Interlimb symmetry of dynamic knee joint stiffness and co-contraction is maintained in early stage knee osteoarthritis

Individuals with knee OA often exhibit greater co-contraction of antagonistic muscle groups surrounding the affected joint which may lead to increases in dynamic joint stiffness. These detrimental changes in the symptomatic limb may also exist in the contralateral limb, thus contributing to its risk of developing knee osteoarthritis. The purpose of this study is to investigate the interlimb symmetry of dynamic knee joint stiffness and muscular co-contraction in knee osteoarthritis.Muscular co-contraction and dynamic knee joint stiffness were assessed in 17 subjects with mild to moderate unilateral medial compartment knee osteoarthritis and 17 healthy control subjects while walking at a controlled speed (1.0 m/s). Paired and independent t-tests determined whether significant differences exist between groups (p < 0.05).There were no significant differences in dynamic joint stiffness or co-contraction between the OA symptomatic and OA contralateral group (p = 0.247, p = 0.874, respectively) or between the OA contralateral and healthy group (p = 0.635, p = 0.078, respectively). There was no significant difference in stiffness between the OA symptomatic and healthy group (p = 0.600); however, there was a slight trend toward enhanced co-contraction in the symptomatic knees compared to the healthy group (p = 0.051).Subjects with mild to moderate knee osteoarthritis maintain symmetric control strategies during gait.     

Stem cell application for osteoarthritis in the knee joint: A minireview

Knee osteoarthritis is a chronic, indolent disease that will affect an ever increasing number of patients, especially the elderly and the obese. It is characterized by degeneration of the cartilage substance inside the knee which leads to pain, stiffness and tenderness. By some estimations in 2030, only in the United States, this medical condition will burden 67 million people. While conventional treatments like physiotherapy or drugs offer temporary relief of clinical symptoms, restoration of normal cartilage function has been difficult to achieve. Moreover, in severe cases of knee osteoarthritis total knee replacement may be required. Total knee replacements come together with high effort and costs and are not always successful. The aim of this review is to outline the latest advances in stem cell therapy for knee osteoarthritis as well as highlight some of the advantages of stem cell therapy over traditional approaches aimed at restoration of cartilage function in the knee. In addition to the latest advances in the field, challenges associated with stem cell therapy regarding knee cartilage regeneration and chondrogenesis in vitro and in vivo are also outlined and analyzed. Furthermore, based on their critical assessment of the present academic literature the authors of this review share their vision about the future of stem cell applications in the treatment of knee osteoarthritis.     

Clinical implications of macrophage dysfunction in the development of osteoarthritis of the knee

Osteoarthritis (OA) is the most common form of arthritic disease, leading to disability and impaired quality of life and no curative treatments exist. Increasing evidence indicates that low-grade inflammation plays a pivotal role in the onset and progression of OA. In this review, we summarize emerging findings on the pathological roles of synovial macrophages, adipose tissue macrophages, and osteoclasts in OA and their potential clinical implications from cell biology to preclinical and preliminary clinical trials. The failure of synovial macrophages to transition from pro-inflammatory M1 to anti-inflammatory M2 subtypes may contribute to the initiation and maintenance of synovitis in OA. M1 macrophages promote the inflammatory microenvironment and progression of OA through interactions with synovial fibroblasts and chondrocytes, thus increasing the secretion of matrix metalloproteinases. Direct inhibition of M1 or promotion of M2 polarization may be useful therapeutic interventions. Adipose tissue macrophages present in the infrapatella fat pad (IPFP) were involved in the progression of obesity-induced OA, which contributed to changes in the integrity of the IPFP. Furthermore, macrophages and osteoclasts in the subchondral bone were involved in bone remodeling and pain through uncoupled osteoclast/osteoblast activity and increased nociceptive signaling. Growing evidence has indicated an important role for macrophage-mediated low-grade inflammation in OA. Fully understanding the link between macrophages and other cells in joints will provide new insights into OA disease modification.     

