Children with generalised joint hypermobility and musculoskeletal complaints: state of the art on diagnostics, clinical characteristics, and treatment.

INTRODUCTION: To provide a state of the art on diagnostics, clinical characteristics, and treatment of paediatric generalised joint hypermobility (GJH) and joint hypermobility syndrome (JHS). METHOD: A narrative review was performed regarding diagnostics and clinical characteristics. Effectiveness of treatment was evaluated by systematic review. Searches of Medline and Central were performed and included nonsymptomatic and symptomatic forms of GJH (JHS, collagen diseases). RESULTS: In the last decade, scientific research has accumulated on all domains of the ICF. GJH/JHS can be considered as a clinical entity, which can have serious effects during all stages of life. However research regarding the pathological mechanism has resulted in new potential opportunities for treatment. When regarding the effectiveness of current treatments, the search identified 1318 studies, from which three were included (JHS: n = 2, Osteogenesis Imperfecta: n = 1). According to the best evidence synthesis, there was strong evidence that enhancing physical fitness is an effective treatment for children with JHS. However this was based on only two studies. CONCLUSION: Based on the sparsely available knowledge on intervention studies, future longitudinal studies should focus on the effect of physical activity, fitness, and joint stabilisation. In JHS and chronic pain, the effectiveness of a multidisciplinary approach should be investigated.

Dynamic balance during gait in children and adults with Generalized Joint Hypermobility.

BACKGROUND: The purpose of the study was to investigate if differences of the head and trunk stability and stabilization strategies exist between subjects classified with Generalized Joint Hypermobility and healthy controls during gait. It was hypothesized that joint hypermobility could lead to decreased head and trunk stability and a head stabilization strategy similar to what have been observed in individuals with decreased locomotor performance. METHODS: A comparative study design was used wherein 19 hypermobile children were compared to 19 control children, and 18 hypermobile adults were compared to 18 control adults. The subjects were tested during normal walking and walking on a line. Kinematics of head, shoulder, spine and pelvis rotations were measured by five digital video cameras in order to assess the segmental stability (angular dispersion) and stabilization strategies (anchoring index) in two rotational components: roll and yaw. FINDINGS: Hypermobile children and adults showed decreased lateral trunk stability in both walking conditions. In hypermobile children, it was accompanied with decreased head stability as the head was stabilized by the inferior segment when walking on a line. Several additional differences were observed in stability and stabilization strategies for both children and adults. INTERPRETATION: Stability of the trunk was decreased in hypermobile children and adults. This may be a consequence of decreased stability of the head. Hypermobile children showed a different mode of head stabilization during more demanding locomotor conditions indicating delayed locomotor development. The findings reflect that Generalized Joint Hypermobility probably include motor control deficits.

Skin signs in Ehlers-Danlos syndrome: clinical tests and para-clinical methods.

OBJECTIVE: The criteria for Ehlers-Danlos syndrome (EDS) and the hypermobility syndrome (HMS) should be reliable. Examination for general joint hypermobility has high reliability but there is only sparse information on the reliability of skin tests, and no information on the level of normal skin extensibility. The present study aimed to assess skin signs by means of clinical and para-clinical methods. METHODS: A total of 31 EDS patients and 28 healthy controls were examined blinded and in random order. Inter-examiner analysis of clinical tests for skin extensibility, consistency, scarring, and bruising was performed, followed by analyses of extensibility with the suction cup (SC), consistency with a soft tissue stiffness meter (STSM), and thickness with ultrasonography (US). Semi-quantitative assessment of skin extensibility in healthy controls was incorporated in the tests. RESULTS: The clinical analyses demonstrated kappa values of: 0.72 for extensibility, 0.23 for consistency, 0.53 for scarring, and 0.63 for bruising. Skin extensibility measurements in healthy controls (n = 28) were 2.79 and 2.93 cm (mean + 2 SD), respectively, by the two examiners. There were significant differences between patients with classical-type EDS and controls with respect to skin extensibility by SC (4.91 vs. 12.52 kPa/mm) and skin consistency by STSM (0.59 vs. 0.76 N). We found no difference in skin thickness. CONCLUSION: The reproducibility of the clinical skin tests was substantial to good, apart from the consistency measurements. We suggest that skin consistency is withdrawn as a diagnostic criterion. The upper level for normal skin extensibility should be 3 cm. SC and STSM are promising para-clinical methods, but their diagnostic sensitivity and specificity need to be determined.

