Louise D McCullough

University of Connecticut, Storrs, Connecticut, United States

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Publications (113)405.32 Total impact

  • Brett Friedler, Joshua Crapser, Louise McCullough
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    ABSTRACT: The deleterious effects of chronic social isolation (SI) have been recognized for several decades. Isolation is a major source of psychosocial stress and is associated with an increased prevalence of vascular and neurological diseases. In addition, isolation exacerbates morbidity and mortality following acute injuries such as stroke or myocardial infarction. In contrast, affiliative social interactions can improve organismal function and health. The molecular mechanisms underlying these effects are unknown. Recently, results from large epidemiological trials and pre-clinical studies have revealed several potential mediators of the detrimental effects of isolation. At least three major biological systems have been implicated: the neuroendocrine (HPA) axis, the immune system, and the autonomic nervous system. This review summarizes studies examining the relationship between isolation and mortality and the pathophysiological mechanisms underlying SI. Cardiovascular, cerebrovascular, and neurological diseases including atherosclerosis, myocardial infarction, ischemic stroke and Alzheimer's disease are given special emphasis in the context of SI. Sex differences are highlighted and studies are separated into clinical and basic science for clarity.
    Acta Neuropathologica 12/2014; · 9.78 Impact Factor
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    ABSTRACT: Substantial evidence from both experimental and clinical studies has demonstrated that social isolation can increase stroke incidence and impair recovery. Social isolation leads to higher rates of recurrent stroke but is often not reported as a risk factor. We examined prospectively collected stroke center database variables, which included prestroke living situation, to determine if social isolation could be determined from existing data using living arrangement as a proxy. Patients were categorized into 4 groups hypothesized to represent increasing levels of social isolation: living with spouse, living with family, living alone with visiting services, and living alone. Initial stroke severity and recovery were measured using the National Institutes of Health Stroke Scale and Barthel Index, respectively. A multivariate model was used to determine the relationship among prestroke living situation, stroke severity, and functional outcome. Patients living alone had less severe strokes on admission and better recovery at 3 months compared with the other cohorts. Patients living alone or those who lived with a spouse had less severe strokes on presentation and better recovery at both 3 and 12 months after stroke compared with the other cohorts. However, on detailed examination, it was found that these patients also had significantly higher prestroke function. Pre-existing depression was significantly higher in women, and depressed patients had poorer outcomes 3 months after stroke. Information regarding isolation is notably absent from most large stroke databases. A more comprehensive evaluation of social interaction should be obtained to more accurately measure social isolation. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 12/2014; · 1.99 Impact Factor
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    ABSTRACT: Epidemiologic studies have shown sex differences in ischemic stroke. The four core genotype (FCG) mouse model, in which the testes determining gene, Sry, has been moved from Y chromosome to an autosome, was used to dissociate the effects of sex hormones from sex chromosome in ischemic stroke outcome. Middle cerebral artery occlusion (MCAO) in gonad intact FCG mice revealed that gonadal males (XXM and XYM) had significantly higher infarct volumes as compared with gonadal females (XXF and XYF). Serum testosterone levels were equivalent in adult XXM and XYM, as was serum estrogen in XXF and XYF mice. To remove the effects of gonadal hormones, gonadectomized FCG mice were subjected to MCAO. Gonadectomy significantly increased infarct volumes in females, while no change was seen in gonadectomized males, indicating that estrogen loss increases ischemic sensitivity. Estradiol supplementation in gonadectomized FCG mice rescued this phenotype. Interestingly, FCG male mice were less sensitive to effects of hormones. This may be due to enhanced expression of the transgene Sry in brains of FCG male mice. Sex differences in ischemic stroke sensitivity appear to be shaped by organizational and activational effects of sex hormones, rather than sex chromosomal complement.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 November 2014; doi:10.1038/jcbfm.2014.186.
