Disruption of gradient expression of Zic3 resulted in abnormal intra-retinal axon projection

The targeting of retinal ganglion axons toward the optic disc is the first step in axon pathfinding in the visual system. The molecular mechanisms involved in guiding the retinal axons to project towards the optic disc are not well understood. We report that a gene encoding a zinc-finger transcription factor, Zic3, is expressed in a periphery-high and center-low gradient in the retina at the stages of active axon extension inside the retina. The gradient expression of Zic3 recedes towards the periphery over the course of development, correlating with the progression of retinal cell differentiation and axonogenesis. Disruption of gradient expression of Zic3 by retroviral overexpression resulted in mis-targeting of retinal axons and some axons misrouted to the sub-retinal space at the photoreceptor side of the retina. Misexpression of Zic3 did not affect neurogenesis or differentiation inside the retina, or grossly alter retinal lamination. By stripe assay, we show that misexpression of Zic3 may induce the expression of an inhibitory factor to the retinal axons. Zic3 appears to play a role in intra-retinal axon targeting, possibly through regulation of the expression of specific downstream genes involved in axon guidance

Design, Synthesis, and Pharmacological Evaluation of Haloperidol Derivatives as Novel Potent Calcium Channel Blockers with Vasodilator Activity

Several haloperidol derivatives with a piperidine scaffold that was decorated at the nitrogen atom with different alkyl, benzyl, or substituted benzyl moieties were synthesized at our laboratory to establish a library of compounds with vasodilator activity. Compounds were screened for vasodilatory activity on isolated thoracic aorta rings from rats, and their quantitative structure–activity relationships (QSAR) were examined. Based on the result of QSAR, N-4-tert-butyl benzyl haloperidol chloride (16c) was synthesized and showed the most potent vasodilatory activity of all designed compounds. 16c dose-dependently inhibited the contraction caused by the influx of extracellular Ca2+ in isolated thoracic aorta rings from rats. It concentration-dependently attenuated the calcium channel current and extracellular Ca2+ influx, without affecting the intracellular Ca2+ mobilization, in vascular smooth muscle cells from rats. 16c, possessing the N-4-tert-butyl benzyl piperidine structure, as a novel calcium antagonist, may be effective as a calcium channel blocker in cardiovascular disease

Risk factors and in-hospital mortality in Chinese patients undergoing coronary artery bypass grafting: Analysis of a large multi-institutional Chinese database

ObjectiveThis study was undertaken to delineate outcomes and to assess risk factors for in-hospital mortality among Chinese patients undergoing coronary artery bypass grafting.MethodsFrom 2007 to 2008, a total of 9838 consecutive adult patients undergoing coronary artery bypass grafting were enrolled in the Chinese Coronary Artery Bypass Grafting Registry, which included 43 centers from 17 province-level regions in China. This registry collected information on 67 preoperative factors and 30 operative factors believed to influence in-hospital mortality. The relationship between risk factors and in-hospital mortality was evaluated by univariate and logistic regression analyses.ResultsOverall in-hospital mortality was 2.5%. Eleven risk factors were found to be significant predictors for outcome: age (continuous), body mass index (continuous), left ventricular ejection fraction (continuous), preoperative New York Heart Association functional class III or IV, chronic renal failure, extracardiac arteriopathy, chronic obstructive pulmonary disease, preoperative atrial fibrillation or flutter (within 2 weeks), preoperative critical state, other than elective surgery, and combined valve procedure. Calibration with the Hosmer-Lemeshow test was satisfactory (P = .35), and the discrimination power was good (area under the receiver operating characteristic curve, 0.81; 95% confidence interval, 0.79–0.84).ConclusionsThe risk profiles and in-hospital mortality of Chinese patients undergoing coronary artery bypass grafting were determined from data in the most up-to-date multi-institutional database. Eleven variables were demonstrated to be independent risk factors for in-hospital death after coronary artery bypass grafting

Irx4-mediated regulation of Slit1 expression contributes to the definition of early axonal paths inside the retina

Although multiple axon guidance cues have been discovered in recent years, little is known about the mechanism by which the spatiotemporal expression patterns of the axon guidance cues are regulated in vertebrates. We report that a homeobox gene Irx4 is expressed in a pattern similar to that of Slit1 in the chicken retina. Overexpression of Irx4 led to specific downregulation of Slit1 expression, whereas inhibition of Irx4 activity by a dominant negative mutant led to induction of Slit1 expression, indicating that Irx4 is a crucial regulator of Slit1 expression in the retina. In addition, by examining axonal behavior in the retinas with overexpression of Irx4 and using several in vivo assays to test the effect of Slit1, we found that Slit1 acts positively to guide the retinal axons inside the optic fiber layer (OFL). We further show that the regulation of Slit1 expression by Irx4 is important for providing intermediate targets for retinal axons during their growth within the retina