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We treated 11 young children (3-6 years old) who had uncomplicated femoral shaft fractures primarily with an external fixator. 9 children were available for follow-up and were evaluated for the amount of overgrowth and rotational deformity. All underwent a clinical examination and an MRI after mean 21 (13-25) months. The mean overgrowth was 0.4 (-0.3 - -1.1) cm and the anteversion angle showed a mean increase of 12°, as compared to the contralateral femur. In 5 children with an anteversion angle difference of 10° or more, a second MRI was done 4 years after the trauma. The mean anteversion angle difference of the femora in these 5 children had diminished from 15° on the first MRI to 7.4° on the second. 3 of the 5 children had a full correction of their rotational deformity. Growth did not correct the rotational deformity in the oldest child in this group. [ABSTRACT FROM AUTHOR]

Bone is a complex natural material with a complex hierarchical multiscale organization, crucial to perform its functions. Ultrastructural analysis of bone is crucial for our understanding of cell to cell communication, the healthy or pathological composition of bone tissue, and its three-dimensional (3D) organization. A variety of techniques has been used to analyze bone tissue. This article describes a combined approach of optical, scanning electron, and transmission electron microscopy for the ultrastructural analysis of bone from the nanoscale to the macroscale, as illustrated by two pathological bone tissues. By following a top-down approach to investigate the multiscale organization of pathological bones, quantitative estimates were made in terms of calcium content, nearest neighbor distances of osteocytes, canaliculi diameter, ordering, and D-spacing of the collagen fibrils, and the orientation of intrafibrillar minerals which enable us to observe the fine structural details. We identify and discuss a series of two-dimensional (2D) and 3D imaging techniques that can be used to characterize bone tissue. By doing so we demonstrate that, while 2D imaging techniques provide comparable information from pathological bone tissues, significantly different structural details are observed upon analyzing the pathological bone tissues in 3D. Finally, particular attention is paid to sample preparation for and quantitative processing of data from electron microscopic analysis., (© 2021 The Authors. Microscopy Research and Technique published by Wiley Periodicals LLC.)

Background and purpose - Involvement of patient organizations is steadily increasing in guidelines for treatment of various diseases and conditions for better care from the patient's viewpoint and better comparability of outcomes. For this reason, the Osteogenesis Imperfecta Federation Europe and the Care4BrittleBones Foundation convened an interdisciplinary task force of 3 members from patient organizations and 12 healthcare professionals from recognized centers for interdisciplinary care for children and adults with osteogenesis imperfecta (OI) to develop guidelines for a basic roadmap to surgery in OI.Methods - All information from 9 telephone conferences, expert consultations, and face-to-face meetings during the International Conference for Quality of Life for Osteogenesis Imperfecta 2019 was used by the task force to define themes and associated recommendations.Results - Consensus on recommendations was reached within 4 themes: the interdisciplinary approach, the surgical decision-making conversation, surgical technique guidelines for OI, and the feedback loop after surgery.Interpretation - The basic guidelines of this roadmap for the interdisciplinary approach to surgical care in children and adults with OI is expected to improve standardization of clinical practice and comparability of outcomes across treatment centers.

Purpose: The correlation between the degree of developmental hip dysplasia (DDH) measured on ultrasound images compared with that measured on radiographs is not clear. Most studies have compared ultrasonography (US) and radiographic images made at different times of follow-up. In this study the correlation between US images and radiographs of the hip made on the same day was evaluated., Methods: US images and radiographs of both hips of 74 infants, who were treated for stable DDH, were reviewed in a retrospective study. Only infants who had an US examination and a radiograph on the same day were included., Results: The correlation between α-angle of Graf and femoral head coverage on US was strong (p ≤ 0.0001). Weak correlations were found between the acetabular index of Tönnis on radiographs and α-angle of Graf on US (p = 0.049) and between acetabular index of Tönnis on radiographs and femoral head coverage of Morin on US (p = 0.100)., Conclusion: This study reports on the correlation between US and radiographic imaging outcomes, both made on the same day in patients for treatment and follow-up of DDH., Level of Evidence: IV.

