Brief episodes of brain ischemia define a patient population at increased risk for stroke. These brief events (TIAs) warrant urgent evaluation and treatment. It is therefore counterintuitive that transient ischemia might induce tolerance and protect the brain from subsequent ischemia. However, accumulating data from studies on both myocardium and brain support such a concept. An understanding of the mechanisms involved in ischemic tolerance may define novel therapeutic strategies for brain protection.Ischemic tolerance in the heart. The observation that multiple episodes of brief regional myocardial ischemia do not produce a cumulative depletion of high-energy phosphate compounds or loss of function provided the first evidence for ischemic tolerance (or ischemic preconditioning).'S2 Such brief episodes of ischemia render the myocardium more tolerant to subsequent lethal ischemia, as evidenced by reduced infarct size, delayed ultrastructural changes, and improved recovery of regional myocardial function during r e p e r f~s i o n .~.~ With ischemic preconditioning, myocardial infarct size is reduced in multiple species from 70% to 30% of the myocardium at r i~k .~-~ The "dose" of ischemia adequate to produce tolerance in the heart varies from 2.5 to 10 minutes, depending on the species with some studies showing a requirement for multiple dosing.6 The protection is substantial, doubling the duration of ischemia needed for infarction to 0ccur.j The time window during which tolerance occurs in the myocardium is brief, starting between 1 and 60 minutes after preconditioning and lasting less than 3 hours in most ~t u d i e s .~ A delayed secondary acquisition of tolerance, a so-called "second window of protection," also occurs in some cases 24 hours after ischemic precond i t i~n i n g .~.~ Some aspects of ischemic preconditioning are observed in the human heart as well, as evidenced by a reduction in anginal pain and STsegment ECG alterations during the second balloon inflation (5 minutes after the first inflation) in patients undergoing percutaneous transluminal coronary angioplasty.1° Mechanisms of ischemic preconditioning in the heart. Adenosine and the A1 receptor. Adenosine, acting a t the A1 receptor, is a neuromodulator of myocardial metabolism and is released from metabolized ATP during ischemia.l' Adenosine stimulation of the A1 receptor decreases cyclic adenosine monophosphate levels, resulting in a negative inotropic effect that decreases myocardial oxygen demand. Adenosine or adenosine A1 agonists induce ischemic tolerance in the rabbit,12 and pharmacologic blockade of the receptor attenuates tolerance in some but not all ~p e c i e s . '~J~ Therefore, adenosine, although protective during ischemia, is probably not the sole mediator of t~l e r a n c e .~ ATP-dependent potassium channels. Involvement of ATP-dependent potassium (KATp) channels in preconditioning protection has been suggested by the findings that selective potassium channel openers (RP 52891 and bimakalism) can mimic ischemic toleranceI5 and ...

Recent research demonstrates that white matter of the brain contains not only long T2 components, but a minority of ultrashort T2* components. Adiabatic inversion recovery prepared dual echo ultrashort echo time (IR-dUTE) sequences can be used to selectively image the ultrashort T2* components in white matter of the brain using a clinical whole body scanner. The T2*s of the ultrashort T2* components can be quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of different TEs. However, accurate T1 measurement of the ultrashort T2* components is technically challenging. Efficient suppression of the signal from the majority of long T2 components is essential for robust T1 measurement. In this paper we describe a novel approach to this problem based on the use of IR-dUTE data acquisitions with different TR and TI combinations to selectively detect the signal recovery of the ultrashort T2* components. Exponential recovery curve fitting provides efficient T1 estimation, with minimized contamination from the majority of long T2 components. A rubber phantom and a piece of bovine cortical bone were used for validation of this approach. Six healthy volunteers were studied. An averaged T2* of 0.32±0.09 ms, and a short mean T1 of 226±46 ms were demonstrated for the healthy volunteers at 3T.

Background and Purpose Dysregulation of the miR-15a/16-1 cluster in plasma has been reported in stroke patients as a potential biomarker for diagnostic and prognostic use. However, the essential role and therapeutic potential of the miR-15a/16-1 cluster in ischemic stroke are poorly understood. This study is aimed at investigating the regulatory role of the miR-15a/16-1 cluster in ischemic brain injury and insight mechanisms. Methods Adult male miR-15a/16-1 knockout and wild-type mice, or adult male C57 BL/6J mice injected via tail vein with the miR-15a/16-1 specific inhibitor (antagomir, 30 pmol/g), were subjected to 1h of middle cerebral artery occlusion (MCAO) and 72h of reperfusion. The neurological scores, brain infarct volume, brain water content, and neurobehavioral tests were then evaluated and analyzed. To explore underlying signaling pathways associated with alteration of miR-15a/16-1 activity, major pro-inflammatory cytokines were measured by qPCR or ELISA and anti-apoptotic proteins were examined by western blotting. Results Genetic deletion of the miR-15a/16-1 cluster or intravenous delivery of miR-15a/16-1 antagomir significantly reduced cerebral infarct size, decreased brain water content and improved neurological outcomes in stroke mice. Inhibition of miR-15a/16-1 significantly decreased the expression of the pro-inflammatory cytokines IL-6, MCP-1, VCAM-1 and TNF-α, and increased Bcl-2 and Bcl-w levels in the ischemic brain regions. Conclusions Our data indicate that pharmacological inhibition of the miR-15a/16-1 cluster reduces ischemic brain injury via both upregulation of anti-apoptotic proteins and suppression of pro-inflammatory molecules. These results suggest that the miR-15a/16-1 cluster is a novel therapeutic target for ischemic stroke.

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ET-26HCl has anesthetic potency and hemodynamic stability similar to etomidate, but it caused less adrenocortical hormone synthesis suppression than etomidate and faster spatial orientation recovery from anesthesia than propofol, which was similar to etomidate.