    Journal of Cerebral Blood Flow & Metabolism 11/2014; · 5.34 Impact Factor
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    ABSTRACT: Neurogenic stress cardiomyopathy (NCM) has been associated with poor outcomes in the setting of aneurysmal subarachnoid hemorrhage (aSAH). Much less is known regarding recovery of cardiac function. The aim of this prospective cohort study was to study the rate of early cardiac recovery after NCM and the potential effect of NCM on short term functional recovery. A secondary aim sought to determine whether certain biomarkers may be associated with the development of NCM.Methods Patients with confirmed aSAH between November 2012 and October 2013 were prospectively enrolled and received echocardiograms within 48 h of admission. Ejection fraction (%) and regional wall motion abnormality score index (RWMI) were noted. All patients with confirmed aSAH had a troponin and BNP level drawn on admission. Patients with confirmed NCM received a follow up echocardiogram 7–21 days after the initial echocardiogram. Clinical follow up at 3 months evaluated mortality, mRS and mBI scores.Results63 patients with confirmed aSAH were enrolled. In this cohort 11 (17%) patients were confirmed to have NCM. The NCM group had higher in-hospital mortality [n = 4(36.4%)] compared to the non-NCM group [n = 5(9.6%)] (p = .021). At 3 months the development of NCM was associated with an unfavorable mRS (p = 0.042) and mBI (p = 0.005). Both an elevated BNP (>100 pg/mL) and elevated troponin (>0.3 mg/dL) were associated with the development of NCM. Follow-up echocardiograms were performed within 21 days of admission on 8 patients with NCM. An abnormal RWMI of 1.5 or higher was present in 5(71%) patients.ConclusionNCM is a frequent complication associated with aSAH. The onset of the disease occurs early in the course of aSAH and an elevated BNP and troponin may be associated with the onset of NCM. Cardiac function often remains impaired during the acute recovery phase potentially impeding resuscitation during this period. The routine use of short term follow-up echocardiography may be recommended.
    Clinical Neurology and Neurosurgery 11/2014; · 1.25 Impact Factor
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    Lin Liu, Louise McCullough, Jun Li
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    ABSTRACT: Background Stroke is the primary cause of long-term disability in the United States. Interestingly, mounting evidence has suggested potential sex differences in the response to stroke treatment in patients as, at least in part, distinct cell death programs may be triggered in females and males following stroke. The NIH has recognized that females are strikingly under-represented in pre-clinical trials. Calcium/calmodulin-dependent protein kinase kinase (CaMKK) is a major kinase that is activated by elevated intracellular calcium. It has recently been suggested that CaMKK and CaMK IV, a downstream target molecule, are neuroprotective in stroke in males. In this study, we examined stroke outcomes in ovariectomized CaMKK ß and CaMK IV deficient females. Cell death/survival signaling and inflammatory responses were assessed.ResultsOur results demonstrated that CaMKK ß or CaMK IV KO exacerbated both ischemic injury and behavioral deficits in female mice. Genetic deletion of CaMKK ß or CaMK IV increased hemorrhagic transformation after stroke, and this was associated with both increased MMP9 activity and loss of the blood brain barrier (BBB) protein collagen IV. Transcriptional inactivation was observed in mice lacking either CaMKK ß or CaMK IV, as indicated by reduced levels of phosphorylated cAMP response element-binding protein (p-CREB) and B-cell lymphoma 2 (BCL-2) proteins. Finally, inhibiting this pathway exacerbated the inflammatory response to stroke as CaMKK ß or CaMK IV KO mice had increased levels of the pro-inflammatory serum cytokines tumor necrosis factor alpha (TNF¿) and interleukin 6 (IL-6) after stroke. This suggests that the CaMKK pathway is involved in the immune response to brain injury.Conclusions Inhibition of CaMKK signaling exacerbated stroke outcome and increased BBB impairment, transcriptional inactivation and inflammatory responses in females after stroke. Therefore, CaMKK signaling may be a potential target for stroke treatment in both males and females.
