Heat Transfer Model of Hyporthermic Intracarotid Infusion of Cold Saline for Stroke Therapy

A 3-dimensional hemispheric computational brain model is developed to simulate infusion of cold saline in the carotid arteries in terms of brain cooling for stroke therapy. The model is based on the Pennes bioheat equation, with four tissue layers: white matter, gray matter, skull, and scalp. The stroke lesion is simulated by reducing blood flow to a selected volume of the brain by a factor of one-third, and brain metabolism by 50%. A stroke penumbra was also generated surrounding the core lesion (blood volume reduction 25%, metabolism reduction 20%). The finite difference method was employed to solve the system of partial differential equations. This model demonstrated a reduction in brain temperature, at the stroke lesion, to 32°C in less than 10 minutes

Local Control of Temperature in a Theoretical Human Model of Selective Brain Cooling

A method of feedback control of local brain temperature during therapeutic intracarotid cold saline infusion is presented and tested on a theoretical cerebral heat transfer model based on the Pennes bioheat equation. In this temperature control method, the infusion rate of cold saline is varied based on the rate of temperature change, and the deviation of temperature to a target, within a voxel in the treated region of brain. This control method is tested in cases where the head is exposed to ambient room temperature, and where the head is packed in ice. In both the ice and non-ice cases, target temperature (33degC) is achieved in the voxel according to the desired time constant (2 minutes). Two hours of treatment decreased the required inflow of ice-cold saline from 30 ml/min to 21 and 7 ml/min in the non-ice and ice cases, respectively. Intracarotid hematocrit had higher values in the non-ice case

The Role of Intracarotid Cold Saline Infusion on a Theoretical Brain Model Incorporating the Circle of Willis and Cerebral Venous Return

This study describes a theoretical model of brain cooling by intracarotid cold saline infusion which takes into account redistribution of cold perfusate through the circle of Willis (CoW) and cold venous return (VR) from the head. This model is developed in spherical coordinates on a four tissue layer hemispherical geometrical configuration. Temperature evolution is modeled according to the Pennes bioheat transfer equation. Simulations were run over a 1 hour period and 30 ml/min of freezing cold saline with the baseline model (no VR, no CoW), VR model (without CoW), and CoW model (with VR). The VR model demonstrates continuing temperature drop in the treatment region of the brain not observed in the baseline model and its final mean ipsilateral anterior temperature was approximately 31 degC. The temperature effect in the CoW model was present but less robust in the ipsilateral anterior region, as final temperature was 32 degC. However, cooling was also achieved in contralateral and posterior brain regions. This model continues to demonstrate the feasibility of intracarotid cold saline infusion for ischemic stroke therapy

Reperfusion injury following cerebral ischemia: pathophysiology, MR imaging, and potential therapies

INTRODUCTION: Restoration of blood flow following ischemic stroke can be achieved by means of thrombolysis or mechanical recanalization. However, for some patients, reperfusion may exacerbate the injury initially caused by ischemia, producing a so-called “cerebral reperfusion injury”. Multiple pathological processes are involved in this injury, including leukocyte infiltration, platelet and complement activation, postischemic hyperperfusion, and breakdown of the blood–brain barrier. METHODS/RESULTS AND CONCLUSIONS: Magnetic resonance imaging (MRI) can provide extensive information on this process of injury, and may have a role in the future in stratifying patients’ risk for reperfusion injury following recanalization. Moreover, different MRI modalities can be used to investigate the various mechanisms of reperfusion injury. Antileukocyte antibodies, brain cooling and conditioned blood reperfusion are potential therapeutic strategies for lessening or eliminating reperfusion injury, and interventionalists may play a role in the future in using some of these therapies in combination with thrombolysis or embolectomy. The present review summarizes the mechanisms of reperfusion injury and focuses on the way each of those mechanisms can be evaluated by different MRI modalities. The potential therapeutic strategies are also discussed

The regulation and functional interaction of the epilethial sodium channel (ENaC) and renal potassium channels

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Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein

The amiloride-sensitive epithelial sodium channel (ENaC) plays a critical role in fluid and electrolyte homeostasis and consists of α, β, and γ subunits. The carboxyl terminus of each ENaC subunit contains a PPXY motif that is believed to be important for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle’s syndrome where mutations delete or alter the PPXY motif of either the β or γ subunits, has been shown to result in increased ENaC activity and arterial hypertension. Here we present evidence that N4WBP5A, a novel Nedd4/Nedd4-2-binding protein, is a potential regulator of ENaC. In Xenopus laevis oocytes N4WBP5A increases surface expression of ENaC by reducing the rate of ENaC retrieval. We further demonstrate that N4WBP5A prevents sodium feedback inhibition of ENaC possibly by interfering with the xNedd4-2-mediated regulation of ENaC. As N4WBP5A binds Nedd4/Nedd4-2 via PPXY motif/WW domain interactions and appears to be associated with specific intracellular vesicles, we propose that N4WBP5A functions by regulating Nedd4/ Nedd4-2 availability and trafficking. Because N4WBP5A is highly expressed in native renal collecting duct and other tissues that express ENaC, it is a likely candidate to modulate ENaC function in vivo.Angelos-Aristeidis Konstas, Linda M. Shearwin-Whyatt, Andrew B. Fotia, Brian Degger, Daniela Riccardi, David I. Cook, Christoph Korbmacher and Sharad Kuma