Browsing by Author "James, Michael L"

Now showing 1 - 20 of 25
  • Thumbnail Image
    ItemOpen Access
    Anti-inflammatory effects of progesterone in lipopolysaccharide-stimulated BV-2 microglia.
    (PLoS One, 2014) Lei, Beilei; Mace, Brian; Dawson, Hana N; Warner, David S; Laskowitz, Daniel T; James, Michael L
    Female sex is associated with improved outcome in experimental brain injury models, such as traumatic brain injury, ischemic stroke, and intracerebral hemorrhage. This implies female gonadal steroids may be neuroprotective. A mechanism for this may involve modulation of post-injury neuroinflammation. As the resident immunomodulatory cells in central nervous system, microglia are activated during acute brain injury and produce inflammatory mediators which contribute to secondary injury including proinflammatory cytokines, and nitric oxide (NO) and prostaglandin E2 (PGE2), mediated by inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), respectively. We hypothesized that female gonadal steroids reduce microglia mediated neuroinflammation. In this study, the progesterone's effects on tumor necrosis factor alpha (TNF-α), iNOS, and COX-2 expression were investigated in lipopolysaccharide (LPS)-stimulated BV-2 microglia. Further, investigation included nuclear factor kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways. LPS (30 ng/ml) upregulated TNF-α, iNOS, and COX-2 protein expression in BV-2 cells. Progesterone pretreatment attenuated LPS-stimulated TNF-α, iNOS, and COX-2 expression in a dose-dependent fashion. Progesterone suppressed LPS-induced NF-κB activation by decreasing inhibitory κBα and NF-κB p65 phosphorylation and p65 nuclear translocation. Progesterone decreased LPS-mediated phosphorylation of p38, c-Jun N-terminal kinase and extracellular regulated kinase MAPKs. These progesterone effects were inhibited by its antagonist mifepristone. In conclusion, progesterone exhibits pleiotropic anti-inflammatory effects in LPS-stimulated BV-2 microglia by down-regulating proinflammatory mediators corresponding to suppression of NF-κB and MAPK activation. This suggests progesterone may be used as a potential neurotherapeutic to treat inflammatory components of acute brain injury.
  • Thumbnail Image
    ItemOpen Access
    Association of Brain Injury Biomarkers and Circulatory Shock Following Moderate-Severe Traumatic Brain Injury: A TRACK-TBI Study.
    (Journal of neurosurgical anesthesiology, 2021-12) Toro, Camilo; Jain, Sonia; Sun, Shelly; Temkin, Nancy; Barber, Jason; Manley, Geoffrey; Komisarow, Jordan M; Ohnuma, Tetsu; Foreman, Brandon; Korley, Frederick; James, Michael L; Laskowitz, Daniel; Vavilala, Monica S; Hernandez, Adrian; Mathew, Joseph P; Markowitz, Amy J; Krishnamoorthy, Vijay; TRACK-TBI Investigators

    Introduction

    Early circulatory shock following traumatic brain injury (TBI) is a multifactorial process; however, the impact of brain injury biomarkers on the risk of shock has not been evaluated. We examined the association between neuronal injury biomarker levels and the development of circulatory shock following moderate-severe TBI.

    Methods

    In this retrospective cohort study, we examined adults with moderate-severe TBI (Glasgow Coma Scale score <13) enrolled in the TRACK-TBI study, an 18-center prospective TBI cohort study. The exposures were day-1 levels of neuronal injury biomarkers (glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], neuron-specific enolase), and of an inflammatory biomarker (high-sensitivity C-reactive protein). The primary outcome was the development of circulatory shock, defined as cardiovascular Sequential Organ Failure Assessment Score ≥2 within 72 hours of admission. Association between day-1 biomarker levels and the development of circulatory shock was assessed with regression analysis.

