The clinical and experimental treatment of Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and comprises of multiple subtypes. The most relevant disease subtypes, grouped upon current insight in disease mechanisms, are nonsystemic (oligo- and polyarticular) JIA and systemic JIA (sJIA). In this review, we summarize some of the main proposed mechanisms of disease in both nonsystemic and sJIA and discuss how current therapeutic modalities target some of the pathogenic immune pathways. Chronic inflammation in nonsystemic JIA is the result of a complex interplay between effector and regulatory immune cell subsets, with adaptive immune cells, specifically T-cell subsets and antigen-presenting cells, in a central role. There is, however, also innate immune cell contribution. SJIA is nowadays recognized as an acquired chronic inflammatory disorder with striking autoinflammatory features in the first phase of the disease. Some sJIA patients develop a refractory disease course, with indications for involvement of adaptive immune pathways as well. Currently, therapeutic strategies are directed at suppressing effector mechanisms in both non-systemic and sJIA. These strategies are often not yet optimally tuned nor timed to the known active mechanisms of disease in individual patients in both non-systemic and sJIA. We discuss current treatment strategies in JIA, specifically the 'Step-up' and 'Treat to Target approach' and explore how increased insight into the biology of disease may translate into future more targeted strategies for this chronic inflammatory disease at relevant time points: preclinical disease, active disease, and clinically inactive disease.

South African Institute of Drug-Free Sport Position Statement on CBD (Cannabidiol) and THC (Tetrahydrocannabinol).

Cannabidiol (CBD) and Tetrahydrocannabinol (THC) have become easily available to athletes over the years. Using these substances may inadvertently expose an athlete to the possibility of an adverse analytical finding (a "positive" test) and a sanction. Athletes need to understand the risk of an anti-doping rule violation or adverse analytical finding should these products be used, especially if no therapeutic use exemption exists. This position statement attempts to clarify the use of CBD and THC and their associated risks with Anti-Doping Rule Violations (ADRV) in the athletic population. The South African Sports Medicine Association supports this position statement.

SPECT/CT imaging of inflammation and calcification in human carotid atherosclerosis to identify the plaque at risk of rupture.

BACKGROUND: Calcification and inflammation are atherosclerotic plaque compositional biomarkers that have both been linked to stroke risk. The aim of this study was to evaluate their co-existing prevalence in human carotid plaques with respect to plaque phenotype to determine the value of hybrid imaging for the detection of these biomarkers. METHODS: Human carotid plaque segments, obtained from endarterectomy, were incubated in [111In]In-DOTA-butylamino-NorBIRT ([111In]In-Danbirt), targeting Leukocyte Function-associated Antigen-1 (LFA-1) on leukocytes. By performing SPECT/CT, both inflammation from DANBIRT uptake and calcification from CT imaging were assessed. Plaque phenotype was classified using histology. RESULTS: On a total plaque level, comparable levels of calcification volume existed with different degrees of inflammation and vice versa. On a segment level, an inverse relationship between calcification volume and inflammation was evident in highly calcified segments, which classify as fibrocalcific, stable plaque segments. In contrast, segments with little or no calcification presented with a moderate to high degree of inflammation, often coinciding with the more dangerous fibrous cap atheroma phenotype. CONCLUSION: Calcification imaging alone can only accurately identify highly calcified, stable, fibrocalcific plaques. To identify high-risk plaques, with little or no calcification, hybrid imaging of calcification and inflammation could provide diagnostic benefit.

Acetabular fracture after cycling related falls: High index of suspicion is required to avoid missing the injury on plain radiographs.

Cycling participation as a medium of transport and as a competitive sport has steadily increased in recent decades. Traumatic injuries secondary to falls and collisions occur relatively frequently. Fractures of the hip and pelvis are uncommon with no studies to date reporting their exact incidence in this sport. Injuries specific to the acetabulum are reported even less frequently. We present four cases that highlight the insidious nature of acetabular fractures in cyclists and document their management and recovery. The number of acetabular fractures following falls from bicycles directly onto the lateral hip result in a relatively high number of fractures. Many of these may be missed due to the absence of findings on plain x-ray imaging.It is therefore important to have a high index of suspicion for hip and pelvis fractures when treating cycling related traumatic injuries.