    BMC Neuroscience 10/2014; 15(1):118. · 2.85 Impact Factor
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    ABSTRACT: Social isolation (SI) increases stroke incidence and delays poststroke recovery. Women may be at greater risk from the negative consequences of SI, but few studies have examined both sexes in experimental models, and none have evaluated the effects of isolation initiated after stroke. The effects of poststroke SI in men and women were examined, and the role of mitochondrial P53 was evaluated.
    Stroke 09/2014; 45(10). · 6.02 Impact Factor
  • Meaghan Roy-O’Reilly, Louise D. McCullough
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    ABSTRACT: Stroke is now the leading cause of adult disability in the United States. Women are disproportionately affected by stroke. Women increasingly outnumber men in the elderly population, the period of highest risk for stroke. However, there is also a growing recognition that fundamental sex differences are present that contribute to differential ischemic sensitivity. In addition, gonadal hormone exposure can impact coagulation and fibrinolysis, key factors in the initiation of thrombosis. In this review we will discuss sex differences in stroke, with a focus on platelets, vascular reactivity and coagulation.
    Experimental Neurology 09/2014; · 4.62 Impact Factor
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    ABSTRACT: and Purpose: Activation of mitogen-activated protein kinases (MAPKs), particularly c-jun-N-terminal kinases (JNK) and p38 exacerbate stroke injury by provoking pro-apoptotic and pro-inflammatory cellular signaling. MAPK phosphatase-1 (MKP-1) restrains the over-activation of MAPKs via rapid de-phosphorylation of the MAPKs. We therefore examined the role of MKP-1 in stroke and studied its inhibitory effects on MAPKs after experimental stroke.
    Experimental Neurology 05/2014; · 4.62 Impact Factor
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    ABSTRACT: Social isolation (SI) has been linked epidemiologically to high rates of morbidity and mortality following stroke. In contrast, strong social support enhances recovery and lowers stroke recurrence. However, the mechanism by which social support influences stroke recovery has not been adequately explored. The goal of this study was to examine the effect of post-stroke pair housing and SI on behavioural phenotypes and chronic functional recovery in mice. Young male mice were paired for 14 days before a 60minute transient middle cerebral artery occlusion (MCAO) or sham surgery and assigned to various housing environments immediately after stroke. Post-stroke mice paired with either a sham or stroke partner showed significantly higher (p<0.05) sociability after MCAO than isolated littermates. Sociability deficits worsened over time in isolated animals. Pair-housed mice showed restored sucrose consumption (p<0.05) and reduced immobility in the tail suspension test compared to isolated cohorts. Pair-housed stroked mice demonstrated significantly reduced cerebral atrophy after 6 weeks (17.5±1.5% in PH vs. 40.8±1.3% in SI; p<0.001). Surprisingly, total brain arginase-1, a marker of a M2 "alternatively activated" myeloid cells was higher in isolated mice. However, a more detailed assessment of cellular expression showed a significant increase in the number of microglia that co-labeled with arginase-1 in the peri-infarct region in PH stroke mice compared to SI mice. Pair housing enhances sociability and reduces avolitional and anhedonic behaviour. Pair housing reduced serum IL-6 and enhanced peri-infarct microglia arginase-1 expression. Social interaction reduces post-stroke depression and improves functional recovery.
    Behavioural brain research 05/2014; · 3.22 Impact Factor
  • Venugopal Reddy Venna, Louise D McCullough
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    ABSTRACT: Stroke is a serious global health care problem. It is now is the fourth leading cause of death and the primary cause of adult disability in the United States. Substantial evidence from both experimental and clinical studies has demonstrated that social isolation (SI) can increase stroke incidence and impair recovery. Epidemiological studies demonstrate that an increasing number of patients are living alone, and as the aging population increases, loneliness will only increase in prevalence. SI is increasingly identified as an independent risk factor for all-cause mortality. In contrast, individuals with high levels of social support exhibit more rapid and extensive functional and cognitive recovery after a wide variety of pathological insults, including stroke. Clinical data suggests that SI is an important risk factor for increased mortality and delayed functional recovery following ischemic stroke. Attesting to the importance of mortality and behavioral factors in stroke outcome is that these same effects can be reproduced in animal models of experimental stroke. This has allowed researchers to identify several mechanistic changes that occur with affiliative interactions. These include decreased systemic inflammation, elaboration of growth factors including brain derived neurotropic factor (BDNF), enhanced neurogenesis, and improved neuroimmune responsiveness in group housed animals. These may mediate the beneficial effects of social interaction on improving stroke recovery and reducing neuronal death. In this review we provide an overview of the effects of SI on ischemic injury and recovery and discuss their clinical and therapeutic implications.