    Results

    The study included 392 subjects, with a mean age of 40 years; 314 (80%) were male and 165 (42%) developed circulatory shock. Median (interquartile range) day-1 levels of UCH-L1 (994.8 [518.7 to 1988.2] pg/mL vs. 548.1 [280.2 to 1151.9] pg/mL; P<0.0001) and S100B (0.47 μg/mL [0.25 to 0.88] vs. 0.27 [0.16 to 0.46] μg/mL; P<0.0001) were elevated in those who developed early circulatory shock compared with those who did not. In multivariable regression, there were associations between levels of both UCH-L1 (odds ratio, 1.63 [95% confidence interval, 1.25-2.12]; P<0.0005) and S100B (odds ratio, 1.73 [95% confidence interval 1.27-2.36]; P<0.0005) with the development of circulatory shock.

    Conclusion

    Neuronal injury biomarkers may provide the improved mechanistic understanding and possibly early identification of patients at risk for early circulatory shock following moderate-severe TBI.
  • Thumbnail Image
    ItemOpen Access
    Association of Early Beta-Blocker Exposure and Functional Outcomes in Critically Ill Patients With Moderate to Severe Traumatic Brain Injury: A Transforming Clinical Research and Knowledge in Traumatic Brain Injury Study.
    (Critical care explorations, 2023-09) Kelly-Hedrick, Margot; Liu, Sunny Yang; Temkin, Nancy; Barber, Jason; Komisarow, Jordan; Manley, Geoffrey; Ohnuma, Tetsu; Colton, Katharine; Treggiari, Miriam M; Monson, Eric E; Vavilala, Monica S; Grandhi, Ramesh; Laskowitz, Daniel T; Mathew, Joseph P; Hernandez, Adrian; James, Michael L; Raghunathan, Karthik; Goldstein, Ben; Markowitz, Amy J; Krishnamoorthy, Vijay

    Objectives

    We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury.

    Design

    Retrospective cohort study.

    Setting

    ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study.

    Patients

    Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of <13) were admitted to the ICU after a blunt TBI.

    Interventions

    None.

    Measurements

    Primary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction.

    Main results

    Of the 450 eligible participants, 57 (13%) received early beta blockers (BB+ group). The BB+ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB+ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB+ group and BB- group (odds ratio = 0.86; 95% CI, 0.48-1.53). There was no association between BB exposure and secondary outcomes.

    Conclusions

    About one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limited by overall low total doses administered compared with prior studies.
  • Thumbnail Image
    ItemOpen Access
    Association of Severe Acute Kidney Injury with Mortality and Healthcare Utilization Following Isolated Traumatic Brain Injury.
    (Neurocritical care, 2021-01-13) Luu, David; Komisarow, Jordan; Mills, Brianna M; Vavilala, Monica S; Laskowitz, Daniel T; Mathew, Joseph; James, Michael L; Hernandez, Adrian; Sampson, John; Fuller, Matt; Ohnuma, Tetsu; Raghunathan, Karthik; Privratsky, Jamie; Bartz, Raquel; Krishnamoorthy, Vijay

    Background/objective

    Traumatic brain injury (TBI) is a leading cause of morbidity, mortality, and disability in the USA. While cardiopulmonary dysfunction can result in poor outcomes following severe TBI, the impact of acute kidney injury (AKI) is poorly understood. We examined the association of severe AKI with hospital mortality and healthcare utilization following isolate severe TBI.

    Methods

    We conducted a retrospective cohort study using the National Trauma Data Bank from 2007 to 2014. We identified a cohort of adult patients with isolated severe TBI and described the incidence of severe AKI, corresponding to Acute Kidney Injury Network stage 3 disease or greater. We examined the association of severe AKI with the primary outcome of hospital mortality using multivariable logistic regression models. In secondary analyses, we examined the association of severe AKI with dialysis catheter placement, tracheostomy and gastrostomy utilization, and hospital length of stay.

    Results

    There were 37,851 patients who experienced isolated severe TBI during the study period. Among these patients, 787 (2.1%) experienced severe (Stage 3 or greater) AKI. In multivariable models, the development of severe AKI in the hospital was associated with in-hospital mortality (OR 2.03, 95% CI 1.64-2.52), need for tracheostomy (OR 2.10, 95% CI 1.52-2.89), PEG tube placement (OR 1.88, 95% CI 1.45-2.45), and increased hospital length of stay (p < 0.001).