The pattern of non-contact injuries in a South African professional football team.

Background: The incidence, pattern and severity of non-contact injuries in European football has been researched extensively. In South African football only two studies have been conducted to date and with disparate outcomes. Further research into injury rates in South African football is therefore warranted. Objectives: To determine the incidence and pattern of non-contact injuries in a South African professional football team during the course of a single season (2016-2017) in relation to competition exposure, training load and playing position. Methods: Thirty-four male professional football players belonging to a single team competing in the Premier Soccer League (PSL) in South Africa were studied. Non-contact time-loss injuries (total training and match injuries) were recorded. Injury incidence, location, severity, type, and playing position (defender, midfielder, attackers, goalkeepers) during either match play or training were recorded. Results: The non-contact incidence was 52 injuries with an injury rate of 3.74 per 1 000 exposures (training and competition). Competitions resulted in an incidence of 26.4 injuries per 1 000 exposure and training incidence 2.08 injuries per 1 000 exposures. Hamstring, groin and quadriceps injuries were the most frequently injured locations and muscle-tendon injuries accounted for the majority of injuries. The majority of injuries (52%) occurred during match play while 48% occurred during training. The greatest absolute number of injuries were sustained by midfielders (50%), followed by defenders (33%) and attackers (17%). However, relative to player numbers, the greatest number of injuries during match play were for defenders (44%), attackers (32%) and midfielders (24%). During training attackers sustained the most injuries (39%), followed by defenders (31%) and midfielders (30%). Goalkeepers did not sustain any non-contact injuries during the duration of the study. Conclusion: The non-contact injury incidence in South African professional football players is similar to European football players. Hamstrings and groin injuries are predominant and were sustained throughout the competitive season. Defenders sustained the most non-contact injuries within the team relative to exposure time compared to attackers and midfielders. To our knowledge, injuries relative to player position have not been reported previously.

Defining consensus opinion to develop randomised controlled trials in rare diseases using Bayesian design: An example of a proposed trial of adalimumab versus pamidronate for children with CNO/CRMO.

INTRODUCTION: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder primarily affecting children and adolescents. It can lead to chronic pain, bony deformities and fractures. The pathophysiology of CNO is incompletely understood. Scientific evidence suggests dysregulated expression of pro- and anti-inflammatory cytokines to be centrally involved. Currently, treatment is largely based on retrospective observational studies and expert opinion. Treatment usually includes nonsteroidal anti-inflammatory drugs and/or glucocorticoids, followed by a range of drugs in unresponsive cases. While randomised clinical trials are lacking, retrospective and prospective non-controlled studies suggest effectiveness of TNF inhibitors and bisphosphonates. The objective of the Bayesian consensus meeting was to quantify prior expert opinion. METHODS: Twelve international CNO experts were randomly chosen to be invited to a Bayesian prior elicitation meeting. RESULTS: Results showed that a typical new patient treated with pamidronate would have an 84% chance of improvement in their pain score relative to baseline at 26 weeks and an 83% chance on adalimumab. Experts thought there was a 50% chance that a new typical patient would record a pain score of 28mm (pamidronate) to 30mm (adalimumab) or better at 26 weeks. There was a modest trend in prior opinion to indicate an advantage of pamidronate vs adalimumab, with a 68% prior chance that pamidronate is superior to adalimumab by some margin. However, it is clear that there is considerable uncertainty about the precise relative merits of the two treatments. CONCLUSIONS: The rarity of CNO leads to challenges in conducting randomised controlled trials with sufficient power to provide a definitive outcome. We address this using a Bayesian design, and here describe the process and outcome of the elicitation exercise to establish expert prior opinion. This opinion will be tested in the planned prospective CNO study. The process for establishing expert consensus opinion in CNO will be helpful for developing studies in other rare paediatric diseases.

Perspectives on Small Animal Radionuclide Imaging; Considerations and Advances in Atherosclerosis.