    Metabolic Brain Disease 04/2014; · 2.40 Impact Factor
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    ABSTRACT: Intracerebral hemorrhage (ICH) is a devastating type of stroke that lacks a specific treatment. An intense immune response develops after ICH, which contributes to neuronal injury, disability, and death. However, the specific mediators of inflammation-induced injury remain unclear. The objective of the present study was to determine whether blood-derived CCR2(+)Ly6C(hi) inflammatory monocytes contribute to disability. ICH was induced in mice and the resulting inflammatory response was quantified using flow cytometry, confocal microscopy, and neurobehavioral testing. Importantly, blood-derived monocytes were distinguished from resident microglia by differential CD45 staining and by using bone marrow chimeras with fluorescent leukocytes. After ICH, blood-derived CCR2(+)Ly6C(hi) inflammatory monocytes trafficked into the brain, outnumbered other leukocytes, and produced tumor necrosis factor. Ccr2(-/-) mice, which have few circulating inflammatory monocytes, exhibited better motor function following ICH than control mice. Chimeric mice with wild-type CNS cells and Ccr2(-/-) hematopoietic cells also exhibited early improvement in motor function, as did wild-type mice after inflammatory monocyte depletion. These findings suggest that blood-derived inflammatory monocytes contribute to acute neurological disability. To determine the translational relevance of our experimental findings, we examined CCL2, the principle ligand for the CCR2 receptor, in ICH patients. Serum samples from 85 patients were collected prospectively at two hospitals. In patients, higher CCL2 levels at 24 h were independently associated with poor functional outcome at day 7 after adjusting for potential confounding variables. Together, these findings suggest that inflammatory monocytes worsen early disability after murine ICH and may represent a therapeutic target for patients.
    Journal of Neuroscience 03/2014; 34(11):3901-9. · 6.75 Impact Factor
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    ABSTRACT: Metformin is currently the first-line treatment drug for type 2 diabetes. Metformin is a well-known activator of AMP-activated protein kinase (AMPK). In experimental studies, metformin has been shown to exert direct vascular effects by increasing vascular endothelial growth factor expression and improving microvascular density. As stroke is the leading cause of long-term disability and angiogenesis is implicated as an important mechanism in functional recovery, we hypothesized that chronic metformin treatment would improve post-stroke functional recovery by enhancing functional microvascular density. For this study, C57BL/6N male mice were subjected to a 60-min middle cerebral artery occlusion, and were given 50 mg/kg/day metformin beginning 24 h post-stroke for 3 weeks. Behavioral recovery was assessed using adhesive-tape removal and the apomorphine-induced turning test. The role of angiogenesis was assessed by counting vessel branch points from fluorescein-conjugated lectin-perfused brain sections. Importantly even if metformin treatment was initiated 24 h after injury it enhanced recovery and significantly improved stroke-induced behavioral deficits. This recovery occurred in parallel with enhanced angiogenesis and with restoration of endogenous cerebral dopaminergic tone and revascularization of ischemic tissue. We assessed if the effects on recovery and angiogenesis were mediated by AMPK. When tested in AMPK α-2 knockout mice, we found that metformin treatment did not have the same beneficial effects on recovery and angiogenesis, suggesting that metformin-induced angiogenic effects are mediated by AMPK. The results from this study suggest that metformin mediates post-stroke recovery by enhancing angiogenesis, and these effects are mediated by AMPK signaling.