    Conclusions

    The overall incidence of severe AKI is relatively low (2.1%), but is associated with increased mortality and multiple markers of increased healthcare utilization following severe TBI.
  • Thumbnail Image
    ItemOpen Access
    Brain Natriuretic Peptide Improves Long-Term Functional Recovery after Acute CNS Injury in Mice
    (2010-01) James, Michael L; Wang, Haichen; Venkatraman, Talaignair; Song, Pingping; Lascola, Christopher D; Laskowitz, Daniel T
    There is emerging evidence to suggest that brain natriuretic peptide (BNP) is elevated after acute brain injury, and that it may play an adaptive role in recovery through augmentation of cerebral blood flow (CBF). Through a series of experiments, we tested the hypothesis that the administration of BNP after different acute mechanisms of central nervous system (CNS) injury could improve functional recovery by improving CBF. C57 wild-type mice were exposed to either pneumatic-induced closed traumatic brain injury (TBI) or collagenase-induced intracerebral hemorrhage (ICH). After injury, either nesiritide (hBNP) (8 μg/kg) or normal saline were administered via tail vein injection at 30 min and 4 h. The mice then underwent functional neurological testing via rotorod latency over the following 5 days and neurocognitive testing via Morris water maze testing on days 24–28. Cerebral blood flow (CBF) was assessed by laser Doppler from 25 to 90 min after injury. After ICH, mRNA polymerase chain reaction (PCR) and histochemical staining were performed during the acute injury phase (<24 h) to determine the effects on inflammation. Following TBI and ICH, administration of hBNP was associated with improved functional performance as assessed by rotorod and Morris water maze latencies (p < 0.01). CBF was increased (p < 0.05), and inflammatory markers (TNF-α and IL-6; p < 0.05), activated microglial (F4/80; p < 0.05), and neuronal degeneration (Fluoro-Jade B; p < 0.05) were reduced in mice receiving hBNP. hBNP improves neurological function in murine models of TBI and ICH, and was associated with enhanced CBF and downregulation of neuroinflammatory responses. hBNP may represent a novel therapeutic strategy after acute CNS injury.
  • Thumbnail Image
    ItemOpen Access
    Clinician judgment vs formal scales for predicting intracerebral hemorrhage outcomes.
    (Neurology, 2016-01-12) Hwang, David Y; Dell, Cameron A; Sparks, Mary J; Watson, Tiffany D; Langefeld, Carl D; Comeau, Mary E; Rosand, Jonathan; Battey, Thomas WK; Koch, Sebastian; Perez, Mario L; James, Michael L; McFarlin, Jessica; Osborne, Jennifer L; Woo, Daniel; Kittner, Steven J; Sheth, Kevin N
    OBJECTIVE: To compare the performance of formal prognostic instruments vs subjective clinical judgment with regards to predicting functional outcome in patients with spontaneous intracerebral hemorrhage (ICH). METHODS: This prospective observational study enrolled 121 ICH patients hospitalized at 5 US tertiary care centers. Within 24 hours of each patient's admission to the hospital, one physician and one nurse on each patient's clinical team were each asked to predict the patient's modified Rankin Scale (mRS) score at 3 months and to indicate whether he or she would recommend comfort measures. The admission ICH score and FUNC score, 2 prognostic scales selected for their common use in neurologic practice, were calculated for each patient. Spearman rank correlation coefficients (r) with respect to patients' actual 3-month mRS for the physician and nursing predictions were compared against the same correlation coefficients for the ICH score and FUNC score. RESULTS: The absolute value of the correlation coefficient for physician predictions with respect to actual outcome (0.75) was higher than that of either the ICH score (0.62, p = 0.057) or the FUNC score (0.56, p = 0.01). The nursing predictions of outcome (r = 0.72) also trended towards an accuracy advantage over the ICH score (p = 0.09) and FUNC score (p = 0.03). In an analysis that excluded patients for whom comfort care was recommended, the 65 available attending physician predictions retained greater accuracy (r = 0.73) than either the ICH score (r = 0.50, p = 0.02) or the FUNC score (r = 0.42, p = 0.004). CONCLUSIONS: Early subjective clinical judgment of physicians correlates more closely with 3-month outcome after ICH than prognostic scales.
  • Thumbnail Image
    ItemOpen Access
    CN-105 in Participants with Acute Supratentorial Intracerebral Hemorrhage (CATCH) Trial.
    (Neurocritical care, 2021-08-23) James, Michael L; Troy, Jesse; Nowacki, Nathaniel; Komisarow, Jordan; Swisher, Christa B; Tucker, Kristi; Hatton, Kevin; Babi, Marc A; Worrall, Bradford B; Andrews, Charles; Woo, Daniel; Kranz, Peter G; Lascola, Christopher; Maughan, Maureen; Laskowitz, Daniel T; CATCH Investigators