This review addresses nuclear SPECT and PET imaging in small animals in relation to the atherosclerotic disease process, one of our research topics of interest. Imaging of atherosclerosis in small animal models is challenging, as it operates at the limits of current imaging possibilities regarding sensitivity, and spatial resolution. Several topics are discussed, including technical considerations that apply to image acquisition, reconstruction, and analysis. Moreover, molecules developed for or applied in these small animal nuclear imaging studies are listed, including target-directed molecules, useful for imaging organs or tissues that have elevated expression of the target compared to other tissues, and molecules that serve as substrates for metabolic processes. Differences between animal models and human pathophysiology that should be taken into account during translation from animal to patient as well as differences in tracer behavior in animal vs. man are also described. Finally, we give a future outlook on small animal radionuclide imaging in atherosclerosis, followed by recommendations. The challenges and solutions described might be applicable to other research fields of health and disease as well.

A tale of two sit-bones: The cyclist's ischial hygroma (Perineal nodular induration).

The ischial hygroma, also known as a perineal nodular induration, is a relatively rare and mostly cycling-specific injury that is often incorrectly diagnosed and managed. Here two cases with divergent managements are described to highlight the spectrum of treatment available to manage this condition. The presentation, assessment and management of two cases of perineal nodular induration are discussed. The management options, namely surgical excision vs conservative management, with saddle pressure mapping highlight that there is no single optimal method and that a multidisciplinary approach should be applied to treat these injuries successfully. Perineal nodular induration should be investigated appropriately to exclude less benign causes of perineal masses. Conservative management and surgical excision can both be successful. Clinicians should be familiar with the assessment and management of this relatively rare but debilitating condition in competitive cyclists.

Alliance and Treatment Outcome in Family-Involved Treatment for Youth Problems: A Three-Level Meta-analysis.

Alliance has been shown to predict treatment outcome in family-involved treatment for youth problems in several studies. However, meta-analytic research on alliance in family-involved treatment is scarce, and to date, no meta-analytic study on the alliance-outcome association in this field has paid attention to moderating variables. We included 28 studies reporting on the alliance-outcome association in 21 independent study samples of families receiving family-involved treatment for youth problems (N = 2126 families, M age youth ranging from 10.6 to 16.1). We performed three multilevel meta-analyses of the associations between three types of alliance processes and treatment outcome, and of several moderator variables. The quality of the alliance was significantly associated with treatment outcome (r = .183, p < .001). Correlations were significantly stronger when alliance scores of different measurement moments were averaged or added, when families were help-seeking rather than receiving mandated care and when studies included younger children. The correlation between alliance improvement and treatment outcome just failed to reached significance (r = .281, p = .067), and no significant correlation was found between split alliances and treatment outcome (r = .106, p = .343). However, the number of included studies reporting on alliance change scores or split alliances was small. Our findings demonstrate that alliance plays a small but significant role in the effectiveness of family-involved treatment. Future research should focus on investigating the more complex systemic aspects of alliance to gain fuller understanding of the dynamic role of alliance in working with families.

The interaction of psychological and physiological homeostatic drives and role of general control principles in the regulation of physiological systems, exercise and the fatigue process - The Integrative Governor theory.

Either central (brain) or peripheral (body physiological system) control mechanisms, or a combination of these, have been championed in the last few decades in the field of Exercise Sciences as how physiological activity and fatigue processes are regulated. In this review, we suggest that the concept of 'central' or 'peripheral' mechanisms are both artificial constructs that have 'straight-jacketed' research in the field, and rather that competition between psychological and physiological homeostatic drives is central to the regulation of both, and that governing principles, rather than distinct physical processes, underpin all physical system and exercise regulation. As part of the Integrative Governor theory we develop in this review, we suggest that both psychological and physiological drives and requirements are underpinned by homeostatic principles, and that regulation of the relative activity of each is by dynamic negative feedback activity, as the fundamental general operational controller. Because of this competitive, dynamic interplay, we propose that the activity in all systems will oscillate, that these oscillations create information, and comparison of this oscillatory information with either prior information, current activity, or activity templates create efferent responses that change the activity in the different systems in a similarly dynamic manner. Changes in a particular system are always the result of perturbations occurring outside the system itself, the behavioural causative 'history' of this external activity will be evident in the pattern of the oscillations, and awareness of change occurs as a result of unexpected rather than planned change in physiological activity or psychological state.

Static versus dynamic kinematics in cyclists: A comparison of goniometer, inclinometer and 3D motion capture.

