Local vibration therapy increases oxygen re-saturation rate and maintains muscle strength following exercise-induced muscle damage.

Context: Exercise induced muscle damage (EIMD) is associated with transient reductions in strength and athletic performance. Studies conclude aetiology is due in part to muscle micro vascular damage and disruption of blood flow. Previous research on vibration therapy reports modulation in muscle blood flow, oxygenation and strength. Objective: The aim of this study was to observe if local vibration therapy (VT) alleviates the impairments and haemodynamic changes associated with EIMD. Design: Controlled laboratory study. Setting: Laboratory and public gymnasium. Patients or other participants: Ten healthy participants (6 males: 4 females; age: 38±15 yrs; height: 1.72±0.48 m; mass 72.0±10.4 kg) were randomized into experimental (VT) and control (CON) groups. Interventions: Both groups performed 10 sets of 10 eccentric wrist flexions at 70% of 1-repetition maximum to induce muscle damage. Subsequent assessment of wrist flexor strength and flexor carpus ulnaris (FCU) muscle oxygen saturation (SmO2) occurred at 1-, 24- and 48 hr-post exercise. VT group underwent 10 min of local VT (45 Hz) starting 1 hr-post exercise and applied twice daily (separated by 8 hrs) for 48 hrs during habitual waking hours. CON group received no local VT. Main outcome measure(s): Grip strength, resting muscle oxygen (SmO2), muscle oxygen de-saturation and re-saturation rate. Results: No difference in grip strength observed pre EIMD, but the VT group demonstrated greater strength at 1 hr (P=0.004), 24 hr (P=0.031) and 48 hr (P=0.021) post EIMD compared to controls. No difference in SmO2 re-saturation over time (P>0.05), but the VT group had a greater re-saturation rate compared to controls at 1 hr (P=0.007, d = 2.6), 24 hr (P=0.001 d = 3.1) and 48 hr (P=0.035, d = 1.7) post EIMD. Conclusions: Local VT successfully attenuated the effects of EIMD and increased SmO2 re-saturation in FCU muscles. Including local VT as part of a recovery protocol post-EIMD could be beneficial for rehabilitation and athletic training purposes

Molecular Analysis of Precursor Lesions in Familial Pancreatic Cancer

PMCID: PMC3553106This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Comparison of serious inhaler technique errors made by device-naïve patients using three different dry powder inhalers: a randomised, crossover, open-label study

Background: Serious inhaler technique errors can impair drug delivery to the lungs. This randomised, crossover, open-label study evaluated the proportion of patients making predefined serious errors with Pulmojet compared with Diskus and Turbohaler dry powder inhalers. Methods: Patients ≥18 years old with asthma and/or COPD who were current users of an inhaler but naïve to the study devices were assigned to inhaler technique assessment on Pulmojet and either Diskus or Turbohaler in a randomised order. Patients inhaled through empty devices after reading the patient information leaflet. If serious errors potentially affecting dose delivery were recorded, they repeated the inhalations after watching a training video. Inhaler technique was assessed by a trained nurse observer and an electronic inhalation profile recorder. Results: Baseline patient characteristics were similar between randomisation arms for the Pulmojet-Diskus (n = 277) and Pulmojet-Turbohaler (n = 144) comparisons. Non-inferiority in the proportions of patients recording no nurse-observed serious errors was demonstrated for both Pulmojet versus Diskus, and Pulmojet versus Turbohaler; therefore, superiority was tested. Patients were significantly less likely to make ≥1 nurse-observed serious errors using Pulmojet compared with Diskus (odds ratio, 0.31; 95 % CI, 0.19–0.51) or Pulmojet compared with Turbohaler (0.23; 0.12–0.44) after reading the patient information leaflet with additional video instruction, if required. Conclusions These results suggest Pulmojet is easier to learn to use correctly than the Turbohaler or Diskus for current inhaler users switching to a new dry powder inhaler

Relative impact of key sources of systematic noise in Affymetrix and Illumina gene-expression microarray experiments

<p>Abstract</p> <p>Background</p> <p>Systematic processing noise, which includes batch effects, is very common in microarray experiments but is often ignored despite its potential to confound or compromise experimental results. Compromised results are most likely when re-analysing or integrating datasets from public repositories due to the different conditions under which each dataset is generated. To better understand the relative noise-contributions of various factors in experimental-design, we assessed several Illumina and Affymetrix datasets for technical variation between replicate hybridisations of Universal Human Reference (UHRR) and individual or pooled breast-tumour RNA.</p> <p>Results</p> <p>A varying degree of systematic noise was observed in each of the datasets, however in all cases the relative amount of variation between standard control RNA replicates was found to be greatest at earlier points in the sample-preparation workflow. For example, 40.6% of the total variation in reported expressions were attributed to replicate extractions, compared to 13.9% due to amplification/labelling and 10.8% between replicate hybridisations. Deliberate probe-wise batch-correction methods were effective in reducing the magnitude of this variation, although the level of improvement was dependent on the sources of noise included in the model. Systematic noise introduced at the chip, run, and experiment levels of a combined Illumina dataset were found to be highly dependant upon the experimental design. Both UHRR and pools of RNA, which were derived from the samples of interest, modelled technical variation well although the pools were significantly better correlated (4% average improvement) and better emulated the effects of systematic noise, over all probes, than the UHRRs. The effect of this noise was not uniform over all probes, with low GC-content probes found to be more vulnerable to batch variation than probes with a higher GC-content.</p> <p>Conclusions</p> <p>The magnitude of systematic processing noise in a microarray experiment is variable across probes and experiments, however it is generally the case that procedures earlier in the sample-preparation workflow are liable to introduce the most noise. Careful experimental design is important to protect against noise, detailed meta-data should always be provided, and diagnostic procedures should be routinely performed prior to downstream analyses for the detection of bias in microarray studies.</p