Knee moment outcomes using inverse dynamics and the cross product function in moderate knee osteoarthritis gait: A comparison study

Inverse dynamics are the cornerstone of biomechanical assessments to calculate knee moments during walking. In knee osteoarthritis, these outcomes have been used to understand knee pathomechanics, but the complexity of an inverse dynamic model may limit the uptake of joint moments in some clinical and research structures. The objective was to determine whether discrete features of the sagittal and frontal plane knee moments calculated using inverse dynamics compare to knee moments calculated using a cross product function. Knee moments from 74 people with moderate knee osteoarthritis were assessed after ambulating at a self-selected speed on an instrumented dual belt treadmill. Standardized procedures were used for surface marker placement, gait speed determination and data processing. Net external frontal and sagittal plane knee moments were calculated using inverse dynamics and the three-dimensional position of the knee joint center with respect to the center of pressure was crossed with the three-dimensional ground reaction forces in the cross product function. Correlations were high between outcomes of the moment calculations (r > 0.9) and for peak knee adduction moment, knee adduction moment impulse and difference between peak flexion and extension moments, the cross product function resulted in absolute values less than 10% of those calculated using inverse dynamics in this treadmill walking environment. This computational solution may allow the integration of knee moment calculations to understand knee osteoarthritis gait without data collection or computational complexity.     

Application of mesenchymal stem cell therapy for the treatment of osteoarthritis of the knee: A concise review

Osteoarthritis(OA) refers to a chronic joint disease characterized by degenerative changes of articular cartilage and secondary bone hyperplasia. Since articular cartilage has a special structure, namely the absence of blood vessels as well as the low conversion rate of chondrocytes in the cartilage matrix, the treatment faces numerous clinical challenges. Traditional OA treatment(e.g., arthroscopic debridement, microfracture, autologous or allogeneic cartilage transplantation,chondrocyte transplantation) is primarily symptomatic treatment and pain management, which cannot contribute to regenerating degenerated cartilage or reducing joint inflammation. Also, the generated mixed fibrous cartilage tissue is not the same as natural hyaline cartilage. Mesenchymal stem cells(MSCs) have turned into the most extensively explored new therapeutic drugs in cell-based OA treatment as a result of their ability to differentiate into chondrocytes and their immunomodulatory properties. In this study, the preliminary results of preclinical(OA animal model)/clinical trials regarding the effects of MSCs on cartilage repair of knee joints are briefly summarized, which lay a solid application basis for more and deeper clinical studies on cell-based OA treatment.     

Prognostic factors for progression of clinical osteoarthritis of the knee: a systematic review of observational studies

IntroductionWe performed a systematic review of prognostic factors for the progression of symptomatic knee osteoarthritis (OA), defined as increase in pain, decline in physical function or total joint replacement.MethodWe searched for available observational studies up to January 2015 in Medline and Embase according to a specified search strategy. Studies that fulfilled our initial inclusion criteria were assessed for methodological quality. Data were extracted and the results were pooled, or if necessary summarized according to a best evidence synthesis.ResultsOf 1,392 articles identified, 30 met the inclusion criteria and 38 determinants were investigated. Pooling was not possible due to large heterogeneity between studies. The best evidence synthesis showed strong evidence that age, ethnicity, body mass index, co-morbidity count, magnetic resonance imaging (MRI)-detected infrapatellar synovitis, joint effusion and baseline OA severity (both radiographic and clinical) are associated with clinical knee OA progression. There was moderate evidence showing that education level, vitality, pain-coping subscale resting, MRI-detected medial femorotibial cartilage loss and general bone marrow lesions are associated with clinical knee OA progression. However, evidence for the majority of determinants was limited (including knee range of motion or markers) or conflicting (including age, gender and joint line tenderness).ConclusionStrong evidence was found for multiple prognostic factors for progression of clinical knee OA. A large variety in definitions of clinical knee OA (progression) remains, which makes it impossible to summarize the evidence through meta-analyses. More research on prognostic factors for knee OA is needed using symptom progression as an outcome measure. Remarkably, only few studies have been performed using pain progression as an outcome measure. The pathophysiology of radiographic factors and their relation with symptoms should be further explored.     

