Imaging Parkinson's disease below the neck

Parkinson's disease is a systemic disorder with widespread and early α-synuclein pathology in the autonomic and enteric nervous systems, which is present throughout the gastrointestinal canal prior to diagnosis. Gastrointestinal and genitourinary autonomic symptoms often predate clinical diagnosis by several years. It has been hypothesized that progressive α-synuclein aggregation is initiated in hyperbranched, non-myelinated neuron terminals, and may subsequently spread via retrograde axonal transport. This would explain why autonomic nerves are so prone to formation of α-synuclein pathology. However, the hypothesis remains unproven and in vivo imaging methods of peripheral organs may be essential to study this important research field. The loss of sympathetic and parasympathetic nerve terminal function in Parkinson's disease has been demonstrated using radiotracers such as 123I-meta-iodobenzylguanidin, 18F-dopamine, and 11C-donepezil. Other radiotracer and radiological imaging methods have shown highly prevalent dysfunction of pharyngeal and esophageal motility, gastric emptying, colonic transit time, and anorectal function. Here, we summarize the methodology and main findings of radio-isotope and radiological modalities for imaging peripheral pathology in Parkinson's disease

Precursors to social and communication difficulties in infants at-risk for autism: gaze following and attentional engagement

Whilst joint attention (JA) impairments in autism have been widely studied, little is known about the early development of gaze following, a precursor to establishing JA. We employed eye-tracking to record gaze following longitudinally in infants with and without a family history of autism spectrum disorder (ASD) at 7 and 13 months. No group difference was found between at-risk and low-risk infants in gaze following behaviour at either age. However, despite following gaze successfully at 13 months, at-risk infants with later emerging socio-communication difficulties (both those with ASD and atypical development at 36 months of age) allocated less attention to the congruent object compared to typically developing at-risk siblings and low-risk controls. The findings suggest that the subtle emergence of difficulties in JA in infancy may be related to ASD and other atypical outcomes

MultiMetEval: comparative and multi-objective analysis of genome-scale metabolic models

Comparative metabolic modelling is emerging as a novel field, supported by the development of reliable and standardized approaches for constructing genome-scale metabolic models in high throughput. New software solutions are needed to allow efficient comparative analysis of multiple models in the context of multiple cellular objectives. Here, we present the user-friendly software framework Multi-Metabolic Evaluator (MultiMetEval), built upon SurreyFBA, which allows the user to compose collections of metabolic models that together can be subjected to flux balance analysis. Additionally, MultiMetEval implements functionalities for multi-objective analysis by calculating the Pareto front between two cellular objectives. Using a previously generated dataset of 38 actinobacterial genome-scale metabolic models, we show how these approaches can lead to exciting novel insights. Firstly, after incorporating several pathways for the biosynthesis of natural products into each of these models, comparative flux balance analysis predicted that species like Streptomyces that harbour the highest diversity of secondary metabolite biosynthetic gene clusters in their genomes do not necessarily have the metabolic network topology most suitable for compound overproduction. Secondly, multi-objective analysis of biomass production and natural product biosynthesis in these actinobacteria shows that the well-studied occurrence of discrete metabolic switches during the change of cellular objectives is inherent to their metabolic network architecture. Comparative and multi-objective modelling can lead to insights that could not be obtained by normal flux balance analyses. MultiMetEval provides a powerful platform that makes these analyses straightforward for biologists. Sources and binaries of MultiMetEval are freely available from https://github.com/PiotrZakrzewski/MetEv​al/downloads

Commentary on the use of the reproduction number R during the COVID-19 pandemic

Since the beginning of the COVID-19 pandemic, the reproduction number R has become a popular epidemiological metric used to communicate the state of the epidemic. At its most basic, R is defined as the average number of secondary infections caused by one primary infected individual. R seems convenient, because the epidemic is expanding if R>1 and contracting if R<1. The magnitude of R indicates by how much transmission needs to be reduced to control the epidemic. Using R in a naïve way can cause new problems. The reasons for this are threefold: (1) There is not just one definition of R but many, and the precise definition of R affects both its estimated value and how it should be interpreted. (2) Even with a particular clearly defined R, there may be different statistical methods used to estimate its value, and the choice of method will affect the estimate. (3) The availability and type of data used to estimate R vary, and it is not always clear what data should be included in the estimation. In this review, we discuss when R is useful, when it may be of use but needs to be interpreted with care, and when it may be an inappropriate indicator of the progress of the epidemic. We also argue that careful definition of R, and the data and methods used to estimate it, can make R a more useful metric for future management of the epidemic

Methods to study splicing from high-throughput RNA Sequencing data

The development of novel high-throughput sequencing (HTS) methods for RNA (RNA-Seq) has provided a very powerful mean to study splicing under multiple conditions at unprecedented depth. However, the complexity of the information to be analyzed has turned this into a challenging task. In the last few years, a plethora of tools have been developed, allowing researchers to process RNA-Seq data to study the expression of isoforms and splicing events, and their relative changes under different conditions. We provide an overview of the methods available to study splicing from short RNA-Seq data. We group the methods according to the different questions they address: 1) Assignment of the sequencing reads to their likely gene of origin. This is addressed by methods that map reads to the genome and/or to the available gene annotations. 2) Recovering the sequence of splicing events and isoforms. This is addressed by transcript reconstruction and de novo assembly methods. 3) Quantification of events and isoforms. Either after reconstructing transcripts or using an annotation, many methods estimate the expression level or the relative usage of isoforms and/or events. 4) Providing an isoform or event view of differential splicing or expression. These include methods that compare relative event/isoform abundance or isoform expression across two or more conditions. 5) Visualizing splicing regulation. Various tools facilitate the visualization of the RNA-Seq data in the context of alternative splicing. In this review, we do not describe the specific mathematical models behind each method. Our aim is rather to provide an overview that could serve as an entry point for users who need to decide on a suitable tool for a specific analysis. We also attempt to propose a classification of the tools according to the operations they do, to facilitate the comparison and choice of methods.Comment: 31 pages, 1 figure, 9 tables. Small corrections adde

