carotid arteries, cognitive testing battery and structure and execution of the coaching program.

Transcranial Color-Coded Doppler Cerebral Hemodynamics Following Aerobic Exercise Training: Outcomes From a Pilot Randomized Clinical Trial.

Introduction: An active lifestyle with regular exercise is thought to decrease or delay the onset of Alzheimer dementia through increasing blood flow to the brain. We examined the mean flow velocity (MFV) and pulsatility index (PI) in the middle cerebral arteries of individuals randomized into two groups-a Usual Physical Activity (UPA) group and an Enhanced Physical Activity (EPA) exercise intervention group-to determine if exercise training is related to changes in cerebral blood flow. Methods: We examined 23 participants, randomized into a UPA group (n=12) and an EPA group (n=11), with transcranial color-coded Doppler (TCCD) and cardiorespiratory fitness (VO2peak, mL/kg/min) testing at baseline and following a 26-week intervention. TCCD was used to measure MFV and PI. Participants in the EPA group completed supervised aerobic exercise training for 26 weeks. Kendall's tau b correlation was used to examine relationships between variables. The Wilcoxon Rank Sum tests were used to examine changes between the UPA and EPA groups. Results: There was no significant change in MFV or PI in the UPA group or the EPA group (p-values >0.05) between baseline and 26 weeks; the change between the UPA and EPA groups was also not significant (p=0.603). There was no evidence of an association between change in VO2peak and change in MFV or PI (all p-values >0.05). Participants in the EPA group significantly increased their VO2peak compared to the UPA group (p=0.027). Conclusion: This study did not demonstrate evidence of a significant change in the MFV in the middle cerebral arteries or evidence of a significant change in the PI between UPA and EPA groups. Future studies should be performed in larger cohorts and should consider use of personalized exercise programs to maximize understanding of how cerebrovascular hemodynamics change in structure and function with exercise for adults at risk for Alzheimer dementia.

Surgical approaches for resection of third ventricle colloid cysts: meta-analysis.

Although outcome studies and systematic reviews have been published on the surgical treatment of third ventricle colloid cysts (TVCC), there are no meta-analyses that compare the outcomes for various surgical approaches. This meta-analysis assesses the outcomes and complications for transcortical, transcallosal, and endoscopic surgical approaches used to excise TVCCs. A meta-analysis of surgically excised TVCCs was performed with an assessment of outcome for transcortical, transcallosal, and endoscopic approaches. A random-effects model analyzed the extent of surgical excision. The analysis included reports that compared at least two of these surgical approaches, for a total of 11 studies comprising a population of 301 patients. The transcortical approach was associated with a higher incidence of complete excision compared to the endoscopic approach (OR = 0.137, p = 0.041), with no significant differences observed between transcortical and transcallosal approaches, and between transcallosal and endoscopic approaches. Comparison between endoscopic and pooled microsurgical approaches was also insignificant (OR = 0.22, p = 1). The risk of motor weakness was increased with the transcortical approach compared to the endoscopic approach (OR = 6.10, p = 0.018). There were no significant differences between transcortical and transcallosal approaches regarding newly onset seizures, and no significant mortality differences between all three approaches. This study demonstrates that microsurgical approaches are associated with a greater extent of resection compared to endoscopic approaches; however, best results are likely achieved based on the surgeon's expertise, flexibility, and case review.

Carotid Plaque Strain Indices Were Correlated With Cognitive Performance in a Cohort With Advanced Atherosclerosis, and Traditional Doppler Measures Showed no Association.

