Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis

Background. Without strong evidence of benefit, the use of carotid endarterectomy for prophylaxis against stroke rose dramatically until the mid-1980s, then declined. Our investigation sought to determine whether carotid endarterectomy reduces the risk of stroke among patients with a recent adverse cerebrovascular event and ipsilateral carotid stenosis. Method. We conducted a randomized trial at 50 clinical centers throughout the United States and Canada, in patients in two predetermined strata based on the severity of carotid stenosis—30 to 69 percent and 70 to 99 percent. We report here the results in the 659 patients in the latter stratum, who had had a hemispheric or retinal transient ischemic attack or a nondisabling stroke within the 120 days before entry and had stenosis of 70 to 99 percent in the symptomatic carotid artery. All patients received optimal medical care, including antiplatelet therapy. Those assigned to surgical treatment underwent carotid endarterectomy performed by neurosurgeons or vascular surgeons. All patients were examined by neurologists 1, 3, 6, 9, and 12 months after entry and then every 4 months. End points were assessed by blinded, independent case review. No patient was lost to follow-up. Results. Life-table estimates of the cumulative risk of any ipsilateral stroke at two years were 26 percent in the 331 medical patients and 9 percent in the 328 surgical patients—an absolute risk reduction (±SE) of 17±3.5 percent (P\u3c0.001). For a major or fatal ipsilateral stroke, the corresponding estimates were 13.1 percent and 2.5 percent — an absolute risk reduction of 10.6±2.6 percent (P\u3c0.001 ). Conclusion. Carotid endarterectomy was still found to be beneficial when all strokes and deaths were included in the analysis (P\u3c0.001). Carotid endarterectomy is highly beneficial to patients with recent hemispheric and retinal transient ischemic attacks or nondisabling strokes and ipsilateral high-grade stenosis (70 to 99 percent) of the internal carotid artery. (N Engl J Med 1991; 325:445–53.). © 1991, Massachusetts Medical Society. All rights reserved

Upregulation of CRABP1 in human neuroblastoma cells overproducing the Alzheimer-typical Aβ42 reduces their differentiation potential

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is characterized by neurodegeneration and changes in cellular processes, including neurogenesis. Proteolytic processing of the amyloid precursor protein (APP) plays a central role in AD. Owing to varying APP processing, several β-amyloid peptides (Aβ) are generated. In contrast to the form with 40 amino acids (Aβ₄₀), the variant with 42 amino acids (Aβ₄₂) is thought to be the pathogenic form triggering the pathological cascade in AD. While total-Aβ effects have been studied extensively, little is known about specific genome-wide effects triggered by Aβ₄₂or Aβ₄₀derived from their direct precursor C99.</p> <p>Methods</p> <p>A combined transcriptomics/proteomics analysis was performed to measure the effects of intracellularly generated Aβ peptides in human neuroblastoma cells. Data was validated by real-time polymerase chain reaction (real-time PCR) and a functional validation was carried out using RNA interference.</p> <p>Results</p> <p>Here we studied the transcriptomic and proteomic responses to increased or decreased Aβ₄₂and Aβ₄₀levels generated in human neuroblastoma cells. Genome-wide expression profiles (Affymetrix) and proteomic approaches were combined to analyze the cellular response to the changed Aβ₄₂- and Aβ₄₀-levels. The cells responded to this challenge with significant changes in their expression pattern. We identified several dysregulated genes and proteins, but only the cellular retinoic acid binding protein 1 (CRABP1) was up-regulated exclusively in cells expressing an increased Aβ₄₂/Aβ₄₀ratio. This consequently reduced all-trans retinoic acid (RA)-induced differentiation, validated by CRABP1 knock down, which led to recovery of the cellular response to RA treatment and cellular sprouting under physiological RA concentrations. Importantly, this effect was specific to the AD typical increase in the Aβ₄₂/Aβ₄₀ratio, whereas a decreased ratio did not result in up-regulation of CRABP1.</p> <p>Conclusion</p> <p>We conclude that increasing the Aβ₄₂/Aβ₄₀ratio up-regulates CRABP1, which in turn reduces the differentiation potential of the human neuroblastoma cell line SH-SY5Y, but increases cell proliferation. This work might contribute to the better understanding of AD neurogenesis, currently a controversial topic.</p