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Purpose: To evaluate whether changes in lower-limb muscle strength explain changes in walking capacity during 14-week periods of usual care, power training and follow-up for children with spastic cerebral palsy., Methods: Secondary analysis of a previously conducted double-baseline controlled trial of 22 children with spastic cerebral palsy. Generalized estimating equations were used to evaluate the relationships between within-subject changes in isometric muscle strength and walking capacity over 3 periods., Results: Changes in hip abductor strength were associated with changes in the Muscle Power Sprint Test, changes in gastrocnemius and hip abductor strength were associated with changes in the Shuttle Run Test, and changes in gastrocnemius strength were associated with changes in the 1-minute walk test. All associations supported better walking capacity with increased strength., Conclusion: Walking capacity, especially sprint capacity, can be improved by increasing strength by functional power training in this population., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Academy of Pediatric Physical Therapy of the American Physical Therapy Association.)

Background: Muscle weakness is one of the most prevalent symptoms in children with cerebral palsy (CP). Although recent studies show that functional power training can improve strength and functional capacity in young children with CP, effects on specific gait parameters have not previously been reported., Research Question: What are the effects of functional power training on gait in children with CP? Specifically, we investigated effects of training on gait kinematics and spatiotemporal parameters, and whether these were dependent on walking speed., Methods: Ten children with CP (age 5-10 years, GMFCS I-II) participated in a functional power training program. At the start and end of the program, children underwent 3D gait analysis on a treadmill at a gradual range of walking speeds (70-175% of their comfortable walking speed). Multilevel (linear mixed model) analysis was used to evaluate effects pre-post training at different walking velocities., Results: Although children's self-chosen comfortable walking speed improved (0.71 ± 0.25 to 0.85 ± 0.25 m/s, p < .05), effects on gait kinematics at similar speed were limited and only exceeded statistical and clinically meaningful thresholds when children walked at higher walking speed. At fast speeds, improvements up to 5° were found in knee and hip extension during stance (p < .01)., Significance: This study demonstrates that gait kinematics can improve after functional power training, but the magnitude of effects is dependent on walking speed. In this light, improvements are underestimated when evaluating gait at pre-training comfortable walking speed only., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: In children with cerebral palsy (CP), strength training programs to improve walking capacity and participation in activities of daily living are commonly used in clinical practice, despite lacking evidence of its effectiveness. It has been suggested that strength training with high movement velocity could be more effective than traditional resistance training to improve functional abilities such as walking. In a recently published study, we have demonstrated the positive effects of functional high-velocity resistance (power) training on muscle strength and walking capacity in young children with CP. Whether this type of training is also effective in achieving individual predefined goals in daily activities and self-reported mobility limitations, has not yet been described however., Aim: To evaluate the effect of functional power-training on parent-reported mobility and achievement of individual goals on activity and participation level in young children with CP., Design: A double-baseline design was used to compare a 14-week period usual care with a 14-week period of functional power-training (3 times a week) and a follow-up period of 14 weeks., Setting: A rehabilitation center, two special needs schools for children with physical disabilities, and a university medical center outpatient clinic., Population: Twenty-two children with spastic CP (13 bilateral, GMFCS level I [N.=10] and level II [N.=12], mean age 7.5 years [SD 1.8, range 4-10 years]) and their parents participated., Methods: Outcome measures were goal attainment scaling (GAS) of individual daily activity related treatment goals, mobility performance as measured using the Functional Mobility Scale (FMS-5 m, 50 m and 500 m), and the parent-reported Mobility Questionnaire (MobQues)., Results: After power-training, 86% of children achieved or exceeded their goal, compared with 14% in the usual care period (P<.001). The probability of improvement by one point or more on the FMS-500 meter after functional power-training was 10 times higher, compared with the usual care period (Relative Risk=10.0 with 95% CI 1.4 - 71.3). No changes were found in the FMS-5m and FMS-50m categories. Improvement on the MobQues was significantly greater after power-training compared with usual care (7.9% (95% CI 2.7 - 13.0, P=.005)). The improvement in performance in the activities defined in the treatment goals continued during the follow-up period., Conclusions and Clinical Rehabilitation Impact: The results indicated that functional power-training is an effective training to achieve personalized treatment goals for activities in daily life and parent-reported mobility performance in young children with cerebral palsy.