OBJECTIVES: Traditional Doppler measures have been used to predict cognitive performance in patients with carotid atherosclerosis. Novel measures, such as carotid plaque strain indices (CPSIs), have shown associations with cognitive performance. We hypothesized that lower mean middle cerebral artery (MCA) velocities, higher bulb-internal carotid artery (ICA) velocities, the MCA pulsatility index (PI), and CPSIs would be associated with poorer cognitive performance in individuals with advanced atherosclerosis. METHODS: Neurocognitive testing, carotid ultrasound imaging, transcranial Doppler imaging, and carotid strain imaging were performed on 40 patients scheduled for carotid endarterectomy. Kendall tau correlations were used to examine relationships between cognitive tests and the surgical-side maximum peak systolic velocity (PSV; from the bulb, proximal, mid, or distal ICA), mean MCA velocity and PI, and maximum CPSIs (axial, lateral, and shear strain indices used to characterize plaque deformations with arterial pulsation). Cognitive measures included age-adjusted indices of verbal fluency, verbal and visual learning/memory, psychomotor speed, auditory attention/working memory, visuospatial construction, and mental flexibility. RESULTS: Participants had a median age of 71.0 (interquartile range, 9.75) years; 26 were male (65%), and 14 were female (35%). Traditional Doppler parameters, PSV, mean MCA velocity, and MCA PI did not predict cognitive performance (all P > .05). Maximum CPSIs were significantly associated with cognitive performance (P < .05). CONCLUSIONS: Traditional velocity measurements of the maximum bulb-ICA PSV, mean MCA velocity, and PI were not associated with cognitive performance in patients with advanced atherosclerotic disease; however, maximum CPSIs were associated with cognitive performance. These findings suggest that cognition may be associated with unstable plaque rather than blood flow.

Deep Learning for Carotid Plaque Segmentation using a Dilated U-Net Architecture.

Carotid plaque segmentation in ultrasound longitudinal B-mode images using deep learning is presented in this work. We report on 101 severely stenotic carotid plaque patients. A standard U-Net is compared with a dilated U-Net architecture in which the dilated convolution layers were used in the bottleneck. Both a fully automatic and a semi-automatic approach with a bounding box was implemented. The performance degradation in plaque segmentation due to errors in the bounding box is quantified. We found that the bounding box significantly improved the performance of the networks with U-Net Dice coefficients of 0.48 for automatic and 0.83 for semi-automatic segmentation of plaque. Similar results were also obtained for the dilated U-Net with Dice coefficients of 0.55 for automatic and 0.84 for semi-automatic when compared to manual segmentations of the same plaque by an experienced sonographer. A 5% error in the bounding box in both dimensions reduced the Dice coefficient to 0.79 and 0.80 for U-Net and dilated U-Net respectively.

Influence of Ultrasound System and Gain on Grayscale Median Values.

OBJECTIVES: The purpose of this study was to determine the reliability of grayscale median (GSM) measurements across different ultrasound (US) systems and effects of gain on GSM values. METHODS: Two vessels in a grayscale vascular phantom were imaged with 7 US systems at 3 gain settings. Two human participants were imaged at 3 gain settings. Each image was normalized, standardized, and segmented by expert and novice readers using grayscale analysis software. The concordance correlation coefficient (CCC) assessed agreement of GSM values for each system across gain settings and vessels and between readers. The intraclass correlation coefficient (ICC) assessed system-level reader concordance across gain settings and vessels. A general linear mixed model for repeated measures was used to assess within- and between-system mean GSM values. RESULTS: Grayscale median measurements performed on images from the same US system yielded excellent (CCC) (95% confidence intervals): 0.85 (0.75, 0.92) to 0.96 (0.92, 0.98). ICC per system were 0.94 to 0.98 for the expert reader and 0.85 to 0.95 for the novice reader. Gain adjustments above and below an optimal setting contributed to significantly different intrasystem GSM values on 4 of 7 systems in the near zone and 5 of 7 systems in the far zone (P < .05). Intersystem GSM values differed on 5 of 7 systems (P < .05). Images from the human participants showed differences in GSM values at optimum gain values ± 10 dB/%. CONCLUSIONS: Grayscale median measurements are highly reproducible when obtained from the same US system with similar gain settings. Grayscale median values differ significantly across gain values and between systems. Researchers should consider the impact of US system and gain settings on GSM values when working to minimize system- and operator-dependent factors.

Lagrangian carotid strain imaging indices normalized to blood pressure for vulnerable plaque.

