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.

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.

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.

Mutations in ABCC6 cause pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a heritable disorder of the connective tissue. PXE patients frequently experience visual field loss and skin lesions, and occasionally cardiovascular complications. Histopathological findings reveal calcification of the elastic fibres and abnormalities of the collagen fibrils. Most PXE patients are sporadic, but autosomal recessive and dominant inheritance are also observed. We previously localized the PXE gene to chromosome 16p13.1 (refs 8,9) and constructed a physical map. Here we describe homozygosity mapping in five PXE families and the detection of deletions or mutations in ABCC6 (formerly MRP6) associated with all genetic forms of PXE in seven patients or families.

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.

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.

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.

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.

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.

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.

Previous experience influences pacing during 20 km time trial cycling.

OBJECTIVE: To investigate how experience and feedback influence pacing and performance during time trial cycling. DESIGN: Twenty-nine cyclists performed three 20 km cycling time trials using a Computrainer. The first two time trials (TT1 and TT2) were performed (1) without any performance feedback (n = 10), (2) with accurate performance feedback (n = 10) or (3) with false feedback showing the speed to be 5% greater than the actual speed (n = 9). All participants received full feedback during the third time trial (TT3), and their performance and pacing data were compared against TT2. RESULTS: Completion time, average power and average speed did not change among the false feedback group, but their pacing strategy did change as indicated by a lower average cadence, 89.2 (SD 5.2) vs 96.4 (6.8) rpm, p<0.05, and higher power during the first 5 km (SMD = 39, 36, 36, 27 and 27 W for 1-5 km respectively). Pacing changed among the blind feedback group indicated by a faster completion time, 35.9 (3.1) vs 36.8 (4.4) min, p<0.05, and power increases during the final 5 km (SMD = 14, 13, 18, 23 and 53 W for 16-20 km respectively). No performance or pacing changes were observed among the accurate feedback group. CONCLUSIONS: Pacing is influenced by an interaction between feedback and previous experience. Conscious cognitive processes that lead to ratings of perceived exertion and pacing appear to be influenced by previous experience.

[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.

Growth and mating of Cryptococcus neoformans var. grubii on woody debris.

A total of 36 Cryptococcus neoformans strains originating from South Africa were screened for wood degrading enzymes. All strains tested positive for cellulase activity while none where capable of xylan degradation. Three C. neoformans var. grubii strains, originating from clinical and environmental samples, representing the same genotype (VNI/AFLP1-C. neoformans var. grubii) and MATalpha, were evaluated for growth on debris of two common tree species in South Africa: Acacia mearnsii and Eucalyptus camaldulensis. The mating capability of all the C. neoformans strains was evaluated on similar debris. Strains grown on A. mearnsii yielded substantially greater yeast populations. A total of 26%, 6%, 46%, and 80% of the 36 C. neoformans strains tested were either able to mate or develop filaments when crossed on A. mearnsii and E. camaldulensis debris, V8 juice, and yeast carbon base (YCB) agar, respectively. Filamentation and monokaryotic fruiting was observed in 3% of strains when C. neoformans was cultured on either A. mearnsii, E. camaldulensis debris, or YCB. The results indicate that this fungus is capable of completing its life cycle and can produce basidiospores on woody debris. In the future, these findings should be considered when studying the epidemiology, microbial ecology, and proposed infection process of this global pathogen.

Exercising with reserve: evidence that the central nervous system regulates prolonged exercise performance.