    Background

    Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.

    Methods

    Eligible patients were aged 30-80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared.

    Results

    In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31-5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort.

    Conclusions

    CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.
  • Thumbnail Image
    ItemOpen Access
    Echocardiogram Utilization Patterns and Association With Mortality Following Severe Traumatic Brain Injury
    (Anesthesia & Analgesia, 2020-08-12) Chen, Fangyu; Komisarow, Jordan M; Mills, Brianna; Vavilala, Monica; Hernandez, Adrian; Laskowitz, Daniel T; Mathew, Joseph P; James, Michael L; Haines, Krista L; Raghunathan, Karthik; Fuller, Matt; Bartz, Raquel R; Krishnamoorthy, Vijay
  • Thumbnail Image
    ItemOpen Access
    Effect of 6% hydroxyethyl starch 130/0.4 in 0.9% sodium chloride (Voluven®) on complications after subarachnoid hemorrhage: a retrospective analysis.
    (Springerplus, 2013-12) Khan, Shariq A; Adogwa, Owoicho; Gan, Tong J; Null, Ulysses T; Verla, Terence; Gokhale, Sankalp; White, William D; Britz, Gavin W; Zomorodi, Ali R; James, Michael L; McDonagh, David L
    BACKGROUND: 6% Hydroxyethyl Starch 130/0.4 in 0.9% Sodium Chloride (Voluven®; 6% HES 130/0.4) is a colloid often used for fluid resuscitation in patients with subarachnoid hemorrhage (SAH), despite a lack of safety data for this use. The purpose of our study was to evaluate the effect of 6% HES 130/0.4 on major complications associated with SAH. METHODS: Medical records of all patients presenting between May 2010 and September 2012 with aneurysmal SAH were analyzed. Patients were divided in two groups based on the administration of 6% HES 130/0.4; HES group (n=57) and Non-HES group (n=72). The primary outcome included a composite of three major complications associated with SAH: Delayed Cerebral Ischemia (DCI), Hydrocephalus (HCP) requiring cerebrospinal fluid (CSF) shunting, and Rebleeding. RESULTS: The study groups were similar with respect to most characteristics except the incidences of hypertension, ischemic heart disease, Fisher grade and lowest hemoglobin during stay. The odds of developing the primary composite outcome was higher in the HES group [OR= 3.1(1.30-7.36), p=0.01]. The patients in the HES group had a significantly longer median duration of hospital (19 vs 14 days) and Neurointensive Care Unit stay (14 vs 10 days) compared to the Non HES group. CONCLUSION: We observed increased complications after SAH with 6% HES 130/0.4 (Voluven®) administration. An adequately powered prospective randomized controlled trial into the safety of 6% HES 130/0.4 in this patient population is warranted.
  • Thumbnail Image
    ItemOpen Access
    Epidemiology and Outcomes of Acute Respiratory Distress Syndrome Following Isolated Severe Traumatic Brain Injury.
    (Journal of intensive care medicine, 2020-11-15) Komisarow, Jordan M; Chen, Fangyu; Vavilala, Monica S; Laskowitz, Daniel; James, Michael L; Krishnamoorthy, Vijay
    Patients with traumatic brain injury (TBI) are at risk for extra-cranial complications, such as the acute respiratory distress syndrome (ARDS). We conducted an analysis of risk factors, mortality, and healthcare utilization associated with ARDS following isolated severe TBI. The National Trauma Data Bank (NTDB) dataset files from 2007-2014 were used to identify adult patients who suffered isolated [other body region-specific Abbreviated Injury Scale (AIS) < 3] severe TBI [admission total Glasgow Coma Scale (GCS) from 3 to 8 and head region-specific AIS >3]. In-hospital mortality was compared between patients who developed ARDS and those who did not. Utilization of healthcare resources (ICU length of stay, hospital length of stay, duration of mechanical ventilation, and frequency of tracheostomy and gastrostomy tube placement) was also examined. This retrospective cohort study included 38,213 patients with an overall ARDS occurrence of 7.5%. Younger age, admission tachycardia, pre-existing vascular and respiratory diseases, and pneumonia were associated with the development of ARDS. Compared to patients without ARDS, patients that developed ARDS experienced increased in-hospital mortality (OR 1.13, 95% CI 1.01-1.26), length of stay (p = <0.001), duration of mechanical ventilation (p = < 0.001), and placement of tracheostomy (OR 2.70, 95% CI 2.34-3.13) and gastrostomy (OR 2.42, 95% CI 2.06-2.84). After isolated severe TBI, ARDS is associated with increased mortality and healthcare utilization. Future studies should focus on both prevention and management strategies specific to TBI-associated ARDS.
