Citations

Better tools for assessing cognitive impairment in the early stages of Alzheimer's disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow for detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer's Association convened a meeting to discuss state‐of‐the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory, and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real‐world situations so as to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally, and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.

AbstractPurpose: Conventional therapies to treat prostate cancer (CaP) of androgen-dependent phenotype (ADPC) and castration-resistant phenotype (CRPC) are deficient in outcome which has necessitated a need to identify those agents that could target AR for both disease types. We provide mechanism-based evidence that lupeol (Lup-20(29)-en-3b-ol) is a potent inhibitor of androgen receptor (AR) in vitro and in vivo.Experimental Design: Normal prostate epithelial cell (RWPE-1), LAPC4 (wild functional AR/ADPC), LNCaP (mutant functional/AR/ADPC), and C4-2b (mutant functional/AR/CRPC) cells were used to test the anti-AR activity of lupeol. Cells grown under androgen-rich environment and treated with lupeol were tested for proliferation, AR transcriptional activity, AR competitive ligand binding, AR–DNA binding, and AR–ARE/target gene binding. Furthermore, in silico molecular modeling for lupeol–AR binding was done. Athymic mice bearing C4-2b and LNCaP cell–originated tumors were treated intraperitoneally with lupeol (40 mg/kg; 3 times/wk) and tumor growth and surrogate biomarkers were evaluated. To assess bioavailability, lupeol serum levels were measured.Results: Lupeol significantly inhibited R1881 (androgen analogue) induced (i) transcriptional activity of AR and (ii) expression of PSA. Lupeol (i) competed antagonistically with androgen for AR, (ii) blocked the binding of AR to AR-responsive genes including PSA, TIPARP, SGK, and IL-6, and (iii) inhibited the recruitment of RNA Pol II to target genes. Lupeol sensitized CRPC cells to antihormone therapy. High-performance liquid chromatography analysis showed that lupeol is bioavailable to mice. Lupeol inhibited the tumorigenicity of both ADPC and CRPC cells in animals. Serum and tumor tissues exhibited reduced PSA levels.Conclusion: Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP. Clin Cancer Res; 17(16); 5379–91. ©2011 AACR.

Background —The Telectronics Accufix pacing leads were recalled in November 1994 after 2 deaths and 2 nonfatal injuries were reported. This multicenter clinical study (MCS) of patients with Accufix leads was designed to determine the rate of spontaneous injury related to the J retention wire and results of lead extraction. Methods and Results —The MCS included 2589 patients with Accufix atrial pacing leads that were implanted at or who were followed up at 12 medical centers. Patients underwent cinefluoroscopic imaging of their lead every 6 months. The risk of J retention wire fracture was ≈5.6%/y at 5 years and 4.7%/y at 10 years after implantation. The annual risk of protrusion was 1.5%. A total of 40 spontaneous injuries were reported to a worldwide registry (WWR) that included data from 34 672 patients (34 892 Accufix leads), including pericardial tamponade (n=19), pericardial effusion (n=5), atrial perforation (n=3), J retention wire embolization (n=4), and death (n=6). The risk of injury was 0.02%/y (95% CI, 0.0025 to 0.072) in the MCS and 0.048%/y (95% CI, 0.035 to 0.067) in the WWR. A total of 5299 leads (13%) have been extracted worldwide. After recall in the WWR, fatal extraction complications occurred in 0.4% of intravascular procedures (16 of 4023), with life-threatening complications in 0.5% (n=21). Extraction complications increased with implant duration, female sex, and J retention wire protrusion. Conclusions —Accufix pacing leads pose a low, ongoing risk of injury. Extraction is associated with substantially higher risks, and a conservative management approach is indicated for most patients.

We describe four patients with episodic bilateral vision impairment related exclusively to light exposure. Each had angiographically documented bilateral high-grade stenosis or occlusion of the internal carotid arteries. This phenomenon appears to be related to bilateral simultaneous retinal ischemia delaying regeneration of visual pigments in the pigment epithelial layer. It must be distinguished from bilateral occipital lobe ischemia caused by vertebrobasilar system disease.