Changes in osteoarthritis associated with the development of a maritime economy among southern California Indians

The severity of osteoarthritis was studied in human skeletal remains from archaeological sites in the Santa Barbara Channel area of southern California. These remains were analyzed to better understand changes in activity patterns associated with the economic shift from hunting and gathering to intensive fishing and craft specialization that occurred in this area. The joints of 967 burials from seven archaeological sites occupied between 3500 B.C. and the time of European contact were scored for osteoarthritis. These data show that the rate at which people developed osteoarthritis increased through time. This suggests that the adaptive shift toward more intensive exploitation of the marine environment resulted in an increase in the time people spent in strenuous physical activity. The increase in osteoarthritis affected males to a greater extent than females. One interpretation of this is that the work load of men increased with the economic importance of fishing.     

The elixir of muscle activity and kinesiology in a health perspective: Evidence of worksite tailored exercise training alleviating muscle disorders

Physical activity is known to benefit health while muscle activation and movements performed during occupational work in contrast may result in work-related musculoskeletal disorders. Therefore, we posed the research question: which mode of muscle activation may result in a reversal of work-related disorders? To address this, we performed electromyographic (EMG) and kinematic assessments of workers with diverse exposure categories: sedentary monotonous work, prolonged walking/standing, and physically heavy work. The various job-specific exposure variables could be categorized in terms of duration, intensity, repetition, static component, peak force etc. that were subsequently identified as risk factors. Based on sports science principles we developed tailored exercise programs to counteract job exposure. EMG activity during exercise training was monitored to identify principal differences between exercise training and job patterns. Evidence from more than 20 RCT studies including >4000 workers showed positive effects such as decreased muscle pain and increased workability. Finally, we identified plausible underlying mechanisms in muscle tissue – human and animal - that confirmed metabolic, morphological, and hormonal changes with e.g. repetitive work that were reversal to adaptations reported with exercise training. Progress has been made in developing intelligent physical exercise training, IPET, as the best complementary activity to job exposure and includes muscle activations and movements that limit work-related inactivity atrophy as well as overload injury.     

Neonatal repetitive needle pricking: Plasticity of the spinal nociceptive circuit and extended postoperative pain in later life

Repetitive exposure of neonates to noxious events is inherent to their health status monitoring in neonatal intensive care units (NICU). Altered basal nociception in the absence of an injury in later life has been demonstrated in ex‐NICU children, but the impact on pain hypersensitivity following an injury in later life is unknown. Also, underlying mechanisms for such long‐term changes are relatively unknown. The objective of this study is to investigate acute and long‐term effects of neonatal repetitive painful skin‐breaking procedures on nociception and to investigate plasticity of the nociceptive circuit. The repetitive needle prick animal model was used in which neonatal rats received four needle pricks into the left hind paw per day during the first postnatal week and control animals received nonpainful tactile stimuli. Repetitive needle pricking during the first week of life induced acute hypersensitivity to mechanical stimuli. At the age of 8 weeks, increased duration of postoperative hypersensitivity to mechanical stimuli after ipsilateral hind paw incision was shown in needle prick animals. Basal nociception from 3 to 8 weeks of age was unaffected by neonatal repetitive needle pricking. Increased calcitonin gene‐related peptide expression was observed in the ipsilateral and contralateral lumbar spinal cord but not in the hind paw of needle prick animals at the age of 8 weeks. Innervation of tactile Aβ‐fibers in the spinal cord was not affected. Ourresults indicate both acute and long‐term effects of repetitive neonatal skin breaking procedures on nociception and long‐term plasticity of spinal but not peripheral innervation of nociceptive afferents. © 2012 Wiley Periodicals, Inc. Develop Neurobiol, 2013     

Effect of eldecalcitol on articular cartilage through the regulation of transcription factor Erg in a murine model of knee osteoarthritis