  • Thumbnail Image
    ItemOpen Access
    Erratum: Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.
    (Sci Rep, 2017-01-05) Lei, Beilei; James, Michael L; Liu, Ji; Zhou, Guanen; Venkatraman, Talaignair N; Lascola, Christopher D; Acheson, Shawn K; Dubois, Laura G; Laskowitz, Daniel T; Wang, Haichen
  • Thumbnail Image
    ItemOpen Access
    Female gonadal hormone effects on microglial activation and functional outcomes in a mouse model of moderate traumatic brain injury.
    (World J Crit Care Med, 2017-05-04) Umeano, Odera; Wang, Haichen; Dawson, Hana; Lei, Beilei; Umeano, Afoma; Kernagis, Dawn; James, Michael L
    AIM: To address the hypothesis that young, gonad-intact female mice have improved long-term recovery associated with decreased neuroinflammation compared to male mice. METHODS: Eight to ten week-old male, female, and ovariectomized (OVX) mice underwent closed cranial impact. Gonad-intact female mice were injured only in estrus state. After injury, between group differences were assessed using complementary immunohistochemical staining for microglial cells at 1 h, mRNA polymerase chain reaction for inflammatory markers at 1 h after injury, Rotarod over days 1-7, and water maze on days 28-31 after injury. RESULTS: Male mice had a greater area of injury (P = 0.0063), F4/80-positive cells (P = 0.032), and up regulation of inflammatory genes compared to female mice. Male and OVX mice had higher mortality after injury when compared to female mice (P = 0.043). No group differences were demonstrated in Rotarod latencies (P = 0.62). OVX mice demonstrated decreased water maze latencies compared to other groups (P = 0.049). CONCLUSION: Differences in mortality, long-term neurological recovery, and markers of neuroinflammation exist between female and male mice after moderate traumatic brain injury (MTBI). Unexpectedly, OVX mice have decreased long term neurological function after MTBI when compared to gonad intact male and female mice. As such, it can be concluded that the presence of female gonadal hormones may influence behavioural outcomes after MTBI, though mechanisms involved are unclear.
  • Thumbnail Image
    ItemOpen Access
    Gender and age interact to affect early outcome after intracerebral hemorrhage.
    (PLoS One, 2013) Umeano, Odera; Phillips-Bute, Barbara; Hailey, Claire E; Sun, Wei; Gray, Marisa C; Roulhac-Wilson, Briana; McDonagh, David L; Kranz, Peter G; Laskowitz, Daniel T; James, Michael L
    BACKGROUND: Intracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH. METHODS: Adult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed. RESULTS: In this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death. CONCLUSION: While independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings.
  • Thumbnail Image
    ItemOpen Access
    Incontinence and gait disturbance after intraventricular extension of intracerebral hemorrhage.
    (Neurology, 2016-03-08) Woo, Daniel; Kruger, Andrew J; Sekar, Padmini; Haverbusch, Mary; Osborne, Jennifer; Moomaw, Charles J; Martini, Sharyl; Hosseini, Shahla M; Ferioli, Simona; Worrall, Bradford B; Elkind, Mitchell SV; Sung, Gene; James, Michael L; Testai, Fernando D; Langefeld, Carl D; Broderick, Joseph P; Koch, Sebastian; Flaherty, Matthew L
    OBJECTIVE: We tested the hypothesis that intraventricular hemorrhage (IVH) is associated with incontinence and gait disturbance among survivors of intracerebral hemorrhage (ICH) at 3-month follow-ups. METHODS: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study was used as the discovery set. The Ethnic/Racial Variations of Intracerebral Hemorrhage study served as a replication set. Both studies performed prospective hot-pursuit recruitment of ICH cases with 3-month follow-up. Multivariable logistic regression analyses were computed to identify risk factors for incontinence and gait dysmobility at 3 months after ICH. RESULTS: The study population consisted of 307 ICH cases in the discovery set and 1,374 cases in the