    European Journal of Neuroscience 03/2014; · 3.67 Impact Factor
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    V R Venna, Y Xu, S J Doran, A Patrizz, L D McCullough
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    ABSTRACT: Stroke survivors often experience social isolation. Social interaction improves quality of life and decreases mortality after stroke. Male mice (20-25 g; C57BL/6N), all initially pair housed, were subjected to middle cerebral artery occlusion (MCAO). Mice were subsequently assigned into one of three housing conditions: (1) Isolated (SI); (2) Paired with their original cage mate who was also subjected to stroke (stroke partner (PH-SP)); or (3) Paired with their original cage mate who underwent sham surgery (healthy partner (PH-HP)). Infarct analysis was performed 72 h after stroke and chronic survival was assessed at day 30. Immediate post-stroke isolation led to a significant increase in infarct size and mortality. Interestingly, mice paired with a healthy partner had significantly lower mortality than mice paired with a stroke partner, despite equivalent infarct damage. To control for changes in infarct size induced by immediate post-stroke isolation, additional cohorts were assessed that remained pair housed for three days after stroke prior to randomization. Levels of brain-derived neurotrophic factor (BDNF) were assessed at 90 days and cell proliferation (in cohorts injected with 5-bromo-2'-deoxyuridine, BrdU) was evaluated at 8 and 90 days after stroke. All mice in the delayed housing protocol had equivalent infarct volumes (SI, PH-HP and PH-SP). Mice paired with a healthy partner showed enhanced behavioral recovery compared with either isolated mice or mice paired with a stroke partner. Behavioral improvements paralleled changes in BDNF levels and neurogenesis. These findings suggest that the social environment has an important role in recovery after ischemic brain injury.
    Translational psychiatry. 01/2014; 4:e351.
  • Fudong Liu, Louise D McCullough
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    ABSTRACT: Transient middle cerebral artery occlusion (tMCAO) in rodents is one of the most widely utilized models in experimental stroke studies on focal cerebral ischemia. tMCAO can be modeled in different ways, all aimed at mimicking the clinical scenario of early reperfusion after an ischemic infarct. Some models utilize mechanical occlusion to transiently occlude blood flow with an intraluminal suture, others use "humanized" clot with adjunctive thrombolytic use. This chapter will focus on these two models; the intraluminal suture and thromboembolic MCAO, as they are widely used in stroke research. In addition, several methods of cerebral blood flow (CBF) monitoring during a tMCAO procedure including laser Doppler flowmetry (LDF), laser speckle flowmetry (LSF), and carbon-14 Iodoantipyrine Autoradiography ((14)C-IAP) will be described.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1135:81-93. · 1.29 Impact Factor
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    ABSTRACT: Aging is an important determinant of ischemic stroke outcomes. Both clinical and experimental stroke studies have shown that aging negatively correlates with infarct volumes but is associated with worsened functional recovery after stroke. This may correspond to a differing cellular and molecular response to stroke in the aged versus young brain. It was hypothesized in this study that the smaller injury seen in the aged ischemic brain is because of structural differences in microvasculature with aging or differences in intraischemic tissue perfusion. Both young and aged C57BL6 mice were subject to middle cerebral artery occlusion modeling. Laser speckle flowmetry was used to study the functional dynamics of cerebral perfusion, and fluorescein isothiocyanate (FITC)-dextran staining was performed to examine the structural change in microvasculature. In separate cohorts, cresyl violet staining and immunohistochemistry with CD31 and IgG antibodies were applied to further assess the microvascular density and blood-brain barrier breakdown after stroke. No difference in cerebral blood flow was seen at the baseline, intraischemically, and postreperfusion in young versus aged mice. FITC-dextran and CD31 staining did not show significant differences in the microvascular density between young and aged ischemic brains. More extravasation of IgG through the blood-brain barrier was found in the young versus aged cohort at both 24 and 72 hours after stroke. Cerebrovascular dynamics and perfusion are not responsible for the different stroke phenotypes seen in the young versus aged animals, which may be more related to different levels of blood-brain barrier breakdown.
