Aging enhances serum cytokine response but not task-induced grip strength declines in a rat model of work-related musculoskeletal disorders

<p>Abstract</p> <p>Background</p> <p>We previously reported early tissue injury, increased serum and tissue inflammatory cytokines and decreased grip in young rats performing a moderate demand repetitive task. The tissue cytokine response was transient, the serum response and decreased grip were still evident by 8 weeks. Thus, here, we examined their levels at 12 weeks in young rats. Since aging is known to enhance serum cytokine levels, we also examined aged rats.</p> <p>Methods</p> <p>Aged and young rats, 14 mo and 2.5 mo of age at onset, respectfully, were trained 15 min/day for 4 weeks, and then performed a high repetition, low force (HRLF) reaching and grasping task for 2 hours/day, for 12 weeks. Serum was assayed for 6 cytokines: IL-1alpha, IL-6, IFN-gamma, TNF-alpha, MIP2, IL-10. Grip strength was assayed, since we have previously shown an inverse correlation between grip strength and serum inflammatory cytokines. Results were compared to naïve (grip), and normal, food-restricted and trained-only controls.</p> <p>Results</p> <p>Serum cytokines were higher overall in aged than young rats, with increases in IL-1alpha, IFN-gamma and IL-6 in aged Trained and 12-week HRLF rats, compared to young Trained and HRLF rats (p < 0.05 and p < 0.001, respectively, each). IL-6 was also increased in aged 12-week HRLF versus aged normal controls (p < 0.05). Serum IFN-gamma and MIP2 levels were also increased in young 6-week HRLF rats, but no cytokines were above baseline levels in young 12-week HRLF rats. Grip strength declined in both young and aged 12-week HRLF rats, compared to naïve and normal controls (p < 0.05 each), but these declines correlated only with IL-6 levels in aged rats (r = -0.39).</p> <p>Conclusion</p> <p>Aging enhanced a serum cytokine response in general, a response that was even greater with repetitive task performance. Grip strength was adversely affected by task performance in both age groups, but was apparently influenced by factors other than serum cytokine levels in young rats.</p

Tailor-made inflammation: how neutrophil serine proteases modulate the inflammatory response

Neutrophil granulocytes are important mediators of innate immunity, but also participate in the pathogenesis of (auto)inflammatory diseases. Neutrophils express a specific set of proteolytic enzymes, the neutrophil serine proteases (NSPs), which are stored in cytoplasmic granules and can be secreted into the extra- and pericellular space upon cellular activation. These NSPs, namely cathepsin G (CG), neutrophil elastase (NE), and proteinase 3 (PR3), have early been implicated in bacterial defense. However, NSPs also regulate the inflammatory response by specifically altering the function of cytokines and chemokines. For instance, PR3 and NE both inactivate the anti-inflammatory mediator progranulin, which may play a role in chronic inflammation. Here, we provide a concise update on NSPs as modulators of inflammation and discuss the biological and pathological significance of this novel function of NSPs. Mounting evidence support an important proinflammatory function for PR3, which may have been underestimated in the past

Increased Serum and Musculotendinous Fibrogenic Proteins following Persistent Low-Grade Inflammation in a Rat Model of Long-Term Upper Extremity Overuse.

We examined the relationship between grip strength declines and muscle-tendon responses induced by long-term performance of a high-repetition, low-force (HRLF) reaching task in rats. We hypothesized that grip strength declines would correlate with inflammation, fibrosis and degradation in flexor digitorum muscles and tendons. Grip strength declined after training, and further in weeks 18 and 24, in reach limbs of HRLF rats. Flexor digitorum tissues of reach limbs showed low-grade increases in inflammatory cytokines: IL-1β after training and in week 18, IL-1α in week 18, TNF-α and IL-6 after training and in week 24, and IL-10 in week 24, with greater increases in tendons than muscles. Similar cytokine increases were detected in serum with HRLF: IL-1α and IL-10 in week 18, and TNF-α and IL-6 in week 24. Grip strength correlated inversely with IL-6 in muscles, tendons and serum, and TNF-α in muscles and serum. Four fibrogenic proteins, TGFB1, CTGF, PDGFab and PDGFbb, and hydroxyproline, a marker of collagen synthesis, increased in serum in HRLF weeks 18 or 24, concomitant with epitendon thickening, increased muscle and tendon TGFB1 and CTGF. A collagenolytic gelatinase, MMP2, increased by week 18 in serum, tendons and muscles of HRLF rats. Grip strength correlated inversely with TGFB1 in muscles, tendons and serum; with CTGF-immunoreactive fibroblasts in tendons; and with MMP2 in tendons and serum. Thus, motor declines correlated with low-grade systemic and musculotendinous inflammation throughout task performance, and increased fibrogenic and degradative proteins with prolonged task performance. Serum TNF-α, IL-6, TGFB1, CTGF and MMP2 may serve as serum biomarkers of work-related musculoskeletal disorders, although further studies in humans are needed