OBJECTIVE: Ultrasound Lagrangian carotid strain imaging (LCSI) utilizes physiological deformation caused by arterial pressure variations to generate strain tensor maps of the vessel walls and plaques. LCSI has been criticized for the lack of normalization of magnitude-based strain indices to physiological stimuli, namely blood pressure. We evaluated the impact of normalization of magnitude-based strain indices to blood pressure measured immediately after the acquisition of radiofrequency (RF) data loops for LCSI. MATERIALS AND METHODS: A complete clinical ultrasound examination along with RF data loops for LCSI was performed on 50 patients (30 males and 20 females) who presented with >60% carotid stenosis and were scheduled for carotid endarterectomy. Cognition was assessed using the 60-minute neuropsychological test protocol. RESULTS: For axial strains correlation of maximum accumulated strain indices (MASI), cognition scores were -0.46 for non-normalized and -0.45, -0.49, -0.37, and -0.48 for systolic, diastolic, pulse pressure, and mean arterial pressure normalized data, respectively. The corresponding area under the curve (AUC) values for classifiers designed using maximum likelihood estimation of a binormal distribution with a median-split of the executive function cognition scores were 0.73, 0.70, 0.71, 0.70, and 0.71, respectively. CONCLUSIONS: No significant differences in the AUC estimates were obtained between normalized and non-normalized magnitude-based strain indices.

Poststroke Induction of α-Synuclein Mediates Ischemic Brain Damage.

UNLABELLED: α-Synuclein (α-Syn), one of the most abundant proteins in the CNS, is known to be a major player in the neurodegeneration observed in Parkinson's disease. We currently report that transient focal ischemia upregulates α-Syn protein expression and nuclear translocation in neurons of the adult rodent brain. We further show that knockdown or knock-out of α-Syn significantly decreases the infarction and promotes better neurological recovery in rodents subjected to focal ischemia. Furthermore, α-Syn knockdown significantly reduced postischemic induction of phospho-Drp1, 3-nitrotyrosine, cleaved caspase-3, and LC-3 II/I, indicating its role in modulating mitochondrial fragmentation, oxidative stress, apoptosis, and autophagy, which are known to mediate poststroke neuronal death. Transient focal ischemia also significantly upregulated serine-129 (S129) phosphorylation (pα-Syn) of α-Syn and nuclear translocation of pα-Syn. Furthermore, knock-out mice that lack PLK2 (the predominant kinase that mediates S129 phosphorylation) showed better functional recovery and smaller infarcts when subjected to transient focal ischemia, indicating a detrimental role of S129 phosphorylation of α-Syn. In conclusion, our studies indicate that α-Syn is a potential therapeutic target to minimize poststroke brain damage. SIGNIFICANCE STATEMENT: Abnormal aggregation of α-synuclein (α-Syn) has been known to cause Parkinson's disease and other chronic synucleinopathies. However, even though α-Syn is linked to pathophysiological mechanisms similar to those that produce acute neurodenegerative disorders, such as stroke, the role of α-Syn in such disorder is not clear. We presently studied whether α-Syn mediates poststroke brain damage and more importantly whether preventing α-Syn expression is neuroprotective and leads to better physiological and functional outcome after stroke. Our study indicates that α-Syn is a potential therapeutic target for stroke therapy.

Deletion of mitochondrial anchoring protects dysmyelinating shiverer: implications for progressive MS.

The demyelinating disease multiple sclerosis (MS) has an early inflammatory phase followed by an incurable progressive phase with subdued inflammation and poorly understood neurodegenerative mechanism. In this study, we identified various parallelisms between progressive MS and the dysmyelinating mouse model Shiverer and then genetically deleted a major neuron-specific mitochondrial anchoring protein Syntaphilin (SNPH) from the mouse. Prevailing evidence suggests that deletion of SNPH is harmful in demyelination. Surprisingly, SNPH deletion produces striking benefits in the Shiverer by prolonging survival, reducing cerebellar damage, suppressing oxidative stress, and improving mitochondrial health. In contrast, SNPH deletion does not benefit clinical symptoms in experimental autoimmune encephalomyelitis (EAE), a model for early-phase MS. We propose that deleting mitochondrial anchoring is a novel, specific treatment for progressive MS.

Neuro-molecular perspectives on long COVID-19 impacted cerebrovascular diseases - a role for dipeptidyl peptidase IV.