replication set. In the discovery set, we found that increasing IVH volume was associated with incontinence (odds ratio [OR] 1.50; 95% confidence interval [CI] 1.10-2.06) and dysmobility (OR 1.58; 95% CI 1.17-2.15) after controlling for ICH location, initial ICH volume, age, baseline modified Rankin Scale score, sex, and admission Glasgow Coma Scale score. In the replication set, increasing IVH volume was also associated with both incontinence (OR 1.42; 95% CI 1.27-1.60) and dysmobility (OR 1.40; 95% CI 1.24-1.57) after controlling for the same variables. CONCLUSION: ICH subjects with IVH extension are at an increased risk for developing incontinence and dysmobility after controlling for factors associated with severity and disability. This finding suggests a potential target to prevent or treat long-term disability after ICH with IVH.
  • Thumbnail Image
    ItemOpen Access
    Intra-operative hydroxyethyl starch is not associated with post-craniotomy hemorrhage.
    (Springerplus, 2015) Feix, James A; Peery, C Andrew; Gan, Tong J; Warner, David S; James, Michael L; Zomorodi, Ali; McDonagh, David L
    BACKGROUND: Intraoperative intravascular volume expansion with hydroxyethyl starch-based colloids is thought to be associated with an increased risk of post-craniotomy hemorrhage. Evidence for this association is limited. Associations between resuscitation with hydroxyethyl starch and risk of repeat craniotomy for hematoma evacuation were examined. METHODS: Using a retrospective cohort of neurosurgical patients at Duke University Medical Center between March 2005 and March 2012, patient characteristics were compared between those who developed post-craniotomy hemorrhage and those who did not. RESULTS: A total of 4,109 craniotomy procedures were analyzed with 61 patients having repeat craniotomy for post-operative hemorrhage (1.5%). The rate of reoperation in the group receiving 6% High Molecular Weight Hydroxyethyl Starch (Hextend(®)) was 2.6 vs. 1.3% for patients that did not receive hetastarch (P = 0.13). The reoperation rate for those receiving 6% hydroxyethyl Starch 130/0.4 (Voluven(®)) was 1.4 vs. 1.6% in patients not receiving Voluven (P = 0.85). CONCLUSIONS: In this retrospective cohort, intra-operative hydroxyethyl starch was not associated with an increased risk of post-craniotomy hemorrhage.
  • Thumbnail Image
    ItemOpen Access
    Intrastriatal injection of autologous blood or clostridial collagenase as murine models of intracerebral hemorrhage.
    (Journal of visualized experiments : JoVE, 2014-07-03) Lei, Beilei; Sheng, Huaxin; Wang, Haichen; Lascola, Christopher D; Warner, David S; Laskowitz, Daniel T; James, Michael L
    Intracerebral hemorrhage (ICH) is a common form of cerebrovascular disease and is associated with significant morbidity and mortality. Lack of effective treatment and failure of large clinical trials aimed at hemostasis and clot removal demonstrate the need for further mechanism-driven investigation of ICH. This research may be performed through the framework provided by preclinical models. Two murine models in popular use include intrastriatal (basal ganglia) injection of either autologous whole blood or clostridial collagenase. Since, each model represents distinctly different pathophysiological features related to ICH, use of a particular model may be selected based on what aspect of the disease is to be studied. For example, autologous blood injection most accurately represents the brain's response to the presence of intraparenchymal blood, and may most closely replicate lobar hemorrhage. Clostridial collagenase injection most accurately represents the small vessel rupture and hematoma evolution characteristic of deep hemorrhages. Thus, each model results in different hematoma formation, neuroinflammatory response, cerebral edema development, and neurobehavioral outcomes. Robustness of a purported therapeutic intervention can be best assessed using both models. In this protocol, induction of ICH using both models, immediate post-operative demonstration of injury, and early post-operative care techniques are demonstrated. Both models result in reproducible injuries, hematoma volumes, and neurobehavioral deficits. Because of the heterogeneity of human ICH, multiple preclinical models are needed to thoroughly explore pathophysiologic mechanisms and test potential therapeutic strategies.
