Epigenetic regulation of adult neural stem cells: implications for Alzheimer's disease.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tReviewExperimental evidence has demonstrated that several aspects of adult neural stem cells (NSCs), including their quiescence, proliferation, fate specification and differentiation, are regulated by epigenetic mechanisms. These control the expression of specific sets of genes, often including those encoding for small non-coding RNAs, indicating a complex interplay between various epigenetic factors and cellular functions.Previous studies had indicated that in addition to the neuropathology in Alzheimer's disease (AD), plasticity-related changes are observed in brain areas with ongoing neurogenesis, like the hippocampus and subventricular zone. Given the role of stem cells e.g. in hippocampal functions like cognition, and given their potential for brain repair, we here review the epigenetic mechanisms relevant for NSCs and AD etiology. Understanding the molecular mechanisms involved in the epigenetic regulation of adult NSCs will advance our knowledge on the role of adult neurogenesis in degeneration and possibly regeneration in the AD brain.Internationale Stichting Alzheimer Onderzoek (ISAO)Netherlands Organization for Scientific Research (NWO)Maastricht University Medical Centre 

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme

Systematic review of results of kissing stents in the treatment of aortoiliac occlusive disease

Introduction: Severe stenosis or occlusion of the aortoiliac bifurcation is typically treated with open surgery. Patency results of aorto-bifemoral bypass are up to 90 % at 5 years. However, the number and severity of complications seem to have reached a plateau level. A less invasive technique, the kissing stent (KS) is available nowadays. The goal of this review was to give an overview of the current results and status of the kissing stent technique. Method: The Scopus search engine was used to retrieve articles concerning KS, this retrieved 78 abstracts, 60 were rejected and 4 more were rejected after full text screening. One article was included after cross referencing. After a quality check, data was extracted for further analysis. Results: 810 patients ( 72.8 % Rutherford classification of 1/2/3) were included. The most prevalent risk factor was hypertension (37.5-96%) and 50% of patients were treated for TASC C & D lesions. Overall the technical success rate was 98.2 %. Procedural protocols greatly differed on applying protrusion and pre or post dilatation. Clinical improvement at 30 days was achieved in 89.9%. Primary patency at 12, 24, and 36 months was 88.8%, 78.9 and 68.5, respectively. A complication rate of 11 % was reported, of which most are minor . No detailed analysis could be performed because individual patient data are lacking. Conclusion: KS treatment of aortoiliac disease is related with only minor complications and acceptable midterm patency results, this can however not surpass the results seen with open surgery

The frequency of missed breast cancers in women participating in a high-risk MRI screening program

Contains fulltext : 191352.pdf (publisher's version ) (Open Access)PURPOSE: To evaluate the frequency of missed cancers on breast MRI in women participating in a high-risk screening program. METHODS: Patient files from women who participated in an increased risk mammography and MRI screening program (2003-2014) were coupled to the Dutch National Cancer Registry. For each cancer detected, we determined whether an MRI scan was available (0-24 months before cancer detection), which was reported to be negative. These negative MRI scans were in consensus re-evaluated by two dedicated breast radiologists, with knowledge of the cancer location. Cancers were scored as invisible, minimal sign, or visible. Additionally, BI-RADS scores, background parenchymal enhancement, and image quality (IQ; perfect, sufficient, bad) were determined. Results were stratified by detection mode (mammography, MRI, interval cancers, or cancers in prophylactic mastectomies) and patient characteristics (presence of BRCA mutation, age, menopausal state). RESULTS: Negative prior MRI scans were available for 131 breast cancers. Overall 31% of cancers were visible at the initially negative MRI scan and 34% of cancers showed a minimal sign. The presence of a BRCA mutation strongly reduced the likelihood of visible findings in the last negative MRI (19 vs. 46%, P < 0.001). Less than perfect IQ increased the likelihood of visible findings and minimal signs in the negative MRI (P = 0.021). CONCLUSION: This study shows that almost one-third of cancers detected in a high-risk screening program are already visible at the last negative MRI scan, and even more in women without BRCA mutations. Regular auditing and double reading for breast MRI screening is warranted

Comparison of breast cancer detection and depiction between planar and rotating synthetic mammography generated from breast tomosynthesis

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Automated detection of breast cancer in false-negative screening MRI studies from women at increased risk

PURPOSE: To evaluate the performance of an automated computer-aided detection (CAD) system to detect breast cancers that were overlooked or misinterpreted in a breast MRI screening program for women at increased risk. METHODS: We identified 40 patients that were diagnosed with breast cancer in MRI and had a prior MRI examination reported as negative available. In these prior examinations, 24 lesions could retrospectively be identified by two breast radiologists in consensus: 11 were scored as visible and 13 as minimally visible. Additionally, 120 normal scans were collected from 120 women without history of breast cancer or breast surgery participating in the same MRI screening program. A fully automated CAD system was applied to this dataset to detect malignant lesions. RESULTS: At 4 false-positives per normal case, the sensitivity for the detection of cancer lesions that were visible or minimally visible in retrospect in prior-negative examinations was 0.71 (95% CI=0.38-1.00) and 0.31 (0.07-0.59), respectively. CONCLUSIONS: A substantial proportion of cancers that were misinterpreted or overlooked in an MRI screening program was detected by a CAD system in prior-negative examinations. It has to be clarified with further studies if such a CAD system has an influence on the number of misinterpreted and overlooked cancers in clinical practice when results are given to a radiologist