IMPORTANCEWhether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear.OBJECTIVE To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome. Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in DESIGN, SETTING, AND PARTICIPANTS

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Stereocontrolled total synthesis of (+)-vinblastine (1) has been achieved using a novel radical-mediated indole synthesis developed in our laboratories. The isothiocyanate 18, prepared readily from quinoline 17, underwent a facile addition of the malonate anion to give 19. The o-alkenylthioanilide 19 was then converted to indole 20 by radical cyclization and protection. (-)-Vindoline (2) was prepared from this key intermediate 20 in a highly efficient manner. The indole core of the 11-membered intermediate 3 was constructed similarly from quinoline. The critical coupling reaction between 2 and the chloroindolenine derived from 3 proceeded with complete control of stereochemistry to give the desired product 66 in 97 % yield, which could be successfully converted to (+)-vinblastine (1).Vinblastine (1), isolated from Catharanthus roseus [1], has been widely known as a prominent agent for cancer chemotherapy. Since chemical modifications of the natural product have been the major means for exploration of the more potent analogs, a limited number of its derivatives have so far been accessible [2a]. Total synthesis of vinblastine, on the other hand, has been the subject of intensive investigations in the area of alkaloid synthesis [2b]. Despite the endeavors spanning the past three decades, only four syntheses have been reported to date [3]. In all cases, however, the supply of the lower half of vinblastine (i.e., vindoline) relied upon the natural sources. The major challenges in the total synthesis of 1 include controlling the stereochemistry of C18′ as well as establishment of efficient routes to the two halves of the indole units.Our synthetic plan is shown in Scheme 1. Model studies by Schill [4] as well as our molecular modeling study strongly suggested that a stereocontrolled coupling with vindoline (2) could be per-*Lecture presented at the

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Thrombolytic therapy was carried out on patients with acute ischemic stroke, and the risk of hemorrhagic transformation was evaluated from the residual cerebral blood flow (CBF) by pretherapeutic single-photon emission-computed tomography (SPECT). Local intra-arterial thrombolytic therapy was carried out using urokinase or recombinant tissue plasminogen activator (rt-PA) within 6 hours from the onset in 34 patients in whom no hypodensity areas were observed on the initial computed tomography examination. In the 20 patients with carotid territory occlusion who underwent 99mTc-labeled hexamethylpropyleneamine oxime (99mTc-HMPAO) SPECT, the residual CBF of the ischemic region was evaluated semiquantitatively by calculating two parameters: the ischemic regional activity to cerebellar activity ratio (R/CE ratio) and asymmetry index (AI). The occluded vessels could be recanalized in 22 (92%) of the 24 patients in the urokinase group and in all 10 of the patients in the rt-PA group. Hemorrhagic transformation appeared in 4 patients in the urokinase group and 3 patients in the rt-PA group. Among the 20 patients who underwent SPECT before the treatment, the residual CBF was lower in the 5 patients who developed hemorrhagic transformation than in the 15 who did not (P < .05). Hemorrhagic transformation occurred in all patients with R/CE ratio of less than 0.35 and AI of more than 1.5. The risk of hemorrhagic transformation after recanalization of occluded vessels by local intra-arterial thrombolytic therapy was considered to be high when the pretherapeutic residual CBF was markedly reduced.

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Background : The bioactive sphingolipid sphingosine 1-phosphate (S1P) is formed by the activation of sphingosine kinase (SPHK) in diverse stimuli, such as platelet-derived growth factor (PDGF). S1P acts not only as an extracellular mediator but also as an intracellular second messenger, resulting in the proliferation of various different types of cells. However, the signal transduction mechanism in S1P-induced proliferation of mesangial cells is poorly known.

This study investigates retrospectively, in selected patients, the ischemic outcome (reversible ischemia, infarction, and hemorrhage) and neurologic outcome of acute stroke treated with intra-arterial thrombolysis and the predictive value of pretreatment single-photon emission-computed tomography (SPECT). Thirty patients with complete recanalization within 12 hours were analyzed. The extent of ischemia was outlined on SPECT, and two CBF parameters were calculated: the ratio of ischemic regional activity to CBF in the cerebellum and the asymmetry index. Reversible ischemia, infarction, and hemorrhage were identified by comparing SPECT and follow-up computed tomography. Nine patients (30%) had no or small infarction, 14 (47%) had medium or large infarction, and seven (23%) had hemorrhage. Forty-two lesions were identified (22 reversible ischemia, 13 infarction, and 7 hemorrhage). Duration of ischemia, urokinase dose, disease type, and occlusion site were nonsignificant factors, whereas neurologic outcome and CBF parameters were significant among the three patient groups and three types of ischemic lesions. Ischemic tissue with CBF greater than 55% of cerebellar flow still may be salvageable, even with treatment initiated 6 hours after onset of symptoms. Ischemic tissue with CBF greater than 35% of cerebellar flow still may be salvageable with early treatment (less than 5 hours). Ischemic tissue with with CBF less than 35% of cerebellar flow may be at risk for hemorrhage within the critical time window. Pretreatment SPECT can provide useful parameters to increase the efficacy of thrombolysis by reducing hemorrhagic complications and improving neurologic outcome.