Using an online survey of healthcare-seeking behaviour to estimate the magnitude and severity of the 2009 H1N1v influenza epidemic in England

Background : During the 2009 H1N1v influenza epidemic, the total number of symptomatic cases was estimated by combining influenza-like illness (ILI) consultations, virological surveillance and assumptions about healthcare-seeking behaviour. Changes in healthcare-seeking behaviour due to changing scientific information, media coverage and public anxiety, were not included in case estimates. The purpose of the study was to improve estimates of the number of symptomatic H1N1v cases and the case fatality rate (CFR) in England by quantifying healthcare-seeking behaviour using an internet-based survey carried out during the course of the 2009 H1N1v influenza epidemic. Methods : We used an online survey that ran continuously from July 2009 to March 2010 to estimate the proportion of ILI cases that sought healthcare during the 2009 H1N1v influenza epidemic. We used dynamic age- and gender-dependent measures of healthcare-seeking behaviour to re-interpret consultation numbers and estimate the true number of cases of symptomatic ILI in 2009 and the case fatality rate (CFR). Results : There were significant differences between age groups in healthcare usage. From the start to the end of the epidemic, the percentage of individuals with influenza-like symptoms who sought medical attention decreased from 43% to 32% (p < 0.0001). Adjusting official numbers accordingly, we estimate that there were 1.1 million symptomatic cases in England, over 320,000 (40%) more cases than previously estimated and that the autumn epidemic wave was 45% bigger than previously thought. Combining symptomatic case numbers with reported deaths leads to a reduced overall CFR estimate of 17 deaths per 100,000 cases, with the largest reduction in adults. Conclusions : Active surveillance of healthcare-seeking behaviour, which can be achieved using novel data collection methods, is vital for providing accurate real-time estimates of epidemic size and disease severity. The differences in healthcare-seeking between different population groups and changes over time have significant implications for estimates of total case numbers and the case fatality rate

Implementing Routine HIV Testing: The Role of State Law

In September 2006, the Centers for Disease Control and Prevention (CDC) recommended routine HIV testing for all Americans aged 13–64, which would eliminate requirements for written consent and pretest counseling as previously required. However, this approach may conflict with state requirements concerning pretest counseling and informed consent for HIV testing. Our survey of state HIV testing laws demonstrates that the majority of states have HIV testing requirements that are inconsistent with the CDC's recommendations. Moreover, states that have recently amended their laws have not eased the requirements for pretest counseling and informed consent. The reasons for the persistence of these legal requirements must be understood to effect policy changes to increase HIV testing

The effect of comorbidity on health-related quality of life for injury patients in the first year following injury: comparison of three comorbidity adjustment approaches

Background: Three approaches exist to deal with the impact of comorbidity in burden of disease studies - the maximum limit approach, the additive approach, and the multiplicative approach. The aim of this study was to compare the three comorbidity approaches in patients with temporary injury consequences as well as comorbid chronic conditions with nontrivial health impacts.Methods: Disability weights were assessed using data from the EQ-5D instrument developed by the EuroQol Group and derived from a postal survey among 2,295 injury patients at 2.5 and 9 months after being treated at an emergency department. We compared the observed and predicted EQ-5D disability weights in comorbid case

Neuromuscular Electrical Stimulation as a Method to Maximize the Beneficial Effects of Muscle Stem Cells Transplanted into Dystrophic Skeletal Muscle

Cellular therapy is a potential approach to improve the regenerative capacity of damaged or diseased skeletal muscle. However, its clinical use has often been limited by impaired donor cell survival, proliferation and differentiation following transplantation. Additionally, functional improvements after transplantation are all-too-often negligible. Because the host microenvironment plays an important role in the fate of transplanted cells, methods to modulate the microenvironment and guide donor cell behavior are warranted. The purpose of this study was to investigate whether the use of neuromuscular electrical stimulation (NMES) for 1 or 4 weeks following muscle-derived stem cell (MDSC) transplantation into dystrophic skeletal muscle can modulate the fate of donor cells and enhance their contribution to muscle regeneration and functional improvements. Animals submitted to 4 weeks of NMES after transplantation demonstrated a 2-fold increase in the number of dystrophin+ myofibers as compared to control transplanted muscles. These findings were concomitant with an increased vascularity in the MDSC+NMES group when compared to non-stimulated counterparts. Additionally, animals subjected to NMES (with or without MDSC transplantation) presented an increased maximal specific tetanic force when compared to controls. Although cell transplantation and/or the use of NMES resulted in no changes in fatigue resistance, the combination of both MDSC transplantation and NMES resulted in a faster recovery from fatigue, when compared to non-injected and non-stimulated counterparts. We conclude that NMES is a viable method to improve MDSC engraftment, enhance dystrophic muscle strength, and, in combination with MDSC transplantation, improve recovery from fatigue. These findings suggest that NMES may be a clinically-relevant adjunct approach for cell transplantation into skeletal muscle. © 2013 Distefano et al