The majority of patients with osteogenesis imperfecta (OI) have mutations in the COL1A1 or COL1A2 gene, which has consequences for the composition of the bone matrix and bone architecture. The mutations result in overmodified collagen molecules, thinner collagen fibres and hypermineralization of bone tissue at a bone matrix level. Trabecular bone in OI is characterized by a lower trabecular number and connectivity as well as a lower trabecular thickness and volumetric bone mass. Cortical bone shows a decreased cortical thickness with less mechanical anisotropy and an increased pore percentage as a result of increased osteocyte lacunae and vascular porosity. Most OI patients have mutations at different locations in the COL1 gene. Disease severity in OI is probably partly determined by the nature of the primary collagen defect and its location with respect to the C-terminus of the collagen protein. The overall bone biomechanics result in a relatively weak and brittle structure. Since this is a result of all of the above-mentioned factors as well as their interactions, there is considerable variation between patients, and accurate prediction on bone strength in the individual patient with OI is difficult. Current treatment of OI focuses on adequate vitamin-D levels and interventions in the bone turnover cycle with bisphosphonates. Bisphosphonates increase bone mineral density, but the evidence on improvement of clinical status remains limited. Effects of newer drugs such as antibodies against RANKL and sclerostin are currently under investigation. This paper was written under the guidance of the Study Group Genetics and Metabolic Diseases of the European Paediatric Orthopaedic Society.

A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome., (© 2017 Wiley Periodicals, Inc.)

Background: Dysostosis multiplex contributes substantially to morbidity in patients with Hurler syndrome (mucopolysaccharidosis type I Hurler phenotype [MPS I-H]), even after successful hematopoietic stem cell transplantation (HSCT). One of the hallmarks of dysostosis multiplex in MPS I-H is hip dysplasia, which often requires surgical intervention. We sought to describe in detail the course of hip dysplasia in this group of patients, as assessed by radiographic analysis, and to identify potential outcome predictors., Methods: Longitudinal data were obtained from digitally scored pelvic radiographs of patients with MPS I-H using OrthoGon software for parameters including, but not limited to, the acetabular index, migration percentage, Smith ratio, and neck-shaft angle. Scoring was performed independently by two blinded observers. Additional information on genotype, enzyme replacement therapy pre-HSCT, donor chimerism, and enzyme activity post-HSCT were obtained. General trends and potential correlations were calculated with mixed-model statistics., Results: Fifty-two patients (192 radiographs) were included in this analysis. Intraobserver and interobserver variation analysis showed an intraclass correlation coefficient ranging from 0.78 to 1.00. Among the twenty-one patients with follow-up beyond the age of five years, the acetabular index was in the range of severe hip dysplasia in up to 86% of the patients. Severe coxa valga was seen in 91% of the patients. Lateral and superior femoral displacement were highly prevalent, with the migration percentage outside the reference range in up to 96% of the patients. Finally, anterior pelvic tilt increased with age (p = 0.001). No correlations were identified between clinical parameters and radiographic findings., Conclusions: Our study shows that progressive acetabular dysplasia as well as coxa valga and hip displacement are highly prevalent and progressive over time in patients with MPS I-H, despite successful HSCT. These data may provide essential natural history determinations for the assessment of efficacy of new therapeutic strategies aimed at improving skeletal outcomes in patients with MPS I-H., (Copyright © 2016 by The Journal of Bone and Joint Surgery, Incorporated.)

Background/aims: To systematically assess contemporary knowledge regarding the effectiveness and safety of bisphosphonates (BPs) in children with osteogenesis imperfecta (OI)., Methods: PubMed/MEDLINE, Embase, and Cochrane were searched for eligible articles up to June 2014. Studies eligible for inclusion were (randomized) controlled trials assessing the effects of BPs in children with OI. Methodological quality was assessed independently by 4 reviewers using the Cochrane Collaboration's tool for risk of bias., Results: Ten studies (519 children) were included. Four studies (40%) showed a low risk of bias. All studies investigating lumbar spine areal bone mineral density indicated a significant increase as a result of BP treatment. Most studies observed a significant decrease in fracture incidence. The most frequently reported adverse events were gastrointestinal complaints, fever, and muscle soreness. A significant decrease in (bone) pain due to BP treatment was observed in more than half of the studies. Most studies measuring urinary markers of bone resorption reported a significant decrease. The majority of studies with intravenous treatment showed a significant increase in lumbar projection area, whereas studies with oral treatment did not., Conclusions: Treatment with oral or intravenous BPs in children with OI results in an increase in bone mineral density and seems to be safe and well tolerated., (© 2015 S. Karger AG, Basel.)