Skin extensibility and consistency in patients with Ehlers-Danlos syndrome and benign joint hypermobility syndrome.

OBJECTIVES: The reproducibility of clinical tests for skin extensibility and consistency, essential for differentiating between types of Ehlers-Danlos syndrome (EDS) and benign joint hypermobility syndrome (BJHS), is unknown. Paraclinical methods may provide objective differential diagnostic methods. METHODS: Six EDS, 11 BJHS, and 19 controls completed the trial. We analysed the overall inter-examiner agreement on clinical tests for skin extensibility and consistency, in addition to analyses on suction cup (SC) and soft tissue stiffness meter (STSM) methods. RESULTS: Overall agreement on tests for skin extensibility and consistency varied between 0.44 and 0.72. Extensibility evaluated by SC showed an insignificant difference between EDS patients and controls (p = 0.056). Consistency evaluated by STSM showed significant differences (p = 0.001). CONCLUSIONS: Overall inter-examiner agreement on clinical tests for skin extensibility and consistency was below 0.80, which was required a priori to conduct a reproducibility study. Further refinement of tests and a training phase are necessary. The SC and STSM results are encouraging but must be reproduced in a larger study population.

Inter-examiner reproducibility of tests and criteria for generalized joint hypermobility and benign joint hypermobility syndrome.

OBJECTIVE: To test the reproducibility of tests and criteria for generalized joint hypermobility (GJH) and benign joint hypermobility syndrome (BJHS). METHODS: A standardized protocol for clinical reproducibility studies was followed using a three-phase study (with a training, an overall agreement and a test phase). An overall agreement of at least 0.80 was required to proceed to the test phase. Phases 1, 2 and 3 used 14 patients (with varying degrees of hypermobility), 20 patients (50% cases) and 40 patients (50% cases), respectively. The inclusion criterion for cases was hypermobility (patients with Ehlers-Danlos Syndrome or BJHS) and for controls, non-hypermobility (patients with shoulder and/or back pain); patients were selected from patients' files (phases 1 and 2) or included consecutively from our outpatient clinic (phase 3). RESULTS: The overall agreement in phase 2 was 0.95 for GJH and 0.90 for BJHS. Reproducibility for diagnosing GJH and BJHS in phase 3 showed kappa values of 0.74 and 0.84, respectively. Kappa in the Beighton tests for diagnosing GJH (currently or historically) was generally above 0.80, except for the fifth fingers and elbows (> or = 0.60). In the Brighton tests for diagnosing BJHS, kappa was above 0.73, except for the skin signs (0.63). Lowest kappa was found in the Rotès-Quérol tests, where it was > or = 0.57, except for the right shoulder (0.31). CONCLUSION: We found a good-to-excellent reproducibility of tests and criteria for GJH and BJHS. Future research on the validity of the tests and criteria for joint hypermobility is urgently needed.

Treatment of "frozen shoulder" with distension and glucorticoid compared with glucorticoid alone. A randomised controlled trial.