Clinical studies have reported an association between low blood levels of 25-hydroxyvitamin D and the progression of osteoarthritis (OA), but the mechanism and effects of vitamin D signaling on articular chondrocytes and cartilage remains unclear. The purpose of this study was to investigate the effects of vitamin D on articular cartilage degeneration using eldecalcitol (ED-71), which is an active vitamin D₃ analog. Eight-week old male C57BL/6NCrSlc mice were subjected to experimental surgery to induce OA and local treatments with 10 μL ED-71 (0.5 μg/mL) were administered weekly. Four and 12 weeks after surgery, joints were evaluated using histological scoring systems. In addition, gene expression was analyzed in chondrocytes that were isolated from wildtype neonatal mice, cultured, and treated with ED-71 (10^?8 M). Joints treated with ED-71 demonstrated slowed progression of OA at 4 weeks after surgery, but few effects were observed at 12 weeks after surgery. Ets-related gene (Erg) expression was upregulated in OA articular cartilage, and further increased by ED-71 treatment. In primary chondrocytes cultured with ED-71, the gene expression of Erg and lubricin/proteoglycan 4 significantly increased, as compared to that of cells cultured without ED-71. Local treatment with ED-71 reduced degenerative changes to the articular cartilage during the early phase of experimental OA. Regulation of Erg by ED-71 in articular cartilage could confer resistance to early osteoarthritic changes.     

Parenting interventions to promote early child development in the first three years of life: A global systematic review and meta-analysis

BackgroundParents are the primary caregivers of young children. Responsive parent–child relationships and parental support for learning during the earliest years of life are crucial for promoting early child development (ECD). We conducted a global systematic review and meta-analysis to evaluate the effectiveness of parenting interventions on ECD and parenting outcomes.Methods and findingsWe searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Global Health Library for peer-reviewed, published articles from database inception until November 15, 2020. We included randomized controlled trials (RCTs) of parenting interventions delivered during the first 3 years of life that evaluated at least 1 ECD outcome. At least 2 reviewers independently screened, extracted data, and assessed study quality from eligible studies. ECD outcomes included cognitive, language, motor, and socioemotional development, behavior problems, and attachment. Parenting outcomes included parenting knowledge, parenting practices, parent–child interactions, and parental depressive symptoms. We calculated intervention effect sizes as the standardized mean difference (SMD) and estimated pooled effect sizes for each outcome separately using robust variance estimation meta-analytic approaches. We used random-effects meta-regression models to assess potential effect modification by country-income level, child age, intervention content, duration, delivery, setting, and study quality. This review was registered with PROSPERO (CRD42018092458 and CRD42018092461). Of the 11,920 articles identified, we included 111 articles representing 102 unique RCTs. Pooled effect sizes indicated positive benefits of parenting interventions on child cognitive development (SMD = 0.32, 95% CI [confidence interval]: 0.23, 0.40, P < 0.001), language development (SMD = 0.28, 95% CI: 0.18 to 0.37, P < 0.001), motor development (SMD = 0.24, 95% CI: 0.15 to 0.32, P < 0.001), socioemotional development (SMD = 0.19, 95% CI: 0.10 to 0.28, P < 0.001), and attachment (SMD = 0.29, 95% CI: 0.18 to 0.40, P < 0.001) and reductions in behavior problems (SMD = −0.13, 95% CI: −0.18 to −0.08, P < 0.001). Positive benefits were also found on parenting knowledge (SMD = 0.56, 95% CI: 0.33 to 0.79, P < 0.001), parenting practices (SMD = 0.33, 95% CI: 0.22 to 0.44, P < 0.001), and parent–child interactions (SMD = 0.39, 95% CI: 0.24 to 0.53, P < 0.001). However, there was no significant reduction in parental depressive symptoms (SMD = −0.07, 95% CI: −0.16 to 0.02, P = 0.08). Subgroup analyses revealed significantly greater effects on child cognitive, language, and motor development, and parenting practices in low- and middle-income countries compared to high-income countries; and significantly greater effects on child cognitive development, parenting knowledge, parenting practices, and parent–child interactions for programs that focused on responsive caregiving compared to those that did not. On the other hand, there was no clear evidence of effect modification by child age, intervention duration, delivery, setting, or study risk of bias. Study limitations include considerable unexplained heterogeneity, inadequate reporting of intervention content and implementation, and varying quality of evidence in terms of the conduct of trials and robustness of outcome measures used across studies.ConclusionsParenting interventions for children during the first 3 years of life are effective for improving ECD outcomes and enhancing parenting outcomes across low-, middle-, and high-income countries. Increasing implementation of effective and high-quality parenting interventions is needed globally and at scale in order to support parents and enable young children to achieve their full developmental potential.