Would the field of cognitive neuroscience be advanced by sharing functional MRI data?

During the past two decades, the advent of functional magnetic resonance imaging (fMRI) has fundamentally changed our understanding of brain-behavior relationships. However, the data from any one study add only incrementally to the big picture. This fact raises important questions about the dominant practice of performing studies in isolation. To what extent are the findings from any single study reproducible? Are researchers who lack the resources to conduct a fMRI study being needlessly excluded? Is pre-existing fMRI data being used effectively to train new students in the field? Here, we will argue that greater sharing and synthesis of raw fMRI data among researchers would make the answers to all of these questions more favorable to scientific discovery than they are today and that such sharing is an important next step for advancing the field of cognitive neuroscience

Use of Motor Abundance in Young and Older Adults during Dual-Task Treadmill Walking

Contains fulltext : 110120.pdf (publisher's version ) (Open Access)Motor abundance allows individuals to perform any task reliably while being variable in movement's particulars. The study investigated age-related differences in this feature when young adults (YA) and older adults (OA) performed challenging tasks, namely treadmill walking alone and while performing a cognitive task. A goal function for treadmill walking was first defined, i.e., maintain constant speed at each step, which led to a goal equivalent manifold (GEM) containing all combinations of step time and step length that equally satisfied the function. Given the GEM, amounts of goal-equivalent and non-goal-equivalent variability were afterwards determined and used to define an index providing information about the set of effective motor solutions relative to the GEM. The set was limited in OA compared to YA in treadmill walking alone, indicating that OA made less flexible use of motor abundance than YA. However, this differentiation between YA and OA disappeared when concurrently performing the cognitive task. It is proposed that OA might have benefited from cognitive compensation

Long-Term Activity-Dependent Plasticity of Action Potential Propagation Delay and Amplitude in Cortical Networks

Background: The precise temporal control of neuronal action potentials is essential for regulating many brain functions. From the viewpoint of a neuron, the specific timings of afferent input from the action potentials of its synaptic partners determines whether or not and when that neuron will fire its own action potential. Tuning such input would provide a powerful mechanism to adjust neuron function and in turn, that of the brain. However, axonal plasticity of action potential timing is counter to conventional notions of stable propagation and to the dominant theories of activity-dependent plasticity focusing on synaptic efficacies. Methodology/Principal Findings: Here we show the occurrence of activity-dependent plasticity of action potentia

Whole genome analysis reveals aneuploidies in early pregnancy loss in the horse

The first 8 weeks of pregnancy is a critical time, with the majority of pregnancy losses occurring during this period. Abnormal chromosome number (aneuploidy) is a common finding in human miscarriage, yet is rarely reported in domestic animals. Equine early pregnancy loss (EPL) has no diagnosis in over 80% of cases. The aim of this study was to characterise aneuploidies associated with equine EPL. Genomic DNA from clinical cases of spontaneous miscarriage (EPLs; 14–65 days of gestation) and healthy control placentae (various gestational ages) were assessed using a high density genotyping array. Aneuploidy was detected in 12/55 EPLs (21.8%), and 0/15 healthy control placentae. Whole genome sequencing (30X) and digital droplet PCR (ddPCR) validated results. The majority of these aneuploidies have never been reported in live born equines, supporting their embryonic/fetal lethality. Aneuploidies were detected in both placental and fetal compartments. Rodents are currently used to study how maternal ageing impacts aneuploidy risk, however the differences in reproductive biology is a limitation of this model. We present the first evidence of aneuploidy in naturally occurring equine EPLs at a similar rate to human miscarriage. We therefore suggest the horse as an alternative to rodent models to study mechanisms resulting in aneuploid pregnancies

Mycobacteria Attenuate Nociceptive Responses by Formyl Peptide Receptor Triggered Opioid Peptide Release from Neutrophils

