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Goldstein, Joshua

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Goldstein

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Goldstein, Joshua
Author's Publications: search.filters.isAuthorOfPublication.66a7ed3f-558c-4857-bf73-b5e1329ee18e

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    Rho‐kinase inhibitors do not expand hematoma volume in acute experimental intracerebral hemorrhage
    (John Wiley and Sons Inc., 2018) Akhter, Murtaza; Qin, Tom; Fischer, Paul; Sadeghian, Homa; Kim, Hyung Hwan; Whalen, Michael; Goldstein, Joshua; Ayata, Cenk
    Abstract Rho‐associated kinase (ROCK) is an emerging target in acute ischemic stroke. Early pre‐hospital treatment with ROCK inhibitors may improve their efficacy, but their antithrombotic effects raise safety concerns in hemorrhagic stroke, precluding use prior to neuroimaging. Therefore, we tested whether ROCK inhibition affects the bleeding times, and worsens hematoma volume in a model of intracerebral hemorrhage (ICH) induced by intrastriatal collagenase injection in mice. Tail bleeding time was measured 1 h after treatment with isoform‐nonselective inhibitor fasudil, or ROCK2‐selective inhibitor KD025, or their vehicles. In the ICH model, treatments were administered 1 h after collagenase injection. Although KD025 but not fasudil prolonged the tail bleeding times, neither drug expanded the volume of ICH or worsened neurological deficits at 48 h compared with vehicle. Although more testing is needed in aged animals and comorbid models such as diabetes, these results suggest ROCK inhibitors may be safe for pre‐hospital administration in acute stroke.
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    Modeling Intracerebral Hemorrhage Growth and Response to Anticoagulation
    (Public Library of Science, 2012) Greenberg, Charles H.; Frosch, Matthew; Goldstein, Joshua; Rosand, Jonathan; Greenberg, Steven
    The mechanism for hemorrhage enlargement in the brain, a key determinant of patient outcome following hemorrhagic stroke, is unknown. We performed computer-based stochastic simulation of one proposed mechanism, in which hemorrhages grow in “domino” fashion via secondary shearing of neighboring vessel segments. Hemorrhages were simulated by creating an initial site of primary bleeding and an associated risk of secondary rupture at adjacent sites that decayed over time. Under particular combinations of parameters for likelihood of secondary rupture and time-dependent decay, a subset of lesions expanded, creating a bimodal distribution of microbleeds and macrobleeds. Systematic variation of the model to simulate anticoagulation yielded increases in both macrobleed occurrence (26.9%, 53.2%, and 70.0% of all hemorrhagic events under conditions simulating no, low-level, and high-level anticoagulation) and final hemorrhage size (median volumes 111, 276, and 412 under the same three conditions), consistent with data from patients with anticoagulant-related brain hemorrhages. Reversal from simulated high-level anticoagulation to normal coagulation was able to reduce final hemorrhage size only if applied relatively early in the course of hemorrhage expansion. These findings suggest that a model based on a secondary shearing mechanism can account for some of the clinically observed properties of intracerebral hemorrhage, including the bimodal distribution of volumes and the enhanced hemorrhage growth seen with anticoagulation. Future iterations of this model may be useful for elucidating the effects of hemorrhage growth of factors related to secondary shearing (such as small vessel pathology) or time-dependent decay (such as hemostatic agents).