Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Aβ levels

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is characterized by a decline in cognitive function and accumulation of amyloid-β peptide (Aβ) in extracellular plaques. Mutations in amyloid precursor protein (APP) and presenilins alter APP metabolism resulting in accumulation of Aβ42, a peptide essential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of Aβ40, the more prevalent Aβ peptide secreted by cells and a major component of cerebral Aβ deposits, is less clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human Aβ42 and Aβ40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD.</p> <p>Results</p> <p>Adeno-associated viral (AAV) vectors encoding BRI-Aβ cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded Aβ peptide. As a comparison the effect of AAV-mediated overexpression of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, passive avoidance, novel object recognition) three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Aβ40 and AAV-BRI-Aβ42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Aβ peptides. BRI-Aβ42 and the combination of BRI-Aβ40+42 overexpression resulted in elevated levels of detergent-insoluble Aβ. No significant increase in detergent-insoluble Aβ was seen in the rats expressing APPsw or BRI-Aβ40. No pathological features were noted in any rats, except the AAV-BRI-Aβ42 rats which showed focal, amorphous, Thioflavin-negative Aβ42 deposits.</p> <p>Conclusion</p> <p>The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology <it>in vivo</it>, and demonstrate that whilst expression of Aβ42 alone is sufficient to initiate Aβ deposition, both Aβ40 and Aβ42 may contribute to cognitive deficits.</p

Measuring and Correcting Wind-Induced Pointing Errors of the Green Bank Telescope Using an Optical Quadrant Detector

Wind-induced pointing errors are a serious concern for large-aperture high-frequency radio telescopes. In this paper, we describe the implementation of an optical quadrant detector instrument that can detect and provide a correction signal for wind-induced pointing errors on the 100m diameter Green Bank Telescope (GBT). The instrument was calibrated using a combination of astronomical measurements and metrology. We find that the main wind-induced pointing errors on time scales of minutes are caused by the feedarm being blown along the direction of the wind vector. We also find that wind-induced structural excitation is virtually non-existent. We have implemented offline software to apply pointing corrections to the data from imaging instruments such as the MUSTANG 3.3 mm bolometer array, which can recover ~70% of sensitivity lost due to wind-induced pointing errors. We have also performed preliminary tests that show great promise for correcting these pointing errors in real-time using the telescope's subreflector servo system in combination with the quadrant detector signal.Comment: 17 pages, 11 figures; accepted for publication in PAS

Holographic Measurement and Improvement of the Green Bank Telescope Surface

We describe the successful design, implementation, and operation of a 12 GHz holography system installed on the Robert C. Byrd Green Bank Telescope (GBT). We have used a geostationary satellite beacon to construct high-resolution holographic images of the telescope mirror surface irregularities. These images have allowed us to infer and apply improved position offsets for the 2209 actuators which control the active surface of the primary mirror, thereby achieving a dramatic reduction in the total surface error (from 390 microns to ~240 microns, rms). We have also performed manual adjustments of the corner offsets for a few panels. The expected improvement in the radiometric aperture efficiency has been rigorously modeled and confirmed at 43 GHz and 90 GHz. The improvement in the telescope beam pattern has also been measured at 11.7 GHz with greater than 60 dB of dynamic range. Symmetric features in the beam pattern have emerged which are consistent with a repetitive pattern in the aperture due to systematic panel distortions. By computing average images for each tier of panels from the holography images, we confirm that the magnitude and direction of the panel distortions, in response to the combination of gravity and thermal gradients, are in general agreement with finite-element model predictions. The holography system is now fully integrated into the GBT control system, and by enabling the telescope staff to monitor the health of the individual actuators, it continues to be an essential tool to support high-frequency observations.Comment: Accepted for publication in PASP. Contains 28 pages with 2 tables and 9 figures (several at reduced quality). The full resolution version is available at http://wwwlocal.gb.nrao.edu/ptcs/papers/Hunter2011/gbtholo.ps.gz (34MB gzip file unpacks to 134MB postscript

Role of genetic testing for inherited prostate cancer risk: Philadelphia prostate cancer consensus conference 2017