Background: Strength training programs for children with cerebral palsy (CP) showed inconclusive evidence for improving walking, despite improvements in strength. Recent studies have suggested that strength training with high movement velocity is more effective for improving walking than traditional resistance training., Objective: The purpose of this study was to evaluate the effect of functional high-velocity resistance training (power-training) to improve muscle strength and walking capacity of children with CP., Method: Twenty-two children with spastic CP participated (13 bilateral, Gross Motor Function Classification System [GMFCS] level I [n = 10] and II [n = 12], 7.5 years [SD 1.8, range 4-10 years]). Within-subjects changes in a 14-weeks usual care period were compared with changes in a 14-week functional power-training period (in groups, 3×/wk). Outcome measures were the muscle power sprint test (MPST), 1-minute walk test (1MWT), 10-m shuttle run test (SRT), gross motor function (GMFM-66), isometric strength of lower-limb muscles and dynamic ankle plantar flexor strength., Results: Changes during the training period were significantly larger than changes in the usual care period for all outcome measures ( P < .05). Large improvements were found during the training period for walking capacity (ΔMPST [mean]: 27.6 W [95%CI 15.84-39.46, 83% increase], Δ1MWT: 9.4 m [95% CI 4.17-14.68, 13%], ΔSRT: 4.2 [95%CI 2.57-5.83, 56%], ΔGMFM-66: 5.5 [95% CI 3.33-7.74, 7%]) and muscle strength (18%-128%), while outcomes remained stable in the usual care period., Conclusions: The results indicate that functional power-training is an effective training for improving walking capacity in young children with cerebral palsy.

Purpose: To evaluate the effect of functional high-velocity resistance (power) training to improve walking ability of young children with cerebral palsy., Methods: Twenty-two children with bi- or unilateral spastic cerebral palsy, Gross Motor Function Classification System levels I and II, aged 4 to 10 years will be recruited. A double-baseline design will be used to compare a 14-week functional power training (3 times a week) program with a 14-week usual care period and a 14-week follow-up period. The power exercises will be loaded and performed at 50% to 70% of the maximum unloaded speed. Load will be increased when exercises are performed faster than 70% of the unloaded speed. Primary outcomes will be sprinting capacity (15-m Muscle Power Sprint Test) and goal attainment scaling score of walking-related treatment goals. Secondary outcomes will be walking speed (1-min walk test), endurance (10-m shuttle run test), gross motor function, lower-limb strength, and parent-reported mobility.

Introduction: Replacement of the missing clotting factor is the mainstay of hemophilia treatment. Whilst historically many hemophilia patients were infected with blood-borne viruses transmitted via plasma-derived products, nowadays the formation of alloantibodies against the missing clotting factor is the main adverse event of treatment. Areas covered: This paper provides an overview of the current national and international adverse event reporting systems, what these surveillance schemes taught us about side effects of the products presently in use, and elaborates on how to adapt these systems to the challenges we face with the changing treatment landscape. Expert commentary: Treatment of inherited bleeding disorders was accompanied by severe complications in the past, resulting in major morbidity and mortality. Current products are much safer, but still require monitoring via efficient safety surveillance systems. Adverse events are reported in national and international systems. With many new products entering the market, as well as non-factor replacement therapies, new safety issues may arise. It is important to identify potential adverse events early by making surveillance systems suitable to pick up unknown or unexpected effects, and to recognize and communicate patterns of adverse events rapidly.

Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. Spontaneous bleeding shows a predilection for joints, and repeated hemarthroses lead to a disabling condition called hemophilic arthropathy. Treatment of this condition consists of preventing joint bleeding on the one hand and orthopedic surgery as a last resort on the other. Up till now, there is no disease modifying therapy available to fill the gap between these extremes. This review provides an overview of the pathogenesis of hemophilic arthropathy in order to identify potential targets for therapy. Joint bleeding induces synovial inflammation, cartilage degeneration and bone damage. These processes interact with each other and result in a vicious circle. Hemarthrosis promotes synovial hypertrophy and neoangiogenesis, increasing the susceptibility to mechanical damage and subsequent bleeding. The inflamed synovium affects the cartilage, while cartilage is also directly affected by blood via the release of cytokines and metalloproteinases, and via hydroxyl radical formation inducing chondrocyte apoptosis. Apart from the inflammatory pathways, iron plays a pivotal role in this process, as does the fibrinolytic system. Considering its pathogenesis, potential targets for disease modifying therapy in hemophilic arthropathy are iron, inflammation, vascular remodeling, hyperfibrinolysis, bone remodeling and cartilage regeneration. So far, iron chelators, anti-inflammatory therapy, anti-fibrinolytics and bone remodeling agents have demonstrated beneficial effects, predominantly in a preclinical setting. There is still a long way to go before these interventions will translate into clinical practice. The most important challenges are: establishing a universal outcome measure to predict efficacy in humans, and determination of the optimal route and timing to administer disease modifying therapy., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Joint bleeding after (sports) trauma, after major joint surgery, or as seen in hemophilia in general leads to arthropathy. Joint degeneration is considered to result from the direct effects of blood components on cartilage and indirectly from synovial inflammation. Blood-provided proinflammatory cytokines trigger chondrocytes and induce the production of cartilage-degrading proteases. In the presence of erythrocyte-derived iron, cytokines stimulate radical formation in the vicinity of chondrocytes inducing apoptosis. To unravel the role of interleukin (IL) 1β and tumor necrosis factor (TNF) α in the pathogenesis of this blood-induced cartilage damage, the effect of antagonizing these cytokines was examined in human in vitro cultures. Addition of recombinant human IL-1β monoclonal antibody or IL-1 receptor antagonist resulted in a dose- and time-dependent protection of cartilage from blood-induced damage. In higher concentrations, almost complete normalization of cartilage matrix proteoglycan turnover was achieved. This was accompanied by a reduction in IL-1β and IL-6 production in whole blood cultures, whereas TNFα production remained unaffected. Interestingly, addition of a TNFα monoclonal antibody, although demonstrated to inhibit the direct (transient) effects of TNFα on cartilage, exhibited no effect on blood-induced (prolonged) cartilage damage. It is demonstrated that IL-1β is crucial in the development of blood-induced joint damage, whereas TNFα is not. This hierarchical position of IL-1β in blood-induced joint damage warrants studies on targeting IL-1β to potentially prevent joint degeneration after a joint bleed., (© 2015 by The American Society of Hematology.)