In a systematic review and meta-analysis, Joshua Jeong and colleagues study the effectiveness of parenting interventions in children 3 years and younger in promoting early childhood development and parenting outcomes.     

Environmental factors affect the response of microbial extracellular enzyme activity in soils when determined as a function of water availability and temperature

Microorganisms govern soil carbon cycling with critical effects at local and global scales. The activity of microbial extracellular enzymes is generally the limiting step for soil organic matter mineralization. Nevertheless, the influence of soil characteristics and climate parameters on microbial extracellular enzyme activity (EEA) performance at different water availabilities and temperatures remains to be detailed. Different soils from the Iberian Peninsula presenting distinctive climatic scenarios were sampled for these analyses. Results showed that microbial EEA in the mesophilic temperature range presents optimal rates under wet conditions (high water availability) while activity at the thermophilic temperature range (60°C) could present maximum EEA rates under dry conditions if the soil is frequently exposed to high temperatures. Optimum water availability conditions for maximum soil microbial EEA were influenced mainly by soil texture. Soil properties and climatic parameters are major environmental components ruling soil water availability and temperature which were decisive factors regulating soil microbial EEA. This study contributes decisively to the understanding of environmental factors on the microbial EEA in soils, specifically on the decisive influence of water availability and temperature on EEA. Unlike previous belief, optimum EEA in high temperature exposed soil upper layers can occur at low water availability (i.e., dryness) and high temperatures. This study shows the potential for a significant response by soil microbial EEA under conditions of high temperature and dryness due to a progressive environmental warming which will influence organic carbon decomposition at local and global scenarios.     

Tail docking in horses: a review of the issues

Routinely performed painful procedures are of increasing interest and, in 2001 (Royal Order, May 17), Belgium prohibited docking in several vertebrates including horses. In 2004, opponents to this decision submitted a Bill (Doc51 0969/001) to Parliament, intending to obtain derogation for Belgian draught horses, which were traditionally docked. The Animal Welfare Council of Belgium, an official body advising the Minister of Public Health, was asked to evaluate this complex question, including biological, ethical and socio-economic aspects, on the basis of the available peer-reviewed studies. In this context, this study reviews legal aspects (overview of the European legislation), zootechnic aspects (uses of the Belgian draught horse) and biological aspects (pain potentially related to docking; horses' welfare linked to insect harassment and hygiene, communication and reproduction) of tail docking in draught horses. We conclude that (1) there is no benefit for horses in tail docking, including Belgian draught horses, (2) potential advantages of docking are essentially in favour of humans and these advantages could be scrupulously re-evaluated, taking into account practices of other countries. Therefore, there is no need to dock any horse other than for veterinary reasons.     

The importance of parentage in assessing temperature effects on fish early life history: a review of the experimental literature

Climate change and human development are altering aquatic thermal regimes, highlighting the need to understand how fish fitness may be impacted across a generational boundary. We reviewed experimental temperature studies investigating the links between parents and progeny, asking questions regarding the taxa studied, broodfish used, offspring traits examined, experimental durations and research motivations. We identified forty-one peer-reviewed articles examining the effects of pre-spawning adult temperature holding on offspring. These studies showed a strong focus on the order Salmoniformes (46% of studies) and aquaculturally driven research (66%). The use of wild broodfish was rare (12%) and the majority of experiments (83%) did not examine offspring consequences beyond hatch. We also identified 56 articles investigating how incubation temperature and parental influences affect embryonic and larval development. We demonstrate that these studies are not common in comparison to the majority of incubation thermal experiments that do not employ controlled parental breeding designs. However, 52 out of 56 studies we reviewed reported maternal, paternal or family identity influenced offspring responses to temperature. In characterizing these studies, Salmoniformes were the most studied order (52%), wild broodfish were more commonly used (55%), aquaculture motivations were less evident (23%), and few studies investigated offspring performance or traits beyond endogenous yolk stages. Overall, we suggest it is beneficial to experimentally examine temperature with consideration to parent-progeny relationships. To broaden our current understanding of intergenerational temperature effects, we recommend an increased focus on wild populations, offspring physiological and performance measures, later offspring development stages, and expanding research in non-salmonid species.     

