Brigid Ryan

Walking Exercise for Chronic Musculoskeletal Pain: Systematic Review and Meta-Analysis

OBJECTIVE To systematically review the evidence examining effects of walking interventions on pain and self-reported function in individuals with chronic musculoskeletal pain. DATA SOURCES Six electronic databases (MEDLINE, CINAHL, PsychINFO, PEDro, Sport Discus, and the Cochrane Central Register of Controlled Trials) were searched from January 1980 to March 2014. STUDY SELECTION Randomized and quasi-randomized controlled trials in adults with chronic low back pain, osteoarthritis, or fibromyalgia comparing walking interventions to a nonexercise or nonwalking exercise control group. DATA EXTRACTION Data were independently extracted using a standardized form. Methodological quality was assessed using the U.S. Preventive Services Task Force system. DATA SYNTHESIS Twenty-six studies (2384 participants) were included, and suitable data from 17 studies were pooled for meta-analysis, with a random effects model used to calculate between-group mean differences and 95% confidence intervals (CIs). Data were analyzed according to the duration of follow-up (short-term, ≤8wk postrandomization; medium-term, >2mo to 12mo; long-term, >12mo). Interventions were associated with small to moderate improvements in pain at short-term (mean difference , -5.31; 95% CI, -8.06 to -2.56) and medium-term (mean difference, -7.92; 95% CI, -12.37 to -3.48) follow-up. Improvements in function were observed at short-term (mean difference, -6.47; 95% CI, -12.00 to -0.95), medium-term (mean difference, -9.31; 95% CI, -14.00 to -4.61), and long-term (mean difference, -5.22; 95% CI, -7.21 to -3.23) follow-up. CONCLUSIONS Evidence of fair methodological quality suggests that walking is associated with significant improvements in outcome compared with control interventions but longer-term effectiveness is uncertain. With the use of the U.S. Preventive Services Task Force system, walking can be recommended as an effective form of exercise or activity for individuals with chronic musculoskeletal pain but should be supplemented with strategies aimed at maintaining participation. Further work is required for examining effects on important health-related outcomes in this population in robustly designed studies.

Temporal Profiling of Gene Networks Associated with the Late Phase of Long-Term Potentiation In Vivo

Long-term potentiation (LTP) is widely accepted as a cellular mechanism underlying memory processes. It is well established that LTP persistence is strongly dependent on activation of constitutive and inducible transcription factors, but there is limited information regarding the downstream gene networks and controlling elements that coalesce to stabilise LTP. To identify these gene networks, we used Affymetrix RAT230.2 microarrays to detect genes regulated 5 h and 24 h (n = 5) after LTP induction at perforant path synapses in the dentate gyrus of awake adult rats. The functional relationships of the differentially expressed genes were examined using DAVID and Ingenuity Pathway Analysis, and compared with our previous data derived 20 min post-LTP induction in vivo. This analysis showed that LTP-related genes are predominantly upregulated at 5 h but that there is pronounced downregulation of gene expression at 24 h after LTP induction. Analysis of the structure of the networks and canonical pathways predicted a regulation of calcium dynamics via G-protein coupled receptors, dendritogenesis and neurogenesis at the 5 h time-point. By 24 h neurotrophin-NFKB driven pathways of neuronal growth were identified. The temporal shift in gene expression appears to be mediated by regulation of protein synthesis, ubiquitination and time-dependent regulation of specific microRNA and histone deacetylase expression. Together this programme of genomic responses, marked by both homeostatic and growth pathways, is likely to be critical for the consolidation of LTP in vivo.

Plasticity-related microRNA and their potential contribution to the maintenance of long-term potentiation

Long-term potentiation (LTP) is a form of synaptic plasticity that is an excellent model for the molecular mechanisms that underlie memory. LTP, like memory, is persistent, and both are widely believed to be maintained by a coordinated genomic response. Recently, a novel class of non-coding RNA, microRNA, has been implicated in the regulation of LTP. MicroRNA negatively regulate protein synthesis by binding to specific messenger RNA response elements. The aim of this review is to summarize experimental evidence for the proposal that microRNA play a major role in the regulation of LTP. We discuss a growing body of research which indicates that specific microRNA regulate synaptic proteins relevant to LTP maintenance, as well as studies that have reported differential expression of microRNA in response to LTP induction. We conclude that microRNA are ideally suited to contribute to the regulation of LTP-related gene expression; microRNA are pleiotropic, synaptically located, tightly regulated, and function in response to synaptic activity. The potential impact of microRNA on LTP maintenance as regulators of gene expression is enormous.

Rapid regulation of microRNA following induction of long-term potentiation in vivo.