    Stroke 12/2013; · 6.02 Impact Factor
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    ABSTRACT: Social isolation in the pre-stroke environment leads to poorer outcomes after an ischemic injury in both animal and human studies. However, the impact of social isolation following stroke, which may be more clinically relevant as a target for therapeutic intervention, has yet to be examined. In this study, we investigated both the sub-acute (2 weeks) and chronic (7 weeks) effects of social isolation on post-stroke functional and histological outcome. Worsened histological damage from ischemic injury and an increase in depressive-like behavior was observed in isolated mice as compared to pair-housed mice. Mice isolated immediately after stroke showed a decrease in the levels of brain-derived neurotrophic factor (BDNF). These changes, both histological and behavioral, suggest an overall negative effect of social isolation on stroke outcome, potentially contributing to post-stroke depression and anxiety. Therefore, it is important to identify patients who have perceived isolation post-stroke to hopefully prevent this exacerbation of histological damage and subsequent depression.
    Behavioural brain research 11/2013; · 3.22 Impact Factor
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    ABSTRACT: Despite the high mortality, there is currently no specific treatment for intracerebral hemorrhage (ICH). Research investigating optimum degree of blood pressure control in patients presenting with ICH and hypertension is ongoing. However, there is limited understanding of the potential benefits of specific classes of antihypertensive therapy. β-Adrenergic antagonists may provide neuroprotection from inflammation-induced injury by inhibiting sympathetic nervous system mediated immune activation. We examined mortality in ICH patients receiving β-adrenergic antagonists to determine whether this class of antihypertensive therapy was associated with improved survival. A retrospective analysis of a large, prospectively collected database of patients presenting with acute ICH was performed. Patients were grouped by inpatient β-blocker treatment to determine an effect on mortality during the inpatient stay and at 3months of follow-up. Additional analysis was conducted comparing β-blocker therapy to any other antihypertensive treatment to determine a class-specific association of β-blocker treatment with mortality. The study population included 426 patients with acute, spontaneous ICH. Inpatient β-blocker use was independently associated with decreased rates of inpatient death and mortality at 3months of follow-up. However, univariate and multivariable analyses comparing β-blocker use to other antihypertensives failed to show any class-specific reduction in mortality at either time point. Our study demonstrates that the improvement seen in patients treated with β-adrenergic antagonists is not an effect unique to this class. This supports ongoing trials to determine optimum levels of blood pressure control using multiple classes of antihypertensives.
    Journal of the neurological sciences 10/2013; · 2.32 Impact Factor
  • Arturo Montaño, Ilene Staff, Louise D McCullough, Gil Fortunato
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    ABSTRACT: Intravenous (IV) tissue plasminogen activator (tPA) administration for ischemic stroke between 3 and 4.5 hours after onset was found to be safe and beneficial in the ECASS III trial. However, its use has remained controversial, and its benefit as applied in routine practice at community stroke centers is less well defined. This retrospective database study compared safety and clinical outcomes in 500 patients given IV tPA either from 0 to 3 or 3 to 4.5 hours after onset at a high-volume community center from January 2008 to October 2012. Additional independent variables included for univariate and multivariate analysis were age, sex, hypertension, diabetes mellitus, National Institutes of Health stroke scale on arrival. There were no significant differences seen in rates of symptomatic intracranial hemorrhage (3.8% vs 5.8%, P > .05), in-hospital mortality, or Barthel index at 3 months between groups. In addition, tPA administration despite ECASS III contraindications did not appear to be an independent predictor of hemorrhage in the first 24 hours. Our results show that the conclusions of the ECASS III trial can be applied to routine stroke treatment at a community center and that IV thrombolysis in the 3- to 4.5-hour window results in similar safety and efficacy functional outcome at 3 months compared with administration before 3 hours after onset.
