A protocol for a randomised double-blind placebo-controlled feasibility study to determine whether the daily consumption of flavonoid-rich pure cocoa has the potential to reduce fatigue in people with relapsing and remitting multiple sclerosis (RRMS)

Background: Dietary interventions including consumption of flavonoids, plant compounds found in certain foods, may have the ability to improve fatigue. However, to date, no well-designed intervention studies assessing the role of flavonoid consumption for fatigue management in people with MS (pwMS) have been performed. The hypothesis is that the consumption of a flavonoid-rich pure cocoa beverage will reduce fatigue in pwMS. The aim of this study is to determine the feasibility and potential outcome of running a trial to evaluate this hypothesis. Methods: Using a randomised (1:1) double-blind placebo-controlled feasibility study, 40 men and women (20 in each trial arm) with a recent diagnosis (< 10 years) of relapsing and remitting MS (RRMS) and who are over 18 years of age will be recruited from neurology clinics and throughout the Thames Valley community. During a 6-week nutrition intervention period, participants will consume the cocoa beverage, high flavonoid or low flavonoid content, at breakfast daily. At baseline, demographic factors and disease-related factors will be assessed. Fatigue, activity and quality of life, in addition to other measures, will be taken at three visits (baseline, week 3 and week 6) in a university setting by a researcher blinded to group membership. Feasibility and fidelity will be assessed through recruitment and retention, adherence and a quantitative process evaluation at the end of the trial.We will describe demographic factors (age, gender, level of education) as well as disease-related factors (disease burden scores, length of time diagnosed with MS) and cognitive assessment, depression and quality of life and general physical activity in order to characterise participants and determine possible mediators to identify the processes by which the intervention may bring about change. Feasibility (recruitment, safety, feasibility of implementation of the intervention and evaluation, protocol adherence and data completion) and potential for benefit (estimates of effect size and variability) will be determined to inform future planned studies. Results will be presented using point estimates, 95% confidence intervals and p values. Primary statistical analysis will be on an intention-to-treat basis and will use the complete case data set. Discussion: We propose that a flavonoid-enriched cocoa beverage for the management of fatigue will be well received by participants. Further, if it is implemented early in the disease course of people diagnosed with RRMS, it will improve mobility and functioning by modifying fatigue. Trial registration: Registered with ISRCTN Registry. Trial registration No: ISRCTN69897291; Date April 2016

Neutrophils Promote Mycobacterial Trehalose Dimycolate-Induced Lung Inflammation via the Mincle Pathway

Trehalose 6,6′-dimycolate (TDM), a cord factor of Mycobacterium tuberculosis (Mtb), is an important regulator of immune responses during Mtb infections. Macrophages recognize TDM through the Mincle receptor and initiate TDM-induced inflammatory responses, leading to lung granuloma formation. Although various immune cells are recruited to lung granulomas, the roles of other immune cells, especially during the initial process of TDM-induced inflammation, are not clear. In this study, Mincle signaling on neutrophils played an important role in TDM-induced lung inflammation by promoting adhesion and innate immune responses. Neutrophils were recruited during the early stage of lung inflammation following TDM-induced granuloma formation. Mincle expression on neutrophils was required for infiltration of TDM-challenged sites in a granuloma model induced by TDM-coated-beads. TDM-induced Mincle signaling on neutrophils increased cell adherence by enhancing F-actin polymerization and CD11b/CD18 surface expression. The TDM-induced effects were dependent on Src, Syk, and MAPK/ERK kinases (MEK). Moreover, coactivation of the Mincle and TLR2 pathways by TDM and Pam3CSK4 treatment synergistically induced CD11b/CD18 surface expression, reactive oxygen species, and TNFα production by neutrophils. These synergistically-enhanced immune responses correlated with the degree of Mincle expression on neutrophil surfaces. The physiological relevance of the Mincle-mediated anti-TDM immune response was confirmed by defective immune responses in Mincle−/− mice upon aerosol infections with Mtb. Mincle-mutant mice had higher inflammation levels and mycobacterial loads than WT mice. Neutrophil depletion with anti-Ly6G antibody caused a reduction in IL-6 and monocyte chemotactic protein-1 expression upon TDM treatment, and reduced levels of immune cell recruitment during the initial stage of infection. These findings suggest a new role of Mincle signaling on neutrophils during anti-mycobacterial responses

Expanding the diversity of mycobacteriophages: Insights into genome architecture and evolution

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists. © 2011 Hatfull et al

Autistic behavior in boys with fragile X syndrome: social approach and HPA-axis dysfunction