OBJECTIVE: The purpose of this study was to measure the effects of an amphetamine (methylphenidate) on exercise performance at a fixed rating of perceived exertion of 16. METHODS: Eight elite cyclists ingested 10 mg methylphenidate in a randomised, placebo-controlled crossover trial. RESULTS: Compared with placebo, subjects receiving methylphenidate cycled for approximately 32% longer before power output fell to 70% of the starting value. At the equivalent time at which the placebo trial terminated, subjects receiving methylphenidate had significantly higher power outputs, oxygen consumptions, heart rates, ventilatory volumes and blood lactate concentrations although electromyographic activity remained unchanged. The ingestion of a centrally acting stimulant thus allowed subjects to exercise for longer at higher cardiorespiratory and metabolic stress indicating the presence of a muscular reserve in the natural state. CONCLUSIONS: This suggests that endurance performance is not only "limited" by mechanical failure of the exercising muscles ("peripheral fatigue"). Rather performance during prolonged endurance exercise under normal conditions is highly regulated by the central nervous system to ensure that whole-body homeostasis is protected and an emergency reserve is always present.

Exercising with reserve: exercise regulation by perceived exertion in relation to duration of exercise and knowledge of endpoint.

OBJECTIVE: The purpose of this study was to examine ratings of perceived exertion (RPE) and performance during repetitive maximal effort 40 km time trials as well as after an intervention that aimed to decrease certainty about the remaining distance of the exercise bout. In addition, we examined the RPE during exercise bouts of markedly different duration. METHODS: Part 1: 12 well-trained, competitive-level cyclists completed five 40 km time trials. During the final time trial all feedback was withheld until the final kilometre. In addition, to cause confusion about the remaining distance, they were asked to report their RPE at random intervals from 18 km to 38 km. Part 2: 6 well-trained, recreation-level cyclists randomly completed a 5 km, 10 km, 40 km and 100 km time trial. RESULTS: Part 1: Mean RPE increased during the first four trials and decreased during the final trial. The rate of RPE progression increased in linearity during the first four trials and became more conservative in the final trial. These changes were directly related to performance. Part 2: Mean RPE for longer duration trials (40 km, 100 km) were lower during the first half of trial duration but matched those of shorter trials in the final 20%. CONCLUSIONS: Increased familiarity of the exercise bout and certainty about its endpoint are associated with a more aggressive RPE strategy that produces a superior exercise performance. Certainty about the endpoint and the duration of exercise affect both the RPE strategy and performance.

Development of a bio-assay for estrogens using estrogen receptor alpha gene expression by MCF7 cells as biomarker.

Estrogenic endocrine disruptors (EDCs) have been identified in soil, food, air, and water, and may produce adverse health effects in both humans and wildlife. Various in vitro assays, including the E-screen that measures estrogen dependent proliferation of the MCF-7 human breast cancer cell line, have been developed and implemented to screen for environmental estrogenic EDCs. This study describes a new amendment to the well known E-screen. A direct ELISA to quantify ERalpha protein levels on MCF-7 cells cultured in a high through put 96-well format were validated as a biomarker for estrogenicity. The ELISA shows that there is an inverse correlation between ERalpha levels and 17beta-estradiol (E2) concentration (R(2) = 1). The detection range of the assay is between 1 and 1000 nM for E2. Results obtained with the ERalpha ELISA showed a good inverse correlation with total cellular LDH levels that is conventionally used to quantify MCF-7 cell proliferation. This ELISA was employed to assess environmental water extracts for estrogenicity.

The development and validation of a quantitative ELISA for in vivo and in vitro synthesized vitellogenin from mossambicus tilapia (Oreochromis mossambicus).

The induction of vitellogenin (VTG), an egg yolk precursor found in most oviparious vertebrates, has been well established as a valuable biomarker for assessing estrogenic endocrine disruption. Oreochromis mossambicus is a tilapiine species indigenous to Southern Africa and, therefore, represents a potential African bio-indicator for the development of in vitro and in vivo screens for estrogenicity using VTG as biomarker. However, few ELISAs have been developed to quantify tilapia VTG protein levels. In the present study, commercially available VTG antiserum that shows cross reactivity with tilapia VTG was used to set up and validate a quantitative competition ELISA for tilapia VTG. This ELISA has a broad detection range between 80 ng/ml-5.4 microg/ml VTG and is able to detect both in vivo and in vitro synthesized VTG. This ELISA is highly repeatable with intra- and inter-assay variations less than 3.4% at the lowest detection limit.

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.

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.

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.