  • Thumbnail Image
    ItemOpen Access
    Longitudinal Changes in Regional Cerebral Perfusion and Cognition Following Cardiac Surgery.
    (The Annals of thoracic surgery, 2018-09-22) Smith, Patrick J; Browndyke, Jeffrey N; Monge, Zachary A; Harshbarger, Todd B; James, Michael L; Gaca, Jeffrey G; Alexander, John H; Berger, Miles M; Newman, Mark F; Milano, Carmelo A; Mathew, Joseph P; Neurologic Outcomes Research Group (NORG)
    Cardiac surgery has been associated with increased risk of postoperative cognitive decline, as well as dementia risk in the general population. Few studies, however, have examined the impact of coronary revascularization or valve replacement / repair surgery on longitudinal cerebral perfusion changes or their association with cognitive function.We examined longitudinal changes in cerebral perfusion among 54 individuals with cardiac disease; 27 undergoing cardiac surgery and 27 matched controls. Arterial spin labeling (ASL) magnetic resonance perfusion imaging was used to quantify cerebral blood flow within the anterior communicating artery (ACA), middle cerebral artery (MCA), and posterior communicating artery (PCA) vascular territories prior to surgery and postoperatively at 6-weeks and 1-year. Cognitive performance was examined during the same intervals using a battery of tests tapping memory, executive, information processing and upper extremity motor functions. Repeated measures, mixed models were used to examine for perfusion changes and the association between perfusion changes and cognition.Significant postoperative increases in perfusion were observed at 6-weeks within the MCA vascular territory following cardiac surgery (P = .035 for interaction). Perfusion changes were most notable in distal territories of the MCA and PCA at 6-weeks, with no additional changes at 1-year. Postoperative increases in MCA perfusion at 6-weeks were associated with improved psychomotor speed (β = 0.35, P = .016); whereas, no significant differences were found between groups in vascular territory perfusion and cognition at 1-year.Cardiac surgery is associated with significant short-term increases in MCA perfusion with associated improvements in psychomotor speed.
  • Thumbnail Image
    ItemOpen Access
    Neuroprotective pentapeptide CN-105 improves functional and histological outcomes in a murine model of intracerebral hemorrhage.
    (Sci Rep, 2016-10-07) Lei, Beilei; James, Michael L; Liu, Ji; Zhou, Guanen; Venkatraman, Talaignair N; Lascola, Christopher D; Acheson, Shawn K; Dubois, Laura G; Laskowitz, Daniel T; Wang, Haichen
    Presently, no pharmacological treatments have been demonstrated to improve long-term functional outcomes following intracerebral hemorrhage (ICH). Clinical evidence associates apolipoprotein E (apoE) genotype with ICH incidence and outcome. While apoE modifies neuroinflammatory responses through its adaptive role in glial downregulation, intact apoE holoprotein is too large to cross the blood-brain barrier (BBB). Therefore, we developed a 5-amino acid peptide - CN-105 - that mimics the polar face of the apoE helical domain involved in receptor interactions. In the current study, we investigated the therapeutic potential of CN-105 in a mouse model of ICH. Three doses of CN-105 (0.05 mg/kg) was administered by tail vein injection within 24 hours after ICH induction. Functional assessment showed durable improvement in vestibulomotor performance after CN-105 treatment, as quantified by increased Rotarod latencies on Days 1-5 post-ICH, and long-term improvement in neurocognitive performance, as quantified by reduced Morris water maze latencies on Days 29-32 post-ICH. Further, brain water content was significantly reduced, neuroinflammation was decreased and hippocampal CA3 neuronal survival was increased, although hemorrhage volume was not affected by CN-105. We concluded, therefore, that pentapeptide CN-105 improved short- and long-term neurobehavioral outcomes in a murine model of ICH, suggesting therapeutic potential for patients with acute ICH.
  • Thumbnail Image
    ItemOpen Access
    Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage.
    (Neuroendocrinology, 2016-01) Hsieh, Justin T; Lei, Beilei; Sheng, Huaxin; Venkatraman, Talagnair; Lascola, Christopher D; Warner, David S; James, Michael L