Joint damage due to (recurrent) joint bleeding in haemophilia causes major morbidity. Although the exact pathogenesis has not been fully elucidated, a central role for iron is hypothesised. Likewise, in hereditary haemochromatosis joint destruction is caused by iron overload. A comparison between these types of arthropathy could provide more insight in the influence of iron in inducing joint damage. A literature review was performed to compare both disorders with respect to their clinical and histological characteristics, and preclinical studies on the influence of iron on different joint components were reviewed. Similarities in the features of arthropathy in haemochromatosis and haemophilia are cartilage degeneration, subchondral bone changes with osteophyte and cyst formation, and osteoporosis. In both disorders synovial inflammation and proliferation are seen, although this is much more explicit in haemophilia. Other substantial differences are the age at onset, the occurrence of chondrocalcinosis radiographically and calcium pyrophosphate dihydrate deposition disease in haemochromatosis, and a rapid progression with joint deformity and neovascularisation in haemophilia. Preclinical studies demonstrate detrimental effects of iron to all components of the joint, resulting in synovial inflammation and hyperplasia, chondrocyte death, and impaired osteoblast function. These effects, particularly the synovial changes, are aggravated in the presence of a pro-inflammatory signal, which is prominent in haemophilic arthropathy and minimal in haemochromatosis. Additional research is needed to further specify the role of iron as a specific target in treating these types of arthropathy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Evaluation whether biomarkers of joint damage are sensitive to change shortly after a joint bleed in hemophilia patients and in a canine model of blood-induced joint damage., Methods: Blood and urine samples were collected from 10 hemophilia patients after they reported a joint bleed: within 2 days, after 3-5 days, and 12-14 days. Additionally, 90 days after the bleed a blood and urine sample was taken and considered to represent baseline condition. Commercial serum and urine biomarker assays were performed: urinary C-terminal telopeptide of type II collagen (uCTX-II), serum cartilage oligomeric matrix protein (sCOMP), serum cartilage cleavage product C1,2C, and serum chondroitin sulfate 846 (sCS846). The same panel of biomarkers was explored in dogs (n = 7) after induction of a first joint bleed by intra-articular blood injections. Biosamples were collected at baseline, day 2, 1 and 2 weeks later., Results: In hemophilia patients, levels of uCTX-II and sCS846 increased 5 days after joint bleeding when compared with baseline (+52%; P = 0.021 and +14%; P = 0.011, respectively). In dogs, uCTX-II increased statistically significant from day 2 to day 7 (from 75% to 155% of baseline; P = 0.018), and sCOMP from baseline to day 2 (+46%; P = 0.028)., Conclusions: This study demonstrates that biochemical markers of joint tissue damage increase shortly after a single joint bleed, both in humans with established hemophilic arthropathy (HA) and in an animal model of joint damage upon a first joint bleed. Biomarkers might be useful in monitoring the impact of a joint bleed and in evaluation of treatment of such bleeds., (Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Quantifying leg muscle strength in young children with cerebral palsy (CP) is essential for identifying muscle groups for treatment and for monitoring progress., Aim: To study the feasibility, intratester reliability and the optimal test design (number of test occasions and repetitions) of measuring lower-limb strength with handheld dynamometry (HHD) and dynamic ankle plantar flexor strength with the standing heel-rise (SH) test in 3-10 year aged children with CP., Design: Test-retest design., Setting: Rehabilitation centre, special needs school for children with disabilities, and university medical centre., Methods: Knee extensor, hip abductor and calf muscle strength was assessed in 20 ambulatory children with spastic CP (3-5 years [N.=10] and 6-10 years [N.=10]) on two test occasions. Intraclass correlation coefficients (ICC) and Smallest Detectable Differences (SDD) were calculated to determine the optimal test design for detecting changes in strength., Results: All isometric strength tests had acceptable SDDs (9-30%), when taking the mean values of 2-3 test occasions (separate days) and 2-3 repetitions. The one-leg SH test had large SDDs (40-128% for younger group, 23-48% for older group)., Conclusion: Isometric strength (improvements) can only be measured reliably with HHD in young children with CP when the average values over at least 2 test occasions are taken. Reliability of the SH test is not sufficient for measuring individual changes in dynamic muscle strength in the younger children., Clinical Rehabilitation Impact: Results of this study can be used to determine the optimal number of test occasions and repetitions for reliable HHD measurements depending on expected changes, muscle group and age in 3-10 year old children with CP.

A 31-year-old man claimed that he had ingested more than 100 tablets of methylphenidate (10 mg), 20 tablets ofibuprofen (400 mg) and 2 bottles of wine. At admission, signs of sympathomimetic syndrome were observed, including agitation, hallucinations, mydriasis and sinus tachycardia. The patient was treated with activated charcoal and an oral laxative. Given the possibly lethal dose of methylphenidate, the patient was admitted to the intensive care unit for observation. He made a full recovery and was discharged 36 hours after admission. Toxicological analysis indicated a plasma-ethanol concentration of 0.27% and a maximum serum-methylphenidate concentration of 176 microg/l (therapeutic range: 5-40 microg/l). The active metabolite ethylphenidate was also present at toxic concentrations. Treatment of potentially lethal methylphenidate poisoning includes prevention of absorption, careful observation and support of vital functions as necessary.