Roles for Treg expansion and HMGB1 signaling through the TLR1-2-6 axis in determining the magnitude of the antigen-specific immune response to MVA85A

© 2013 Matsumiya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedA better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2Rα two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans.This work was funded by the Wellcome Trust. MM has a Wellcome Trust PhD studentship and HM is a Wellcome Trust Senior Fello

Enhanced wheat yield by biochar addition under different mineral fertilization levels

Climate change and global warming have worldwide adverse consequences. Biochar production and its use in agriculture can play a key role in climate change mitigation and help improve the quality and management of waste materials coming from agriculture and forestry. Biochar is a carbonaceous material obtained from thermal decomposition of residual biomass at relatively low temperature and under oxygen limited conditions (pyrolysis). Biochar is currently a subject of active research worldwide because it can constitute a viable option for sustainable agriculture due to its potential as a long-term sink for carbon in soil and benefits for crops. However, to date, the results of research studies on biochar effects on crop production show great variability, depending on the biochar type and experimental conditions. Therefore, it is important to identify the beneficial aspects of biochar addition to soil on crop yield in order to promote the adoption of this practice in agriculture. In this study, the effects of two types of biochar from agricultural wastes typical of Southern Spain: wheat straw and olive tree pruning, combined with different mineral fertilization levels on the growth and yield of wheat (Triticum durum L. cv. Vitron) were evaluated. Durum wheat was pot-grown for 2 months in a growth chamber on a soil collected from an agricultural field near Córdoba, Southern Spain. Soil properties and plant growth variables were studied in order to assess the agronomic efficiency of biochar. Our results show that biochar addition to a nutrientpoor, slightly acidic loamy sand soil had little effect on wheat yield in the absence of mineral fertilization. However, at the highest mineral fertilizer rate, addition of biochar led to about 20–30 % increase in grain yield compared with the use of the mineral fertilizer alone. Both biochars acted as a source of available P, which led to beneficial effects on crop production. In contrast, the addition of biochar resulted in decreases in available N and Mn. A maximum reduction in plant nutrient concentration of 25 and 80% compared to nonbiochar-treated soils for N and Mn, respectively, was detected. This fact was related to the own nature of biochar: low available nitrogen content, high adsorption capacity, and low mineralization rate for N; and alkaline pH and high carbonate content for Mn. Our results indicate that biochar-based soil management strategies can enhance wheat production with the environmental benefits of global warming mitigation. This can contribute positively to the viability and benefits of agricultural production systems. However, the nutrient–biochar interactions should receive special attention due to the great variability in the properties of biochar-type materials

Dynamic changes in gene expression in vivo predict prognosis of tamoxifen-treated patients with breast cancer

Introduction: Tamoxifen is the most widely prescribed anti-estrogen treatment for patients with estrogen receptor (ER)-positive breast cancer. However, there is still a need for biomarkers that reliably predict endocrine sensitivity in breast cancers and these may well be expressed in a dynamic manner. Methods: In this study we assessed gene expression changes at multiple time points (days 1, 2, 4, 7, 14) after tamoxifen treatment in the ER-positive ZR-75-1 xenograft model that displays significant changes in apoptosis, proliferation and angiogenesis within 2 days of therapy. Results: Hierarchical clustering identified six time-related gene expression patterns, which separated into three groups: two with early/transient responses, two with continuous/late responses and two with variable response patterns. The early/transient response represented reductions in many genes that are involved in cell cycle and proliferation (e.g. BUB1B, CCNA2, CDKN3, MKI67, UBE2C), whereas the continuous/late changed genes represented the more classical estrogen response genes (e.g. TFF1, TFF3, IGFBP5). Genes and the proteins they encode were confirmed to have similar temporal patterns of expression in vitro and in vivo and correlated with reduction in tumour volume in primary breast cancer. The profiles of genes that were most differentially expressed on days 2, 4 and 7 following treatment were able to predict prognosis, whereas those most changed on days 1 and 14 were not, in four tamoxifen treated datasets representing a total of 404 patients. Conclusions: Both early/transient/proliferation response genes and continuous/late/estrogen-response genes are able to predict prognosis of primary breast tumours in a dynamic manner. Temporal expression of therapy-response genes is clearly an important factor in characterising the response to endocrine therapy in breast tumours which has significant implications for the timing of biopsies in neoadjuvant biomarker studies.Publisher PDFPeer reviewe

Detailed Analysis of <em>ITPR1 </em>Missense Variants Guides Diagnostics and Therapeutic Design

\ua9 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Background: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3) receptor type 1 (IP3R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. Objectives: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. Methods: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. Results: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3-binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype–phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. Conclusions: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. \ua9 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society