This study is a comparison of treatments of idiopathic "Frozen Shoulder" (adhesive capsulitis), distension combined with steroid is compared with steroid alone. Evaluation was based on pain scales, analgesic usage, and range of motion outcome scales. Out of one-hundred twenty patients (age, mean 51, range 21-70) that were referred under the diagnosis FS, twenty-six fulfilled the criteria for inclusion in the study, but four patients did not want to participate in the trial, giving a total of 22 patients (age, mean 53, range 40-65) in the study. Patients were randomised by the envelope method. Two patients dropped-out, one in each treatment group thus leaving the study with 20 patients for the final statistical analysis. Eight were treated with steroid alone and 12 with distension combined with steroid. Patients received one treatment per week for a six weeks period with a follow-up at 12 weeks. They were evaluated by pain VAS on function and at rest within the study period, the different ranges of motion (ROM) were measured at inclusion time and subsequent afterwards at 3, 6, and 12 weeks. The VAS outcomes showed no difference between the treatments (VAS-function p=0,1; VAS-rest p=0.1), while in the distension group ROM showed significant improvement in all directions except extension (external p=0.0007, flexion p=0.03, extension p=0,01). The analgesic usage was significantly lower in the group treated with distension at the end of the study (p=0.008). A blinded clinical assessment of ROM also showed significant improvement (p=0.002). It is concluded that distension with steroid can seem to help in management of "Frozen Shoulder". Other studies seems to support the conclusion.

Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials.

OBJECTIVES: Most randomised trials of anticoagulant therapy for suspected acute myocardial infarction have been small and, in some, aspirin and fibrinolytic therapy were not used routinely. A systematic overview (meta-analysis) of their results is needed, in particular to assess the clinical effects of adding heparin to aspirin. DESIGN: Computer aided searches, scrutiny of reference lists, and inquiry of investigators and companies were used to identify potentially eligible studies. On central review, 26 studies were found to involve unconfounded randomised comparisons of anticoagulant therapy versus control in suspected acute myocardial infarction. Additional information on study design and outcome was sought by correspondence with study investigators. SUBJECTS: Patients with suspected acute myocardial infarction. INTERVENTIONS: No routine aspirin was used among about 5000 patients in 21 trials (including half of one small trial) that assessed heparin alone or heparin plus oral anticoagulants, and aspirin was used routinely among 68,000 patients in six trials (including the other half of one small trial) that assessed the addition of intravenous or high dose subcutaneous heparin. MAIN OUTCOME MEASUREMENTS: Death, reinfarction, stroke, pulmonary embolism, and major bleeds (average follow up of about 10 days). RESULTS: In the absence of aspirin, anticoagulant therapy reduced mortality by 25% (SD 8%; 95% confidence interval 10% to 38%; 2P = 0.002), representing 35 (11) fewer deaths per 1000. There were also 10 (4) fewer strokes per 1000 (2P = 0.01), 19 (5) fewer pulmonary emboli per 1000 (2P < 0.001), and non-significantly fewer reinfarctions, with about 13 (5) extra major bleeds per 1000 (2P = 0.01). Similar sized effects were seen with the different anticoagulant regimens studied. In the presence of aspirin, however, heparin reduced mortality by only 6% (SD 3%; 0% to 10%; 2P = 0.03), representing just 5 (2) fewer deaths per 1000. There were 3 (1.3) fewer reinfarctions per 1000 (2P = 0.04) and 1 (0.5) fewer pulmonary emboli per 1000 (2P = 0.01), but there was a small non-significant excess of stroke and a definite excess of 3 (1) major bleeds per 1000 (2P < 0.0001). CONCLUSIONS: The clinical evidence from randomised trials dose not justify the routine addition of either intravenous or subcutaneous heparin to aspirin in the treatment of acute myocardial infarction (irrespective of whether any type of fibrinolytic therapy is used).

Exercises for chronic low back pain: a clinical trial.

Different training models are effective for the treatment of chronic low back pain, but no consensus has been found. Earlier studies have emphasized training of spinal mobility and back strength. To evaluate if other physiological parameters, such as coordination, are of equal importance, we performed a randomized trial on 40 consecutive patients with chronic low back pain. Two training models were compared: 1) intensive training of muscle endurance and 2) muscle training, including coordination. In both groups, training was performed 1 hour twice a week for 3 months. Pain score, disability score, and spinal mobility improved in both training groups without differences between the two groups. Only intensive training of muscle endurance improved isokinetic back muscle strength. At study entry, we found a significant correlation between spinal mobility and dysfunction, but after the training, no correlation was found between improvement of spinal mobility or isokinetic back extension strength and improvement of function or pain level. We conclude that coordination training for patients with chronic low back pain is as equally effective as endurance training.