    Background

    Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats.

    Methods

    ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridial collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h after injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, proinflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury.

    Results

    Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and proinflammatory transcription factor phosphorylated nuclear factor-x03BA;B p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected.

    Conclusions

    Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.
  • Thumbnail Image
    ItemOpen Access
    Sparcl1/Hevin drives pathological pain through spinal cord astrocyte and NMDA receptor signaling.
    (JCI insight, 2022-10) Chen, Gang; Xu, Jing; Luo, Hao; Luo, Xin; Singh, Sandeep K; Ramirez, Juan J; James, Michael L; Mathew, Joseph P; Berger, Miles; Eroglu, Cagla; Ji, Ru-Rong
    Hevin/Sparcl1 is an astrocyte-secreted protein and regulates synapse formation. Here we show that astrocytic hevin signaling plays a critical role in maintaining chronic pain. Compared to wild-type mice, hevin-null mice exhibited normal mechanical and heat sensitivity but reduced inflammatory pain. Interestingly, hevin-null mice have faster recovery than wild-type mice from neuropathic pain after nerve injury. Intrathecal injection of wild-type hevin was sufficient to induce persistent mechanical allodynia in naïve mice. In hevin-null mice with nerve injury, AAV-mediated re-expression of hevin in GFAP-expressing spinal cord astrocytes could reinstate neuropathic pain. Mechanistically, hevin is crucial for spinal cord NMDA receptor (NMDAR) signaling. Hevin potentiated NMDA currents mediated by the GluN2B-containing NMDARs. Furthermore, intrathecal injection of a neutralizing antibody against hevin alleviated acute and persistent inflammatory pain, postoperative pain, and neuropathic pain. Secreted hevin was detected in mouse cerebrospinal fluid (CSF) and nerve injury significantly increased CSF hevin abundance. Finally, neurosurgery caused rapid and substantial increases in SPARCL1/HEVIN levels in human CSF. Collectively, our findings support a critical role of hevin and astrocytes in the maintenance of chronic pain. Neutralizing of secreted hevin with monoclonal antibody may provide a new therapeutic strategy for treating acute and chronic pain and NMDAR-medicated neurodegeneration.