    The American journal of emergency medicine 09/2013; · 1.15 Impact Factor
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    ABSTRACT: Hypothyroidism is associated with increased ischemic stroke risk but paradoxically results in more favorable outcomes once a stroke occurs. Whether a similar pattern emerges in patients with primary intracerebral hemorrhage (ICH) is unknown. A retrospective analysis of a prospective stroke center database was performed to analyze the clinical presentation and outcomes of hypothyroid patients with spontaneous ICH. Patients were classified into groups with no history of thyroid disease (n = 491) versus those with hypothyroidism (n = 72). Hypothyroid patients were further classified into patients receiving thyroid replacement on admission or those without replacement. The Glasgow Coma Scale, ICH score, and the National Institutes of Health Stroke Scale (NIHSS) were used to assess the initial severity. Outcome was assessed by admission to discharge change in the NIHSS and modified Barthel Index (mBI), in-hospital mortality, discharge disposition and mortality, and the mBI at 3 and 12 months. There were 563 patients in the analysis. Seventy-two patients had a history of hypothyroidism, and of these, 63% received thyroid hormone replacement. Patients receiving replacement had significantly lower NIHSS at presentation (median 4 [IQR 1, 11]) compared with either the control group (median 8 [IQR 3, 16]) or hypothyroid patients without replacement (median 9 [IQR 3.8, 15.5]; P = .004). There was no difference in in-hospital and 3-month mortality or functional outcomes at 3 and 12 months among the groups. This study suggests that the history of hypothyroidism does not affect clinical severity or outcome after ICH.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 09/2013; · 1.99 Impact Factor
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    ABSTRACT: Aging and biological sex are critical determinants of stroke outcome. Post-ischemic inflammatory response strongly contributes to the extent of ischemic brain injury, but how this response changes with age and sex is unknown. We subjected young (5-6months), middle aged (14-15months) and aged (20-22months), C57BL/6 male and female mice to transient middle cerebral artery occlusion (MCAO) and found that a significant age by sex interaction influenced histological stroke outcomes. Acute functional outcomes were worse with aging. Neutrophils, inflammatory macrophages, macrophages, dendritic cells (DCs) and microglia significantly increased in the brain post MCAO. Cycling females had higher Gr1(-) non-inflammatory macrophages and lower T cells in the brain after stroke and these correlated with serum estradiol levels. Estrogen loss in acyclic aged female mice exacerbated stroke induced splenic contraction. Advanced age increased T cells, DCs and microglia at the site of injury, which may be responsible for the exacerbated behavioral deficits in aged. We conclude that aging and sex have differential effects on the post stroke inflammatory milieu. Putative immunomodulatory therapies need to account for this heterogeneity.
    Experimental Neurology 08/2013; · 4.62 Impact Factor

Publication Stats

2k Citations
405.32 Total Impact Points


  • 2011–2014
    • University of Connecticut
      • • Department of Neurology
      • • Department of Neuroscience
      Storrs, Connecticut, United States
    • Saint Francis Hospital And Medical Center, Hartford, Ct
      Hartford, Connecticut, United States
    • National Institutes of Health
      Maryland, United States
  • 2013
    • Duke University Medical Center
      Durham, North Carolina, United States
  • 2005–2013
    • Hartford Hospital
      • • Department of Neurosurgery
      • • Department of Neurology
      • • Stroke Center
      Hartford, Connecticut, United States
  • 2005–2012
    • UConn Health Center
      • • Department of Neuroscience
      • • Department of Neurology
      Farmington, CT, United States
  • 2010
    • Yale University
      • Department of Neurology
      New Haven, CT, United States
    • Wannan Medical College
      Wu-hu-shih, Anhui Sheng, China
  • 2003–2005
    • Johns Hopkins Medicine
      • • Department of Neurology
      • • Department of Anesthesiology and Critical Care Medicine
      Baltimore, MD, United States