Kinematic measurements conducted during bike set-ups utilise either static or dynamic measures. There is currently limited data on reliability of static and dynamic measures nor consensus on which is the optimal method. The aim of the study was to assess the difference between static and dynamic measures of the ankle, knee, hip, shoulder and elbow. Nineteen subjects performed three separate trials for a 10-min duration at a fixed workload (70% of peak power output). Static measures were taken with a standard goniometer (GM), an inclinometer (IM) and dynamic three-dimensional motion capture (3DMC) using an eight camera motion capture system. Static and dynamic joint angles were compared over the three trials to assess repeatability of the measurements and differences between static and dynamic values. There was a positive correlation between GM and IM measures for all joints. Only the knee, shoulder and elbow were positively correlated between GM and 3DMC, and IM and 3DMC. Although all three instruments were reliable, 3D motion analysis utilised different landmarks for most joints and produced different means. Changes in knee flexion angle from static to dynamic are attributable to changes in the positioning of the foot. Controlling for this factor, the differences are negated. It was demonstrated that 3DMC is not interchangeable with GM and IM, and it is recommended that 3DMC develop independent reference values for bicycle configuration.

Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry.

BACKGROUND: Percutaneous renal denervation (RDN) has recently been introduced as a treatment for therapy-resistant hypertension. Also, it has been suggested that RDN may be beneficial for other conditions characterised by increased sympathetic nerve activity. There are still many uncertainties with regard to efficacy, safety, predictors for success and long-term effects. To answer these important questions, we initiated a Dutch RDN registry aiming to collect data from all RDN procedures performed in the Netherlands. METHODS: The Dutch RDN registry is an ongoing investigator-initiated, prospective, multicentre cohort study. Twenty-six Dutch hospitals agreed to participate in this registry. All patients who undergo RDN, regardless of the clinical indication or device that is used, will be included. Data are currently being collected on eligibility and screening, treatment and follow-up. RESULTS: Procedures have been performed since August 2010. At present, data from 306 patients have been entered into the database. The main indication for RDN was hypertension (n = 302, 99%). Patients had a mean office blood pressure of 177/100 (±29/16) mmHg with a median use of three (range 0-8) blood pressure lowering drugs. Mean 24-hour blood pressure before RDN was 157/93 (±18/13) mmHg. RDN was performed with different devices, with the Simplicity™ catheter currently used most frequently. CONCLUSION: Here we report on the rationale and design of the Dutch RDN registry. Enrolment in this investigator-initiated study is ongoing. We present baseline characteristics of the first 306 participants.

Competition between a Lawn-Forming Cynodon dactylon and a Tufted Grass Species Hyparrhenia hirta on a South-African Dystrophic Savanna.

South African savanna grasslands are often characterised by indigestible tufted grass species whereas lawn grasses are far more desirable in terms of herbivore sustenance. We aimed to investigate the role of nutrients and/or the disturbance (grazing, trampling) by herbivores on the formation of grazing lawns. We conducted a series of common garden experiments to test the effect of nutrients on interspecific competition between a typical lawn-forming grass species (Cynodon dactylon) and a species that is frequently found outside grazing lawns (Hyparrhenia hirta), and tested for the effect of herbivore disturbance in the form of trampling and clipping. We also performed a vegetation and herbivore survey to apply experimentally derived insights to field observations. Our results showed that interspecific competition was not affected by soil nutrient concentrations. C. dactylon did show much more resilience to disturbance than H. hirta, presumably due to the regenerative capacity of its rhizomes. Results from the field survey were in line with these findings, describing a correlation between herbivore pressure and C. dactylon abundance. We conclude that herbivore disturbance, and not soil nutrients, provide C. dactylon with a competitive advantage over H. hirta, due to vegetative regeneration from its rhizomes. This provides evidence for the importance of concentrated, high herbivore densities for the creation and maintenance of grazing lawns.

Mesenchymal stem cell therapy in proteoglycan induced arthritis.

