From synaptic spines to nuclear signaling: nuclear and synaptic actions of the amyloid precursor protein

Despite intensive studies of the secretase‐mediated processing of the amyloid precursor protein (APP) to form the amyloid β‐peptide (Aβ), in relation to Alzheimer's disease (AD), no new therapeutic agents have reached the clinics based on reducing Aβ levels through the use of secretase inhibitors or immunotherapy. Furthermore, the normal neuronal functions of APP and its various metabolites still remain under‐investigated and unclear. Here, we highlight emerging areas of APP function that may provide new insights into synaptic development, cognition, and gene regulation. By modulating expression levels of endogenous APP in primary cortical neurons, the frequency and amplitude of calcium oscillations is modified, implying a key role for APP in maintaining neuronal calcium homeostasis essential for synaptic transmission. Disruption of this homeostatic mechanism predisposes to aging and AD. Synaptic spine loss is a feature of neurogeneration resulting in learning and memory deficits, and emerging evidence indicates a role for APP, probably mediated via one or more of its metabolites, in spine structure and functions. The intracellular domain of APP (AICD) has also emerged as a key epigenetic regulator of gene expression controlling a diverse range of genes, including APP itself, the amyloid‐degrading enzyme neprilysin, and aquaporin‐1. A fuller understanding of the physiological and pathological actions of APP and its metabolic network could provide new opportunities for therapeutic intervention in AD.     

A compact unc45b‐promoter drives muscle‐specific expression in zebrafish and mouse

Summary: Gene therapeutic approaches to cure genetic diseases require tools to express the rescuing gene exclusively within the affected tissues. Viruses are often chosen as gene transfer vehicles but they have limited capacity for genetic information to be carried and transduced. In addition, to avoid off‐target effects the therapeutic gene should be driven by a tissue‐specific promoter in order to ensure expression in the target organs, tissues, or cell populations. The larger the promoter, the less space will be left for the respective gene. Thus, there is a need for small but tissue‐specific promoters. Here, we describe a compact unc45b promoter fragment of 195 bp that retains the ability to drive gene expression exclusively in skeletal and cardiac muscle in zebrafish and mouse. Remarkably, the described unc45b promoter fragment not only drives muscle‐specific expression but presents heat‐shock inducibility, allowing a temporal and spatial quantity control of (trans)gene expression. Here, we demonstrate that the transgenic expression of the smyd1b gene driven by the unc45b promoter fragment is able to rescue the embryonically lethal heart and skeletal muscle defects in smyd1b‐deficient flatline mutant zebrafish. Our findings demonstrate that the described muscle‐specific unc45b promoter fragment might be a valuable tool for the development of genetic therapies in patients suffering from myopathies. genesis 54:431–438, 2016. © 2016 The Authors. Genesis Published by Wiley Periodicals, Inc.     

Comparison of methods to correct survival estimates and survival regression analysis on a large HIV African cohort

Objective

The evaluation of HIV treatment programs is generally based on an estimation of survival among patients receiving antiretroviral treatment (ART). In large HIV programs, loss to follow-up (LFU) rates remain high despite active patient tracing, which is likely to bias survival estimates and survival regression analyses.

Methods

We compared uncorrected survival estimates derived from routine program data with estimates obtained by applying six correction methods that use updated outcome data by a field survey targeting LFU patients in a rural HIV program in Malawi. These methods were based on double-sampling and differed according to the weights given to survival estimates in LFU and non-LFU subpopulations. We then proposed a correction of the survival regression analysis.

Results

Among 6,727 HIV-infected adults receiving ART, 9% were LFU after one year. The uncorrected survival estimates from routine data were 91% in women and 84% in men. According to increasing sophistication of the correction methods, the corrected survival estimates ranged from 89% to 85% in women and 82% to 77% in men. The estimates derived from uncorrected regression analyses were highly biased for initial tuberculosis mortality ratios (RR; 95% CI: 1.07; 0.76–1.50 vs. 2.06 to 2.28 with different correction weights), Kaposi sarcoma diagnosis (2.11; 1.61–2.76 vs. 2.64 to 3.9), and year of ART initiation (1.40; 1.17–1.66 vs. 1.29 to 1.34).

Conclusions

In HIV programs with high LFU rates, the use of correction methods based on non-exhaustive double-sampling data are necessary to minimise the bias in survival estimates and survival regressions.     

Guide du bon usage de la TDM en médecine nucléaire. IntroductionCT good practices for hybrid nuclear medicine (SPECT/CT and PET/CT): Introduction

Nuclear medicine hybrid imaging is a technological evolution of gamma camera scintigraphy or positron emission tomography imaging methods that are now often coupled with an anatomical imaging device, essentially a CT scanner. Following a large demand from the nuclear physicians themselves, but also from the French Nuclear Safety Authority, this guide is intended for the entire nuclear medicine community to integrate both the aspects of radiation protection related to coupled CT and those related to the quality of the CT images according to the clinical context.     

Rappels physiques et outils d’optimisation de la qualité image et de la dose

Many parameters can affect the patient's dose and the CT image quality. It is therefore essential, in order to optimize the patient's dosimetry, to know the influence of these parameters as well as their link with the dose modulation tools.     

Illustrations cliniques en ostéo-articulaire

The examples and clinical cases presented in this section are not intended to be considered as absolute models in terms of image quality or device parameter settings. They must initiate an individual analysis according to CT parameters and image quality. Nevertheless, they present practically different CT levels, which can be used according to the clinical context and the type of device.     

Illustrations cliniques en pneumologie (embolie pulmonaire)

The examples and clinical cases presented in this section are not intended to be considered as absolute models in terms of image quality or device parameter settings. They must initiate an individual analysis according to CT parameters and image quality. Nevertheless, they present practically different CT levels, which can be used according to the clinical context and the type of device.     

Illustrations cliniques en endocrinologie

The examples and clinical cases presented in this section are not intended to be considered as absolute models in terms of image quality or device parameter settings. They must initiate an individual analysis according to CT parameters and image quality. Nevertheless, they present practically different CT levels, which can be used according to the clinical context and the type of device.     

Illustrations cliniques en cardiologie

The examples and clinical cases presented in this section are not intended to be considered as absolute models in terms of image quality or device parameter settings. They must initiate an individual analysis according to CT parameters and image quality. Nevertheless, they present practically different CT levels which can be used according to the clinical context and the type of device.