The coronavirus disease 2019 (COVID-19) has caused immense devastation globally with many outcomes that are now extending to its long-term sequel called long COVID. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects not only lungs, but also the brain and heart in association with endothelial cell dysfunction, coagulation abnormalities, and thrombosis leading to cardio-cerebrovascular health issues. Fatigue, cognitive decline, and brain fog are common neurological symptoms in persisting long COVID. Neurodegenerative processes and SARS-CoV-2 infection manifest overlapping molecular mechanisms, such as cytokine dysregulation, inflammation, protein aggregation, mitochondrial dysfunction, and oxidative stress. Identifying the key molecules in these processes is of importance for prevention and treatment of this disease. In particular, Dipeptidyl peptidase IV (DPPIV), a multifunctional peptidase has recently drawn attention as a potential co-receptor for SARS-CoV-2 infection and cellular entry. DPPIV is a known co-receptor for some other COVID viruses including MERS-Co-V. DPPIV regulates the immune responses, obesity, glucose metabolism, diabetes, and hypertension that are associated with cerebrovascular manifestations including stroke. DPPIV likely worsens persisting COVID-19 by disrupting inflammatory signaling pathways and the neurovascular system. This review highlights the neurological, cellular and molecular processes concerning long COVID, and DPPIV as a potential key factor contributing to cerebrovascular dysfunctions following SARS-CoV-2 infection.

Lumen segmentation using a Mask R-CNN in carotid arteries with stenotic atherosclerotic plaque.

In patients at high risk for ischemic stroke, clinical carotid ultrasound is often used to grade stenosis, determine plaque burden and assess stroke risk. Analysis currently requires a trained sonographer to manually identify vessel and plaque regions, which is time and labor intensive. We present a method for automatically determining bounding boxes and lumen segmentation using a Mask R-CNN network trained on sonographer assisted ground-truth carotid lumen segmentations. Automatic lumen segmentation also lays the groundwork for developing methods for accurate plaque segmentation, and wall thickness measurements in cases with no plaque. Different training schemes are used to identify the Mask R-CNN model with the highest accuracy. Utilizing a single-channel B-mode training input, our model produces a mean bounding box intersection over union (IoU) of 0.81 and a mean lumen segmentation IoU of 0.75. However, we encountered errors in prediction when the jugular vein is the most prominently visualized vessel in the B-mode image. This was due to the fact that our dataset has limited instances of B-mode images with both the jugular vein and carotid artery where the vein is dominantly visualized. Additional training datasets are anticipated to mitigate this issue.

A Novel Approach for Free, Affordable, and Sustainable Microsurgery Laboratory Training for Low- and Middle-Income Countries: University of Wisconsin-Madison Microneurosurgery Laboratory Experience.

BACKGROUND AND OBJECTIVES: In low- and middle-income countries (LMICs), approximately 5 million essential neurosurgical operations per year remain unaddressed. When compared with high-income countries, one of the reasons for this disparity is the lack of microsurgery training laboratories and neurosurgeons trained in microsurgical techniques. In 2020, we founded the Madison Microneurosurgery Initiative to provide no-cost, accessible, and sustainable microsurgery training opportunities to health care professionals from LMICs in their respective countries. METHODS: We initially focused on enhancing our expertise in microsurgery laboratory training requirements. Subsequently, we procured a wide range of stereo microscopes, light sources, and surgical instrument sets, aiming to develop affordable, high-quality, and long-lasting microsurgery training kits. We then donated those kits to neurosurgeons across LMICs. After successfully delivering the kits to designated locations in LMICs, we have planned to initiate microsurgery laboratory training in these centers by providing a combination of live-streamed, offline, and in-person training assistance in their institutions. RESULTS: We established basic microsurgery laboratory training centers in 28 institutions across 18 LMICs. This was made possible through donations of 57 microsurgery training kits, including 57 stereo microscopes, 2 surgical microscopes, and several advanced surgical instrument sets. Thereafter, we organized 10 live-streamed microanastomosis training sessions in 4 countries: Lebanon, Paraguay, Türkiye, and Bangladesh. Along with distributing the recordings from our live-streamed training sessions with these centers, we also granted them access to our microsurgery training resource library. We thus equipped these institutions with the necessary resources to enable continued learning and hands-on training. Moreover, we organized 7 in-person no-cost hands-on microanastomosis courses in different institutions across Türkiye, Georgia, Azerbaijan, and Paraguay. A total of 113 surgical specialists successfully completed these courses. CONCLUSION: Our novel approach of providing microsurgery training kits in combination with live-streamed, offline, and in-person training assistance enables sustainable microsurgery laboratory training in LMICs.