Supervised endurance exercise training compared to home training after first lumbar diskectomy: a clinical trial.

OBJECTIVE: We performed a randomised trial to evaluate if intensive supervised training of the back should be offered to all patients after a first lumbar diskectomy. METHODS: Forty consecutive patients were, after a first lumbar diskectomy, randomly allocated to 2 groups undergoing "supervised training" twice a week for 3 months in an outpatient clinic or "home training" after 2 hours of instruction. RESULTS: The two rehabilitation models both showed a significant effect on spinal mobility, isokinetic trunk flexion strength, isokinetic trunk extension strength and daily function. These improvements were unchanged at follow up 3 months later. The pain score remained unchanged, however, throughout the trial in both groups. No differences in effect between the two rehabilitation models could be found for any of the assessed parameters. Thirteen patients did not complete the trial, including 9 from the supervised endurance trained group, mainly because of increased pain and reprolaps (n = 4). Four patients dropped out of the home trained group, only one because of increased pain. The differences in drop-out rate and training side effects were, however, not statistically significant. CONCLUSION: We conclude that it is not worthwhile to implement 3 months of supervised intensive endurance training as opposed to home training in all cases of first lumbar diskectomy, although a beneficial effect and better compliance might be found for a selected group of such patients.

Low energy laser therapy in rheumatoid arthritis.

Low energy laser (LEL) is a widely used treatment for a variety of musculoskeletal disorders although convincing documentation of the effect is missing. We have examined the LEL effect on Rheumatoid Arthritis (RA) in a double blind placebo controlled study. Twenty-two patients completed the study (10 receiving LEL treatment) according to the protocol. A significant effect on pain score was found due to LEL treatment, but when data were corrected for disease variation the effect disappeared. No effect of LEL could be demonstrated on the other assessed variables: grip strength, morning stiffness, flexibility, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP). In conclusion, we did not find that LEL had any clinically relevant effects on RA.

[Sarcoidosis presenting as symptomatic myopathy]. / Sarkoidose visende sig alene ved symptomgivende myopati.

We report the case of a 46-year old man who presented with symptomatic myopathy. Muscle biopsy revealed epithelioid granulomas consistent with sarcoidosis. The patient had no symptoms other than those of muscle involvement. He responded well to a moderate dose of corticosteroid. We discuss the differential diagnosis of this rare illness.

Prophylactic effect of self-administered pump-driven subcutaneous IgG infusion in patients with antibody deficiency: a triple-blind cross-over study comparing P-IgG levels of 3 g l-1 versus 6 g l-1.

Eight adult patients with hypoimmunoglobulinaemia were randomly allocated to initiation of low- or high-level IgG-substitution. IgG was administered subcutaneously, at 50 or 150 mg ml-1, 20 ml per infusion, by means of a pocket-portable electric infusion pump. Infusions were given 2 to 4 times weekly for 24 months, with a change of dose regimen after 12 months. The desired plasma IgG levels were reached after a mean lag phase of 3 months (range 1-5 months). The median (and ranges) of the individual mean plasma IgG levels during the ensuing 9-month periods were as follows: high-level period, 6.5 g l-1 (range 6.2-7.8 g l-1); low-level period, 3.2 g l-1 (range 3.0-4.0 g l-1). During the high-level period, compared to the low-level period, there was a significant decrease in the following parameters: 'days in bed at home', 'days missed work' and 'days with fever'. No serious side-effects were observed. It is concluded that a plasma IgG concentration of 6 g l-1 can readily be achieved by subcutaneous IgG substitution, and the prophylactic effect is superior to that obtained with a plasma IgG concentration of 3 g l-1.

Biological assays for interleukin 1 detection. Comparison of human T lymphocyte, murine thymocyte and NOB-1 assays.