In inflammation, pain is regulated by a balance of pro- and analgesic mediators. Analgesic mediators include opioid peptides which are secreted by neutrophils at the site of inflammation, leading to activation of opioid receptors on peripheral sensory neurons. In humans, local opioids and opioid peptides significantly downregulate postoperative as well as arthritic pain. In rats, inflammatory pain is induced by intraplantar injection of heat inactivated Mycobacterium butyricum, a component of complete Freund's adjuvant. We hypothesized that mycobacterially derived formyl peptide receptor (FPR) and/or toll like receptor (TLR) agonists could activate neutrophils, leading to opioid peptide release and inhibition of inflammatory pain. In complete Freund's adjuvant-induced inflammation, thermal and mechanical nociceptive thresholds of the paw were quantified (Hargreaves and Randall-Selitto methods, respectively). Withdrawal time to heat was decreased following systemic neutrophil depletion as well as local injection of opioid receptor antagonists or anti-opioid peptide (i.e. Met-enkephalin, β-endorphin) antibodies indicating an increase in pain. In vitro, opioid peptide release from human and rat neutrophils was measured by radioimmunoassay. Met-enkephalin release was triggered by Mycobacterium butyricum and formyl peptides but not by TLR-2 or TLR-4 agonists. Mycobacterium butyricum induced a rise in intracellular calcium as determined by FURA loading and calcium imaging. Opioid peptide release was blocked by intracellular calcium chelation as well as phosphoinositol-3-kinase inhibition. The FPR antagonists Boc-FLFLF and cyclosporine H reduced opioid peptide release in vitro and increased inflammatory pain in vivo while TLR 2/4 did not appear to be involved. In summary, mycobacteria activate FPR on neutrophils, resulting in tonic secretion of opioid peptides from neutrophils and in a decrease in inflammatory pain. Future therapeutic strategies may aim at selective FPR agonists to boost endogenous analgesia

Aneuploidy and prognosis of non-small-cell lung cancer: a meta-analysis of published data

In lung cancer, DNA content abnormalities have been described as a heterogeneous spectrum of impaired tumour cell DNA histogram patterns. They are merged into the common term of aneuploidy and probably reflect a high genotypic instability. In non-small-cell lung cancer, the negative effect of aneuploidy has been a subject of controversy inasmuch as studies aimed at determining the survival–DNA content relationship have reported conflicting results. We made a meta-analysis of published studies aimed at determining the prognostic effect of aneuploidy in surgically resected non-small-cell lung cancer. 35 trials have been identified in the literature. A comprehensive collection of data has been constructed taking into account the following parameters: quality of specimen, DNA content assessment method, aneuploidy definition, histology and stage grouping, quality of surgical resection and demographic characteristics of the analysed population. Among the 4033 assessable patients, 2626 suffered from non-small-cell lung cancer with aneuploid DNA content (overall frequency of aneuploidy: 0.65; 95% CI: (0.64–0.67)). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death for patients affected by a nearly diploid (non-aneuploid) non-small-cell lung cancer. Survivals following surgical resection, from 1 to 5 years, were chosen as the end-points of our meta-analysis. Patients suffering from a nearly diploid tumour benefited from a significant reduction in risk of death at 1, 2, 3 and 4 years with respective OR: 0.51, 0.51, 0.45 and 0.67 (P< 10−4for each end-point). 5 years after resection, the reduction of death was of lesser magnitude: OR: 0.87 (P = 0.08). The test for overall statistical heterogeneity was conventionally significant (P< 0.01) for all 5 end-points, however. None of the recorded characteristics of the studies could explain this phenomenon precluding a subset analysis. Therefore, the DerSimonian and Laird method was applied inasmuch as this method allows a correction for heterogeneity. This method demonstrated an increase in survival at 1, 2, 3, 4 and 5 years for patients with diploid tumours with respective size effects of 0.11, 0.15, 0.20, 0.20 and 0.21 (value taking into account the correction for heterogeneity;P< 10−4for each end-point). Patients who benefit from a surgical resection for non-small-cell lung cancer with aneuploid DNA content prove to have a higher risk of death. This negative prognostic factor decreases the probability of survival by 11% at one year, a negative effect deteriorating up to 21% at 5 years following surgery. © 2001 Cancer Research Campaign http://www.bjcancer.co