Purpose: To investigate acute and long-term changes in hormonal and inflammatory biomarkers in nonambulant children with cerebral palsy in response to dynamic standing exercise.

Methods: Fourteen children with severe cerebral palsy were recruited. Anthropometrics and body composition measures were obtained. Physical activity levels before the study were assessed using hip-worn accelerometry. All children underwent a 30-minute dynamic standing exercise using the Innowalk standing aid. Respiratory data during exercise were collected using indirect calorimetry. Blood samples were collected before and after exercise. Blood samples were also obtained after two 16-week exercise protocols, in a resting state. Hormonal and inflammatory metabolites were measured from blood serum/plasma, and acute and long-term changes in biomarker levels were assessed using Wilcoxon signed-rank tests.

Results: Of the 14 children at baseline, all had slightly/moderately/severely elevated C-reactive protein and cortisol levels. C-reactive protein levels were decreased following a 30-minute bout of dynamic standing (before exercise: 53 mg/L [interquartile range: 40-201]; after exercise: 39 mg/L [interquartile range: 20-107]; P = .04).

Conclusions: We show that several hormonal and inflammatory biomarkers are dysregulated in children with cerebral palsy. Our preliminary results from a small, but deep-phenotyped prospective cohort indicate acute and long-term alterations of several biomarkers in response to exercise. ©2023 The Authors.

Introduction: Children gain increased health and wellbeing by participating in physical activity (PA). In children and adolescents with cerebral palsy who are non-ambulant (children with CP-NA), levels of PA have been indicated to be lower compared to children and adolescents without physical disabilities. However, research on PA in children with CP-NA is limited. Therefore, this study aims to evaluate objectively assessed PA over the course of one year when using ActiGraph GT3X accelerometer in children with CP-NA. 

Participants and methods: Accelerometer data were retrieved from 32 children with CP-NA (4 - 17 years) in Region Skane, Sweden. Participants wore the ActiGraph GT3X accelerometer all waking hours for up to four periods of seven consecutive days over a year. Statistically sensitivity analyses were run to explore differences in PA between subtypes of cerebral palsy and GMFCS level IV and V. 

Results: In total 481 days and 85 periods of valid accelerometer data were obtained. Light PA was statically significantly higher for children with dyskinetic CP-NA compared to spastic CP-NA (median (IQR) 57 (37.42-88.1) vs. 34.42 (20.42-55.96), p = <0.001). Light PA (median (IQR) 57 (36.67-88.5) vs. 25.42 (17-38.75), p = <0.001) and moderate to vigorous PA (median (IQR) 1.83 (1-4.17) vs. 1.67 (0.67-2), p = <0.001) were statically significantly higher for children with CP-NA GMFCS level IV compared to level V. 

Conclusion: Preliminary results indicate differences in PA levels between subtype of cerebral palsy and GMFCS level. Further analyses to explore potential differences in PA over the year will be run.

Background: Physical exercise is an important treatment for individuals with axial spondyloarthritis (axSpA). Although high-intensity training (HIT) has been shown to reduce disease symptoms and risk of comorbidity without exacerbating disease activity (1), compliance tends to decrease over time. Increased knowledge is needed on how to optimize and tailor individual exercise programs for continued regular exercising and improved health.

Objective: To study the effects of HIT on aerobic capacity, body composition, disease activity, physical function, health status and fatigue in individuals with axSpA after a 12-week intervention supported by digital coaching.

Methods: Twenty-two individuals (women, n=12), recruited from two rheumatology clinics in southern Sweden, were randomized to a HIT intervention group (HG; n=11) or a control group (CG; n=11). The HG completed three HIT sessions/week, including two interval training sessions (4x4 min), in self-selected activities for 12 weeks. The individuals in the HG were individually coached and had regular support from a physical therapist primarily by digital coaching. The CG continued exercising as usual. Assessment of aerobic capacity (VO2max), body composition (BMI and visceral fat area [cm2]), disease activity (CRP [µg/ml], BASDAI, 0-10 best-worst), physical function (BASFI, 0-10 best-worst), health status (EQ5D, 0-1 worst-best, ASAS health index [ASAS-HI], 0-17 best-worst), and fatigue (fatigue severity scale [FFS], 0-7 best-worst) were sampled at baseline and after 12 weeks. Mean and standard deviation (SD) were used for descriptive statistics. Repeated measures analysis of variance (ANOVA) was used to investigate effect of group (HG*CG) and time (PRE*POST), with a post-hoc analysis using t-tests when ANOVA indicated a significant difference in main effects or interactions. A significance level of p≤0.05 was used. Fisher´s exact test was used to study the effects over time for CRP (as dichotomized variable, > or < 4 µg/ml).

Results: Results presented are part of an ongoing RCT based on 19 individuals (women n=11) that have completed the 12-week follow-up analyses. The participants mean (SD) age was 48 (10) years, BMI 25 (4), VO2max 37 (6) mlO2/kg/min, and BASDAI 2.6 (0.3). No differences were present between the HG (n=9) and the CG group (n=10) at baseline for the studied variables. After 12 weeks of HIT an ANOVA interaction (p<0.05 showed that HG increased their VO2max (6.4 [3.6] mlO2/kg/min; p<0.001) but CG did not. For BMI, visceral fat area, disease activity (BASDAI), physical function (BASFI), fatigue (FFS) no differences in main effects or interactions were found (p>0.05). Health status (EQ5D) showed an ANOVA time main effect (p=0.007) where the HG increased their health status (0.10 [0.06] units; p=0.02) after 12-weeks, but CG did not. For health status measured with ASAS-HI no differences between groups were found. For dichotomized CRP-values no differences were found in either of the group’s pre-post. 