New insights into protease-activated receptor 4 signaling pathways in the pathogenesis of inflammation and neuropathic pain: a literature review

Pain is an unpleasant sensory and emotional experience that is commonly associated with actual or potential tissue damage. Despite decades of pain research, many patients continue to suffer from chronic pain that is refractory to current treatments. Accumulating evidence has indicated an important role of protease-activated receptor 4 (PAR4) in the pathogenesis of inflammation and neuropathic pain. Here we reviewed PAR4 expression and activation via intracellular signaling pathways and the role of PAR4 signaling pathways in the development and maintenance of pain. Understanding PAR4 and its corresponding signaling pathways will provide insight to further explore the molecular basis of pain, which will also help to identify new targets for pharmacological intervention for pain relief.     

New insights into protease-activated receptor 4 signaling pathways in the pathogenesis of inflammation and neuropathic pain: a literature review

Pain is an unpleasant sensory and emotional experience that is commonly associated with actual or potential tissue damage. Despite decades of pain research, many patients continue to suffer from chronic pain that is refractory to current treatments. Accumulating evidence has indicated an important role of protease-activated receptor 4 (PAR4) in the pathogenesis of inflammation and neuropathic pain. Here we reviewed PAR4 expression and activation via intracellular signaling pathways and the role of PAR4 signaling pathways in the development and maintenance of pain. Understanding PAR4 and its corresponding signaling pathways will provide insight to further explore the molecular basis of pain, which will also help to identify new targets for pharmacological intervention for pain relief.     

Piperazine skeleton in the structural modification of natural products: a review

Piperazine moiety is a cyclic molecule containing two nitrogen atoms in positions 1 and 4, as well as four carbon atoms. Piperazine is one of the most sought heterocyclics for the development of new drug candidates with a wide range of applications. Over 100 molecules with a broad range of bioactivities, including antitumor, antibacterial, anti-inflammatory, antioxidant, and other activities, were reviewed. This article reviewed investigations regarding piperazine groups for the modification of natural product derivatives in the last decade, highlighting parameters that affect their biological activity.     

Effect of blood-flow restriction exercise on falls and fall related risk factors in older adults 60 years or above: a systematic review

This systematic review investigated the effect of low-load resistance training combined with blood-flow restriction (LL-BFR) on falls in older adults ≥60 years of age. The databases Embase, Medline, and Cochrane Library were searched from inception to October 1^st, 2019 and reference lists of retrieved publications. Main outcomes were fall rates or proportion of fallers. Additional outcomes were physical performance, lower extremity muscle strength or function, and balance. Mean difference ±SD on falls and fall related outcomes were reported and Cochrane Collaboration’s risk of bias tool was used to evaluate quality of evidence. Eight RCT-studies met the inclusion criteria. None reported falls data. Assessing physical performance tests (n=12), 8/12 of the LL-BFR groups showed a significant within-group improvement and 5/12 significant between-group effects comparing LL-BFR to respective controls. For muscle strength tests (n=16), 9/16 showed significant positive within-group improvement and 3/16 significant between-group effects. One study reported data on balance with conflicting results. In conclusion, LL-BFR might increase physical performance and muscle strength in older adults ≥60 years of age. None of the included studies investigated the effect on falls. Larger adequately powered studies are required before introducing LL-BFR as an alternative exercise modality to decrease fall risk.