OBJECTIVES: To explore the immunosuppressive effect and mechanism of action of intraperitoneal (ip) and intra-articular (ia) mesenchymal stem cell (MSC) injection in proteoglycan induced arthritis (PGIA). METHODS: MSC were administered ip or ia after establishment of arthritis. We used serial bioluminescence imaging (BLI) to trace luciferase-transfected MSC. Mice were sacrificed at different time points to examine immunomodulatory changes in blood and secondary lymphoid organs. RESULTS: Both ip and local ia MSC injection resulted in a beneficial clinical and histological effect on established PGIA. BLI showed that MSC ip and ia in arthritic mice are largely retained for several weeks in the peritoneal cavity or injected joint respectively, without signs of migration. Following MSC treatment pathogenic PG-specific IgG2a antibodies in serum decreased. The Th2 cytokine IL-4 was only upregulated in PG-stimulated lymphocytes from spleens in ip treated mice and in lymphocytes from draining lymph nodes in ia treated mice. An increase in production of IL-10 was seen with equal distribution. Although IFN-γ was also elevated, the IFN-γ/IL-4 ratio in MSC treated mice was opposite to the ratio in (untreated) active PGIA. CONCLUSIONS: MSC treatment, both ip and ia, suppresses PGIA, a non-collagen induced arthritis model. MSC are largely retained for weeks in the injection region. MSC treatment induced at the region of injection a deviation of PG-specific immune responses, suggesting a more regulatory phenotype with production of IL-4 and IL-10, but also of IFN-γ, and a systemic decrease of pathogenic PG-specific IgG2a antibodies. These findings underpin the potential of MSC treatment in resistant arthritis.

Mesenchymal stromal cells for treatment of arthritis.

Patients with refractory inflammatory arthritis can still respond favourable to autologous haematopoietic stem cell transplantation. However, this treatment has a high morbidity and even 5% mortality. Mesenchymal stromal cells (MSC), a subset of the non-haematopoietic stromal cells obtained from bone marrow, were found to have a strong immunosuppressive effect. MSC treatment is explored in many diseases like diabetes, SLE, MS and RA. This review covers all relevant literature regarding MSC treatment of inflammatory arthritis (RA and JIA). This review contains data of in vitro studies, animal studies and clinical studies. The following subjects will be discussed in detail: properties of MSC, presence of MSC in the joint, intra-articular versus intravenous route, autologous versus allogeneic, ideal source of MSC, distribution, transdifferentiation, engraftment, rejection, efficacy and toxicology. After reading this review the reader will be totally updated in this quickly evolving field of MSC therapy.

Public participation in genomics research in the Netherlands: validating a measurement scale.

Nowadays, new technologies, like genomics, cannot be developed without the support of the public. However, although interested, the public does not always actively participate in science issues when offered the opportunity via public participation activities. In a study aimed at validating a measurement scale, first, we investigated if public participation existed, and, secondly, we investigated how levels of public participation in genomics research varied among groups. Finally, we studied which factors predicted public participation. Results were based on a questionnaire with four subsamples. Results confirmed, first of all, the internal consistency of the measurement scale to assess levels of public participation. Secondly, the groups differed significantly with regard to their levels of participation in genomics research. Finally, the findings revealed that information-seeking behaviour, knowledge and education were main predictors of public participation, while interest, social involvement, and trust and influence had some influence together with age and gender.

Predictors of health-related quality of life in children and adolescents with juvenile idiopathic arthritis: results from a Web-based survey.

OBJECTIVE: Children with juvenile idiopathic arthritis (JIA) experience functional impairment due to joint manifestations of the disease. The aim of our present study was to assess health-related quality of life (HRQOL) and its predictors in a group of children and adolescents with JIA. METHODS: The study sample includes all JIA patients (ages 6-18 years) who consulted a pediatric rheumatologist in Amsterdam, The Netherlands, between February 2009 and March 2010. HRQOL was measured using the Paediatric Quality of Life Inventory 4.0 (ages 6-18 years). Functional ability was measured using the Childhood Health Assessment Questionnaire, and medical and sociodemographic parameters were assessed. The study sample was compared to a Dutch youth norm population including children with other chronic health conditions. The proportion of children with JIA with an impaired HRQOL (<1 SD) was evaluated and multivariate regression analyses were performed to predict HRQOL outcome. RESULTS: Of the eligible patients, 64.1% (n = 152) participated. Both children (ages 6-12 years) and adolescents (ages 13-18 years) with JIA reported a significantly lower HRQOL in almost all domains compared to either healthy controls or children with other chronic health conditions. Approximately half of the children with JIA showed an impaired HRQOL. The main predictors of HRQOL were functional ability, pain, subjective burden of medication use, and school absence. CONCLUSION: The HRQOL is severely affected in children and adolescents with JIA. These findings underline the necessity to systematically monitor HRQOL in daily clinical practice.