Various biological assays are used for qualitative and quantitative measurements of interleukin 1 (IL-1) in supernatants from cell cultures. The purpose of the present study was to compare the specificity and variability of three cellular IL-1 bioassays: the PHA co-stimulatory human T lymphocyte proliferation assay, the PHA co-stimulatory murine thymocyte (THY) proliferation assay, and the 2-step NOB-1 conversion assay. Three different ways of IL-1 unit calculation, based on a semi-logarithmic plot, a double-logarithmic plot, or a probit-analysis plot were also compared. The T lymphocyte assay can be used only to demonstrate qualitative differences in IL-1-like activity, whereas the THY assay is excellent as a semi-quantitative assay, with a low intra-assay variability, but also with a low specificity. The NOB-1 assay is probably more specific with respect to IL-1 measurement, although, with a high intra-assay variance. The THY and the NOB-1 assays both have a high inter-assay variability, and measurement of samples from longitudinal clinical studies must be done in one and the same analysis if quantitative differences are to be illustrated. Probit analysis for unit calculation is recommended. To generate a consensus view as to assay performance, collaborative laboratory studies are needed.

Interleukin 1, but not interleukin 1 inhibitor, is released from human monocytes by immune complexes.

Immune complexes (IC) are believed to play a role in the pathogenesis of some autoimmune diseases in which interleukin 1 (IL-1) and probably other cytokines also take part. This investigation shows that tetanus toxoid-human anti-tetanus toxoid IC induce human monocytes to release IL-1. The activity was identified as being mainly IL-1 beta by molecular size chromatography, isoelectric focusing, and anti-IL-1 beta affinity chromatography. Endotoxins were eliminated by repetitive washing of the IC suspension and by preincubation of IC with polymyxin B. The IL-1-inducing effect of IC was destroyed by heating at 80 degrees C, and it was not blocked by the cytoskeleton inhibitor cytochalasin B. IL-1 inhibitors were not detected in the supernatants.

Salicylazosulfapyridine (Salazopyrin) effect on endotoxin-induced production of interleukin-1-like factor from human monocytes in vitro.

Monocytes (M phi) were simultaneously preincubated with salicylazosulfapyridine (Salazopyrin) (SAZ), 0.78-12.5 mM, and lipopolysaccharide from E. coli, 1 X 10(-9) g/ml. Presence of SAZ resulted in a dose-dependent decrease in the co-stimulatory activity in M phi culture supernatants, corresponding to a 50% reduction by SAZ, 2.0 mM. Co-stimulatory activity was estimated by the mitogen-induced thymocyte proliferation assay (THY assay). The results indicate an inhibitory effect of SAZ in vitro on the production of IL-1 and other possible co-stimulatory factors. This inhibitory effect was not due to decreased M phi viability, production of suppressive substances, or to drug interference with the THY assay. Equimolar preincubations with sulfapyridine, 5-aminosalicylic acid and N-acety-1-5-aminosalicylic acid were without effect on the production of co-stimulatory factors.

Dialysis membrane interference in human T-lymphocyte proliferation assays.

Dialysis with cellulose acetate membranes is frequently performed in the laboratory in order to remove possible interfering substances from various biological fluids. However, retentates from dialysis, compared to undialysed samples, inhibited the sub-maximal phytohaemagglutinin-induced proliferation of human T-lymphocytes. This inhibition was accentuated when the samples to be dialysed contained normal human serum. Four different membranes all produced similar degrees of inhibition when samples of varied composition were dialysed. It is unlikely that the inhibitory effect on the MNC/M phi-DC proliferations is due to glycerol, heavy metals or sulphuric compounds in the retentate. The most likely explanation of the inhibition is liberation of a substance from the membrane to the retentate during dialysis. Our experiments suggested two solutions. Simply boiling the dialysis tubing--internal as well as external--solved the problem. Another way to circumvent the problem is to use a commercially available dialysis membrane which is completely devoid of this inhibitory effect.