Coordinated regulation of gene expression is essential for consolidation of the memory mechanism, long-term potentiation (LTP). Triggering of LTP by N-methyl-D-aspartate receptor (NMDAR) activation rapidly activates constitutive and inducible transcription factors, which promote expression of genes responsible for LTP maintenance. As microRNA (miRNA) coordinate expression of genes related through seed sites, we hypothesize that miRNA contribute to the regulation of the LTP-induced gene response. MiRNA function primarily as negative regulators of gene expression. As LTP induction promotes a generalized rapid up-regulation of gene expression, we predicted a complementary rapid down-regulation of miRNA levels. Accordingly, we carried out global miRNA expression profiling in the rat dentate gyrus 20 min post-LTP induction in vivo. Consistent with our hypothesis, we found a large number of differentially expressed miRNA, the majority down-regulated. Detailed analysis of miR-34a-5p and miR-132-3p revealed this down-regulation was transient and NMDAR-dependent, whereby block of NMDARs released an activity-associated inhibitory mechanism. Furthermore, down-regulation of mature miR-34a-5p and miR-132-3p occurred solely by post-transcriptional mechanisms, occurring despite an associated up-regulation of the pri-miR-132 transcript. To understand how down-regulation of miR-34a-5p and miR-132-3p intersects with the molecular events occurring following LTP, we used bioinformatics to identify potential targets. Previously validated targets included the key LTP-regulated genes Arc and glutamate receptor subunits. Predicted targets included the LTP-linked kinase, Mapk1, and neuropil-associated transcripts Hn1 and Klhl11, which were validated using luciferase reporter assays. Furthermore, we found that the level of p42-Mapk1, the protein encoded by the Mapk1 transcript, was up-regulated following LTP. Together, these data support the interpretation that miRNA, in particular miR-34a-5p and miR-132-3p, make a surprisingly rapid contribution to synaptic plasticity via dis-inhibition of translation of key plasticity-related molecules.

Laser photobiostimulation of wound healing: reciprocity of irradiance and exposure time on energy density for splinted wounds in diabetic mice.

We have used a 660 nm laser diode in genetic diabetic mice to stimulate the healing of wounds covered with a Tegaderm HP dressing that causes a retardation of contraction (splinted wounds). The influence of irradiance (power density) on wound healing has been examined with the same energy dose delivered to the wounds. This energy dose caused maximal stimulation of healing in a previous study.

MicroRNAs, miR-23a-3p and miR-151-3p, Are Regulated in Dentate Gyrus Neuropil following Induction of Long-Term Potentiation In Vivo

Translation of synaptic mRNA contributes to alterations in the proteome necessary to consolidate long-term potentiation (LTP), a model of memory processes. Yet, how this process is controlled is not fully resolved. MicroRNAs are non-coding RNAs that negatively regulate gene expression by suppressing translation or promoting mRNA degradation. As specific microRNAs are synaptically located, we hypothesized that they are ideally suited to couple synaptic activation, translational regulation, and LTP persistence. The aim of this study was to identify LTP-regulated microRNAs at or near synapses. Accordingly, LTP was induced unilaterally at perforant path-dentate gyrus synapses in awake adult Sprague-Dawley rats. Five hours later, dentate gyrus middle molecular layer neuropil, containing potentiated synapses, was laser-microdissected. MicroRNA expression profiling, using TaqMan Low Density MicroRNA Microarrays (n = 4), identified eight regulated microRNAs. Subsequent individual TaqMan assays confirmed upregulation of miR-23a-3p (1.30 ± 0.10; p = 0.015) and miR-151-3p (1.17 ± 0.19; p = 0.045) in a second cohort (n = 7). Interestingly, bioinformatic analysis indicated that miR-151-3p and miR-23a-3p regulate synaptic reorganisation and transcription, respectively. In summary, we have demonstrated for the first time that microRNAs are regulated in isolated neuropil following LTP induction in vivo, supporting the hypothesis that synaptic, LTP-responsive microRNAs contribute to LTP persistence via regulation of the synaptic proteome.

Novel microRNA revealed by systematic analysis of the microRNA transcriptome in dentate gyrus granule cells

Post-transcriptional control of gene expression by microRNAs provides an important regulatory system within neurons, allowing co-ordinate and fine-tuned expression of plasticity-related proteins. Indeed, specific microRNAs have been shown to be regulated by synaptic activity in the dentate gyrus, and contribute to the regulated gene expression that underlies the persistence of long-term potentiation (LTP), a model of memory. To fully explore the contribution of microRNAs in synaptic plasticity, it is important to characterize the complete microRNA transcriptome in regions such as the dentate gyrus. Accordingly we used deep sequencing and miRDeep* analysis to search for novel microRNAs expressed in the dentate gyrus granule cell layer. Drawing on combined sequencing and bioinformatics analyses, including hairpin stability and patterns of precursor microRNA processing, we identified nine putative novel microRNAs. We did not find evidence of differential expression of any of these putative microRNAs following LTP at perforant path-granule cell synapses in awake rats (5h post-tetanus; p>0.05). Focusing on novel_miR-1, the most abundant novel miRNA, we showed that this sequence could be amplified from RNA extracted from dentate gyrus granule cells by reverse transcription-quantitative polymerase chain reaction. Further, by computationally predicting mRNA targets of this microRNA, we found that this novel microRNA likely contributes to the regulation of proteins that function at synapses.