Pathophysiology, cellular and molecular mechanisms of large and small vessel diseases.

Cerebrovascular disease (CVD) is the second most common cause of cognitive impairment and dementia in aged population. CVD presents in a myriad number of clinical ways based on the functional location of pathology. While primary clinical emphasis has been placed on motor, speech and visual deficits, vascular cognitive decline is a vastly under recognized and devastating condition afflicting millions of Americans. CVD, a disease of the blood vessels that supply blood to brain involves an integration between small and large vessels. Cerebral large vessel diseases (LVD) are associated with atherosclerosis, artery-to-artery embolism, intracardiac embolism and a large vessel stroke leading to substantial functional disability. Cerebral small vessel disease (SVD) is critically involved in stroke, brain hemorrhages, cognitive decline and functional loss in elderly patients. An evolving understanding of cellular and molecular mechanisms emphasizes that inflammatory vascular changes contribute to systemic pathologic conditions of the central nervous systems (CNS), with specific clinical presentations including, cognitive decline. Advances in an understanding of pathophysiology of disease processes and therapeutic interventions may help improve outcomes. This review will focus on large and small vessels diseases and their relationship to vascular cognitive decline, atherosclerosis, stroke, and inflammatory neurodegeneration. We will also emphasize the molecular and cellular mechanisms, as well as genetic and epigenetic factors associated with LVD and SVD.

Status of Maternal Cardiovascular Health in American Indian and Alaska Native Individuals: A Scientific Statement From the American Heart Association.

Cardiovascular disease is the leading cause of pregnancy-related death in the United States. American Indian and Alaska Native individuals have some of the highest maternal death and morbidity rates. Data on the causes of cardiovascular disease-related death in American Indian and Alaska Native individuals are limited, and there are several challenges and opportunities to improve maternal cardiovascular health in this population. This scientific statement provides an overview of the current status of cardiovascular health among American Indian and Alaska Native birthing individuals and causes of maternal death and morbidity and describes a stepwise multidisciplinary framework for addressing cardiovascular disease and cerebrovascular disease during the preconception, pregnancy, and postpartum time frame. This scientific statement highlights the American Heart Association's factors for cardiovascular health assessment known collectively as Life's Essential 8 as they pertain to American Indian and Alaska Native birthing individuals. It summarizes the impact of substance use, adverse mental health conditions, and lifestyle and cardiovascular disease risk factors, as well as the cascading effects of institutional and structural racism and the historical trauma faced by American Indian and Alaska Native individuals. It recognizes the possible impact of systematic acts of colonization and dominance on their social determinants of health, ultimately translating into worse health care outcomes. It focuses on the underreporting of American Indian and Alaska Native disaggregated data in pregnancy and postpartum outcomes and the importance of engaging key stakeholders, designing culturally appropriate care, building trust among communities and health care professionals, and expanding the American Indian and Alaska Native workforce in biomedical research and health care settings to optimize the cardiovascular health of American Indian and Alaska Native birthing individuals.

MicroRNA miR-21 Decreases Post-stroke Brain Damage in Rodents.

Due to their role in controlling translation, microRNAs emerged as novel therapeutic targets to modulate post-stroke outcomes. We previously reported that miR-21 is the most abundantly induced microRNA in the brain of rodents subjected to preconditioning-induced cerebral ischemic tolerance. We currently show that intracerebral administration of miR-21 mimic decreased the infarct volume and promoted better motor function recovery in adult male and female C57BL/6 mice subjected to transient middle cerebral artery occlusion. The miR-21 mimic treatment is also efficacious in aged mice of both sexes subjected to focal ischemia. Mechanistically, miR-21 mimic treatment decreased the post-ischemic levels of several pro-apoptotic and pro-inflammatory RNAs, which might be responsible for the observed neuroprotection. We further observed post-ischemic neuroprotection in adult mice administered with miR-21 mimic intravenously. Overall, the results of this study implicate miR-21 as a promising candidate for therapeutic translation after stroke.

Enhanced expression of pentraxin-3 in glioblastoma cells correlates with increased invasion and IL8-VEGF signaling axis.