A novel submaximal cycle test to monitor fatigue and predict cycling performance.

OBJECTIVE: The purpose of this study was to determine the reliability and predictive value of performance parameters, measured by a new novel submaximal cycle protocol, on peak power and endurance cycling performance in well-trained cyclists. METHODS: Seventeen well-trained competitive male road racing cyclists completed four peak power output (PPO) tests and four 40-km time trials (40-km TT). Before each test, all cyclists performed a novel submaximal cycle test (Lamberts and Lambert Submaximal Cycle Test (LSCT)). Parameters associated with performance such as power, speed, cadence and rating of perceived exertion (RPE) were measured during the three stages of the test when cyclists rode at workloads coinciding with fixed predetermined heart rates. Heart rate recovery (HRR) was measured after the last stage of the test. RESULTS: Parameters measured during the second and third stages of the LSCT were highly reliable (intraclass correlation range: R=0.85-1.00) with low typical error of measurements (range: 1.3-4.4%). Good relationships were found between the LSCT and cycling performance measured by the PPO and 40-km TT tests. Mean power had stronger relationships with measures of cycling performance during the second (r=0.80-0.89) and third stages (r=0.91-0.94) of the LSCT than HRR (r=0.55-0.68). CONCLUSIONS: The LSCT is a reliable novel test which is able to predict peak and endurance cycling performance from submaximal power, RPE and HRR in well-trained cyclists. As these parameters are able to detect meaningful changes more accurately than VO(2max), the LSCT has the potential to monitor cycling performance with more precision than other current existing submaximal cycle protocols.

[Deviant language development following cochlear implantation? Applicability of the parent questionnaire ELFRA-2]. / Abweichende Sprachentwicklung nach Cochleaimplantation? Zur Anwendbarkeit des Elternfragebogens ELFRA-2.

BACKGROUND: The parent questionnaire ELFRA-2 is considered a valid tool for early detection of delayed language development in 2-year-old children. Applicability for children treated with cochlear implants (CI) is to be investigated. METHODS: By means of the ELFRA-2 we documented longitudinally for up to 24 months post implantation language development in 27 children treated before 3 years of age. The critical developmental criteria (related to age) were applied to CI children (related to duration of CI use) and gender-related normative data were taken as a reference. RESULTS: Only two boys were identified as showing a language delay after 2 years of CI use. However, using normative data 11-44% of the children performed below average. Development in girls was faster than in boys. The influence of preoperative hearing experience declined over time. CONCLUSION: The critical developmental criteria of ELFRA-2 have proved to be unreliable for the identification of varying development after CI. Modified and gender-related evaluation is necessary.

Heart rate recovery as a guide to monitor fatigue and predict changes in performance parameters.

Determining the optimal balance between training load and recovery contributes to peak performance in well-trained athletes. The measurement of heart rate recovery (HRR) to monitor this balance has become popular. However, it is not known whether the impairment in performance, which is associated with training-induced fatigue, is accompanied by a change in HRR. Therefore, the aim of this study was to retrospectively analyze the relationship between changes in HRR and cycling performance in a group of well-trained cyclists (n=14) who participated in a 4-week high-intensity training (HIT) program. Subjects were assigned to either a group that continuous had a increase in HRR (G(Incr)) or a group that showed a decrease in HRR (G(Decr)) during the HIT period. Both groups, G(Incr) and G(Decr), showed improvements in the relative peak power output (P=0.001 and 0.016, respectively) and endurance performance parameters (P=0.001 and <0.048, respectively). The average power during the 40-km time trial (40-km TT), however, improved more in G(Incr) (P=0.010), resulting in a tendency for a faster 40-km TT time (P=0.059). These findings suggest that HRR has the potential to monitor changes in endurance performance and contribute to a more accurate prescription of training load in well-trained and elite cyclists.