The primary goal of this study was to examine environmental and neuroendocrine factors that convey increased risk for elevated autistic behavior in boys with Fragile X syndrome (FXS). This study involves three related analyses: (1) examination of multiple dimensions of social approach behaviors and how they vary over time, (2) investigation of mean levels and modulation of salivary cortisol levels in response to social interaction, and (3) examination of the relationship of social approach and autistic behaviors to salivary cortisol. Poor social approach and elevated baseline and regulation cortisol are discernible traits that distinguish boys with FXS and ASD from boys with FXS only and from typically developing boys. In addition, blunted cortisol change is associated with increased severity of autistic behaviors only within the FXS and ASD group. Boys with FXS and ASD have distinct behavioral and neuroendocrine profiles that differentiate them from those with FXS alone and typically developing boys

Detection of cosmic structures using the bispectrum phase. II. First results from application to cosmic reionization using the Hydrogen Epoch of Reionization Array

Characterizing the epoch of reionization (EoR) at $z\gtrsim 6$ via the redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR HI fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the IGM brightness temperature. From this limited data, at $z=7.7$ we infer "$1\sigma$" upper limits on the IGM brightness temperature to be $\le 316$ "pseudo" mK at $\kappa_\parallel=0.33\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (data-limited) and $\le 1000$ "pseudo" mK at $\kappa_\parallel=0.875\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (noise-limited). The "pseudo" units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic HI signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at $\gtrsim 10^6$ dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues

Detection of cosmic structures using the bispectrum phase. II. First results from application to cosmic reionization using the Hydrogen Epoch of Reionization Array

Characterizing the epoch of reionization (EoR) at $z\gtrsim 6$ via the redshifted 21 cm line of neutral Hydrogen (HI) is critical to modern astrophysics and cosmology, and thus a key science goal of many current and planned low-frequency radio telescopes. The primary challenge to detecting this signal is the overwhelmingly bright foreground emission at these frequencies, placing stringent requirements on the knowledge of the instruments and inaccuracies in analyses. Results from these experiments have largely been limited not by thermal sensitivity but by systematics, particularly caused by the inability to calibrate the instrument to high accuracy. The interferometric bispectrum phase is immune to antenna-based calibration and errors therein, and presents an independent alternative to detect the EoR HI fluctuations while largely avoiding calibration systematics. Here, we provide a demonstration of this technique on a subset of data from the Hydrogen Epoch of Reionization Array (HERA) to place approximate constraints on the IGM brightness temperature. From this limited data, at $z=7.7$ we infer "$1\sigma$" upper limits on the IGM brightness temperature to be $\le 316$ "pseudo" mK at $\kappa_\parallel=0.33\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (data-limited) and $\le 1000$ "pseudo" mK at $\kappa_\parallel=0.875\,\textrm{"pseudo"}\,h$ Mpc$^{-1}$ (noise-limited). The "pseudo" units denote only an approximate and not an exact correspondence to the actual distance scales and brightness temperatures. By propagating models in parallel to the data analysis, we confirm that the dynamic range required to separate the cosmic HI signal from the foregrounds is similar to that in standard approaches, and the power spectrum of the bispectrum phase is still data-limited (at $\gtrsim 10^6$ dynamic range) indicating scope for further improvement in sensitivity as the array build-out continues

Effects of an adapted physical activity program in a group of elderly subjects with flexed posture: clinical and instrumental assessment

<p>Abstract</p> <p>Background</p> <p>Flexed posture commonly increases with age and is related to musculoskeletal impairment and reduced physical performance. The purpose of this clinical study was to systematically compare the effects of a physical activity program that specifically address the flexed posture that marks a certain percentage of elderly individuals with a non specific exercise program for 3 months.</p> <p>Methods</p> <p>Participants were randomly divided into two groups: one followed an Adapted Physical Activity program for flexed posture and the other one completed a non-specific physical activity protocol for the elderly. A multidimensional clinical assessment was performed at baseline and at 3 months including anthropometric data, clinical profile, measures of musculoskeletal impairment and disability. The instrumental assessment of posture was realized using a stereophotogrammetric system and a specific biomechanical model designed to describe the reciprocal position of the body segments on the sagittal plane in a upright posture.</p> <p>Results</p> <p>The Adapted Physical Activity program determined a significant improvement in several key parameters of the multidimensional assessment in comparison to the non-specific protocol: decreased occiput-to-wall distance, greater lower limb range of motion, better flexibility of pectoralis, hamstrings and hip flexor muscles, increased spine extensor muscles strength. Stereophotogrammetric analysis confirmed a reduced protrusion of the head and revealed a reduction in compensative postural adaptations to flexed posture characterized by knee flexion and ankle dorsiflexion in the participants of the specific program.</p> <p>Conclusion</p> <p>The Adapted Physical Activity program for flexed posture significantly improved postural alignment and musculoskeletal impairment of the elderly. The stereophotogrammetric evaluation of posture was useful to measure the global postural alignment and especially to analyse the possible compensatory strategies at lower limbs in flexed posture.</p