Purpose: Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-dri

Implementing detention intake reform: The judicial response

This study examines several influences on judges\u27 attitudes toward implementation of new detention intake policies in Florida. Based on a statewide survey of all circuit judges on the juvenile bench, the analysis focuses specifically on the relative impact of judges\u27 agreement with the statutory purpose of detention, working relationships with other juvenile justice professionals, and a variety of demographic and occupational variables on support for these reforms. The findings, which indicate that agreement with the statutory purpose of detention exerts the dominant influence, have implications for policy-makers interested in improving the implementation process in juvenile justice. © 1996 Sage Publications, Inc

Relationship Between Socioeconomic Factors, Distribution of Public Access Defibrillators and Incidence of Out-of-hospital Cardiac Arrest

Background: Survival from out-of-hospital cardiac arrest (OHCA) is improved when public access defibrillators are used. Areas of socioeconomic deprivation may have higher rates of OHCA and thus a greater demand for public access defibrillators. We aimed to determine if there was a relationship between socioeconomic factors, the geographic distribution of public access defibrillators (PADs) and incidence of OHCA. Method: Socioeconomic deprivation data was obtained from the Census-based 2013 Index of Deprivation. Spatial information for PADs was obtained from a New Zealand PAD database (AED Locations) in 2016 and 2018. Location data for OHCA was obtained from the St John New Zealand OHCA registry for the period 1 October 2013 to 30 June 2016. Relationships between these variables were analysed using a Poisson regression analysis. Results: Cardiac arrest incidence increased with increasing deprivation. The incidence in the most deprived areas of 156.5 events per 100,000 person years (135.4–180.9, 95% CI) is double the incidence in the least deprived areas at 78.0 events per 100,000 person years (66.4–91.7, 95% CI). Significant increases in the rates of OHCA were observed with every 1% increase in proportions of Māori (1.0%, 0.61–1.4%, 95% CI, p = 0.001), Pacific Peoples (0.6%, 0.21–0.9%, p = 0.005), >65 year olds (3.7%, 3.0–4.3%, p < 0.001), and males (3.7%, 1.8–5.6%, p < 0.001). In 2018, the decile 10 areas had the lowest coverage of PADs (65% of these areas contained a PAD) compared with less deprived areas (68–84%, median 81%). Conclusions: The most socioeconomically deprived communities had the highest incidence of OHCA and the least availability of PADs. This provides impetus for targeted PAD placement in areas of higher deprivation

Kartlegging av fødselsasfyksi hos fullbårne nyfødte i Troms og Finnmark

Asfyksi hos fullbårne nyfødte er en sjelden tilstand, men med høy morbiditet og mortalitet hos de som rammes. Sekveler forekommer i form av cerebral parese, mental retardasjon, blindhet/døvhet og epilepsi. Risikofødsler bør derfor selekteres til kvinneklinikker og større fødeavdelinger, med nødvendige kompetanse i beredskap for optimal behandling. Asfyktiske barn som blir født i distriktene hentes av ambulansefly med barnelege og neonatalsykepleier (kuvøseteamet) og fraktes til Nyfødt intensiv(NI)/UNN. Vi har gjennomført en kvalitetsundersøkelse ved hjelp av journaler ved UNN for perioden 1994-2005 samt data fra Medisinsk Fødselsregister (MFR) for samme periode for å avdekke om insidensen av alvorlig fødsels-asfyksi hos fullbårne i Troms og Finnmark er økende, og om det er noen fødeinstitusjoner som har relativt høyere insidens enn andre. Dessuten har vi studert de medisinske konsekvenser av asfyksi. Undersøkelsen har ikke gitt grunnlag for å konkludere med en generelt økende asfyksiinsidens. Det er heller ingen av de mindre fødeinstitusjonene som skiller seg ut med en større asfyksiinsidens enn de andre institusjonene (gjennomsnittlig asfyksiinsidens er 0,1 % på fødestuene (se vedlegg 1, tabell 9)). UNN har en asfyksiinsidens på 1,3 % av fullbårne nyfødte (se vedlegg 1, tabell 9). Når det gjelder asfyksi hos fullbårne ser det dermed ut til at den eksisterende svangerskaps- og fødselsomsorgen i Troms og Finnmark fungerer tilfredsstillende, både med hensyn til selektering av risikofødsler til KK/UNN og overflytting/transport til NI/UNN ved hjelp av kuvøseteamet