Conclusions: This pilot RCT shows that after 12 weeks of digital-based HIT intervention, the HG increased their aerobic capacity and EQ5D health status compared to CG, while body composition, disease activity, physical function, and fatigue did not show any significant differences between the groups. 

References

(1) Sveaas SH, Bilberg a, Berg IJ, Provan SA, Rollefstad S, Semb AG, et al. high intensity exercise for 3 months reduces disease activity in axial spondyloarthritis (axSpA): a multicentre randomised trial of 100 patients. Br J Sports med. 2019

Purpose: To investigate the acute exercise effects of dynamic standing exercise (DyS) on blood glucose and blood lactate among children and adolescent with cerebral palsy (CP) who are non-ambulant. 

Methods: Twenty-four participants with CP who are non-ambulant performed 30 minutes of DyS using a motorized device enabling assisted passive movements in an upright weight-bearing position. Capillary blood-samples were taken from the fingertip for measurement of blood glucose and blood lactate at rest and at the end of exercise. 

Results: At rest, the participants had hyperlactatemia that was unaffected after exercise presented as median and interquartile range at rest 1.8 [1.3:2.7] mmol/L and after exercise 2.0 [1.1:2.5] mmol/L. Children and adolescents with GMFCS-E&R V had higher lactate levels at rest (2.5 [1.8:2.9] vs 1.4 [1.0:2.0]; p=0.030) and after exercise (2.3 [2.0:2.6] vs 1.2 [0.9:2.2]; p=0.032) compared to children and adolescents with GMFCS-E&R IV respectively. A statistically significant larger decrease in blood lactate levels after exercise was observed in children and adolescents with higher resting blood lactate levels (rho=0.56;p=0.004). There were no statistically significant changes in blood glucose. 

Conclusions: Forty percent of the participants had mild hyperlactatemia at rest and participants with the highest blood lactate levels at rest had the greatest decrease in blood lactate levels after one bout of exercise. Children and adolescents with classified into higher level of GMFCS-E&R had higher blood lactate levels. More studies are needed on how to prevent chronically high resting levels of lactate with exercise in children with CP who are non-ambulant. 

Background: Susceptibility to Rheumatoid Arthritis (RA) is dependent on complex interactions among genetic and environmental factors. Protein candidates and their role in pathways leading to chronic inflammation of the joints, in addition to their potential as drug targets, can be revealed with the help of experimental models for disease (1). From the results of functional genetic studies, we have recently shown that the T-box gene, TBX3, is a candidate gene in Collagen Induced Arthritis (CIA), an experimental model for RA (2). TBX3 encodes a transcriptional regulator involved in differentiation of several organs, including bone, during embryonic development. It has, in addition, been demonstrated important in oncogenesis (3). Our studies suggest that TBX3 has a role in B-cell activation and is important for the severity of disease in the CIA model (2). Objectives: The objective of this project is to understand the role for the transcriptional regulator TBX3 in development of RA. Methods: Bioinformatics based comparative studies of mouse and human alleles in the regulatory region of TBX3. CRISPR/Cas9-introduced deletions and base modifications in human B-cell lines. Activation of genetically modified B-cells in vitro, followed by analyses of proliferative response and antibody production. Results: Studies of CIA development in mice with single nucleotide polymorphisms (SNPs) in the regulatory region of Tbx3 revealed a significant difference in severity of arthritis. In line with this, the anti-collagen type II antibody titers were shown substantially higher in mice with more severe arthritis, even before onset of disease. In addition, preliminary data shows that the proliferative response to Type II collagen upon re-challenge of lymph node cells in vitro is higher in these mice, suggesting a more active response to the disease-inducing antigen. Because the TBX3 gene is conserved between mouse and human, we are investigating whether similar genetic variations are found in the regulatory region of the human TBX3 gene and whether the putative genetic variation would lead to a distinct B-cell phenotype upon activation in vitro. Conclusion: We suggest that the oncoprotein TBX3 is a novel candidate contributing to disease severity in experimental arthritis. Investigations of genetic variation in the TBX3 gene and its role in the activation of human B-cells will reveal whether this protein is a candidate for influencing also development of RA.

Background: Development of autoimmune diseases is the result of a complex interplay between hereditary and environmental factors, with multiple genes contributing to the pathogenesis in human disease as well as in experimental models for disease. The T-box protein 3 is a transcriptional repressor essential during early embryonic development, in the formation of bone and additional organ systems, and in tumorigenesis.

Methods: With the aim to find novel genes important for autoimmune inflammation, we have performed genetic studies of collagen-induced arthritis, a mouse experimental model for Rheumatoid Arthritis.

Results: We show that a small genetic fragment on mouse chromosome 5, including Tbx3 and three additional protein-coding genes, is linked to severe arthritis and high titers of anti-collagen antibodies. Gene expression studies have revealed differential expression of Tbx3 in B-cells, where low expression was accompanied by a higher B-cell response upon B-cell receptor stimulation in vitro. Furthermore, we show that serum TBX3 levels rise concomitantly with increasing severity of CIA.

Conclusions: From these results, we suggest that TBX3 is a novel factor important for the regulation of gene transcription in the immune system and that genetic polymorphisms, resulting in lower expression of Tbx3, are contributing to a more severe form of collagen-induced arthritis and high titers of autoantibodies. We also propose TBX3 as a putative diagnostic biomarker for rheumatoid arthritis.

Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg’s binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis. © 2018 The Author(s)