Glioblastoma (GB) is highly invasive and resistant to multimodal treatment partly due to distorted vasculature and exacerbated inflammation. The aggressiveness of brain tumors may be attributed to the dysregulated release of angiogenic and inflammatory factors. The glycoprotein pentraxin-3 (PTX3) is correlated with the severity of some cancers. However, the mechanism responsible for the invasive oncogenic role of PTX3 in GB malignancy remains unclear. In this study, we examined the role of PTX3 in GB growth, angiogenesis, and invasion using in vitro and in vivo GB models, proteomic profiling, molecular and biochemical approaches. Under in vitro conditions, PTX3 over-expression in U87 cells correlated with cell cycle progression, increased migratory potential, and proliferation under hypoxic conditions. Conditioned media containing PTX3 enhanced the angiogenic potential of endothelial cells. While silencing of PTX3 by siRNA decreased the proliferation, migration, and angiogenic potential of U87 cells in vitro. Importantly, PTX3 over-expression increased tumor growth, angiogenesis, and invasion in an orthotopic mouse model. Higher levels of PTX3 in these tumors were associated with the upregulation of inflammatory and angiogenic markers including interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), but decreased levels of thrombospondin-1, an anti-angiogenic factor. Mechanistically, exogenous production of PTX3 triggered an IKK/NFκB signaling pathway that enhances the expression of the motility genes AHGEF7 and Rac1. Taken together, PTX3 expression is dysregulated in GB. PTX3 may augment invasion through enhanced angiogenesis in the GB microenvironment through the IL8-VEGF axis. Thus, PTX3 may represent a potential therapeutic target to mitigate the aggressive behavior of gliomas.

Neurosurgery residency and fellowship education in the United States: 2 decades of system development by the One Neurosurgery Summit organizations.

The purpose of this report is to chronicle a 2-decade period of educational innovation and improvement, as well as governance reform, across the specialty of neurological surgery. Neurological surgery educational and professional governance systems have evolved substantially over the past 2 decades with the goal of improving training outcomes, patient safety, and the quality of US neurosurgical care. Innovations during this period have included the following: creating a consensus national curriculum; standardizing the length and structure of neurosurgical training; introducing educational outcomes milestones and required case minimums; establishing national skills, safety, and professionalism courses; systematically accrediting subspecialty fellowships; expanding professional development for educators; promoting training in research; and coordinating policy and strategy through the cooperation of national stakeholder organizations. A series of education summits held between 2007 and 2009 restructured some aspects of neurosurgical residency training. Since 2010, ongoing meetings of the One Neurosurgery Summit have provided strategic coordination for specialty definition, neurosurgical education, public policy, and governance. The Summit now includes leadership representatives from the Society of Neurological Surgeons, the American Association of Neurological Surgeons, the Congress of Neurological Surgeons, the American Board of Neurological Surgery, the Review Committee for Neurological Surgery of the Accreditation Council for Graduate Medical Education, the American Academy of Neurological Surgery, and the AANS/CNS Joint Washington Committee. Together, these organizations have increased the effectiveness and efficiency of the specialty of neurosurgery in advancing educational best practices, aligning policymaking, and coordinating strategic planning in order to meet the highest standards of professionalism and promote public health.

Exacerbated brain damage, edema and inflammation in type-2 diabetic mice subjected to focal ischemia.

One of the limiting factors in stroke therapeutic development is the use of animal models that do not well represent the underlying medical conditions of patients. In humans, diabetes increases the risk of stroke incidence as well as post-stroke mortality. To understand the mechanisms that render diabetics to increased brain damage, we evaluated the effect of transient middle cerebral artery occlusion in adult db/db mice. The db/db mouse is a model of type-2 diabetes with four times higher blood sugar than its normoglycemic genetic control(db/+ mouse). Following transient middle cerebral artery occlusion, the db/db mice showed significantly higher mortality, bigger infarcts, increased cerebral edema, worsened neurological status compared to db/+ mice. The db/db mice also showed significantly higher post-ischemic inflammatory markers (ICAM1(+) capillaries, extravasated macrophages/neutrophils and exacerbated proinflammatory gene expression) compared to db/+ mice. In addition, the post-ischemic neuroprotective heat-shock chaperone gene expression was curtailed in the db/db compared to db/+ mice.