Background and Purpose: Osteogenesis imperfecta (OI) is a heritable disorder of connective tissue caused by a defect in collagen type I synthesis. For bone, this includes fragility, low bone mass, and progressive skeletal deformities, which can result in various degrees of short stature. The purpose of this study was to investigate development of bone mineral density in children with OI., Patients and Methods: Development of lumbar bone mineral density was studied retrospectively in a cohort of 74 children with OI. Mean age was 16.3 years (SD 4.3). In 52 children, repeated measurements were available. Mean age at the start of measurement was 8.8 years (SD 4.1), and mean follow-up was 9 years (SD 2.7). A longitudinal data analysis was performed. In the total cohort (74 children), a cross-sectional analysis was performed with the latest-measured BMD. Age at the latest BMD measurement was almost equal for girls and boys: 17.4 and 17.7 years respectively., Result: Mean annual increase in BMD in the 52 children was 0.038 g/cm(2)/year (SD 0.024). Annual increase in BMD was statistically significantly higher in girls, in both the unadjusted and adjusted analysis. In cross-sectional analysis, in the whole cohort the latest-measured lumbar BMD was significantly higher in girls, in the children with OI of type I, in walkers, and in those who were older, in both unadjusted and adjusted analysis., Interpretation: During 9 years of follow-up, there appeared to be an increase in bone mineral density, which was most pronounced in girls. One possible explanation might be a later growth spurt and older age at peak bone mass in boys.

Ultrasound screening for developmental dysplasia of the hip (DDH) is an innovation in preventive child health care in the Netherlands. Parental participation in the screening will be essential for the success of implementation of the screening. The aim of the current study was to investigate whether psychosocial factors (attitude, subjective norm, self-efficacy, perceived susceptibility, perceived severity, perceived effectiveness) predicted parental participation in the screening. A cross-sectional survey was conducted. Using a questionnaire, several background variables (organization, sociodemographic variables, and knowledge) and psychosocial variables were collected. Blockwise logistic regression was used to analyze the relations. A total of 703 questionnaires of participating parents (response 61.7%) and 393 questionnaires of nonparticipating parents were received (response 37.2%). When controlling for the background variables, attitude, subjective norm, self-efficacy, perceived susceptibility, and perceived effectiveness predicted parental participation in the screening (p < .05). Perceived severity of the dysplasia did not predict participation (p > .05). Psychosocial determinants influenced parental participation in the ultrasound screening for DDH. Emphasizing the positive aspects of the screening, highlighting the effectiveness, removing practical barriers, and being conscious of the influential role of child health care professionals on decision making are areas to focus on when organizing the ultrasound screening for DDH. Health care policy decision makers and child health care professionals should consider these determinants in order to stimulate parental participation., (PsycINFO Database Record (c) 2013 APA, all rights reserved.)

Purpose: The aim of this cross-sectional cohort study is to describe the incidence of joint laxity and the correlation between joint laxity and radiological migration of the hip in children with Down syndrome., Methods: Sixty-five children (2-19 years) with Down's syndrome were examined for joint laxity. For each subject, laxity scores for joints were carried out with the Bulbena method. Plane pelvic radiographs were used to determine the migration of the hip, according to Reimer's migration index., Results: In this study, 26 out of 65 children with Down's syndrome (40 %) were diagnosed with general joint laxity. On the radiographs of the hips we found a mean Reimer's Migration Index of 5.2 % for all the subjects. Children with general joint laxity showed a lower Reimer's Migration Index (2.1 %). No significant correlation was found between general joint laxity and migration of the hip., Conclusions: This study showed no relationship between joint laxity and migration of the hip in children with Down's syndrome. This implicates that we were not able to prove that joint laxity is the major factor in developing hip migration in children with Down's syndrome.

Prior research has shown ultrasound (US) screening for developmental dysplasia of the hip (DDH) in preventive child health care to be more effective than the current screening method. In the present study, 3-month-old infants were screened for DDH with US. The objective of this study was to examine parental satisfaction with the screening and determinants that affect satisfaction. Parental satisfaction was measured using a questionnaire. Independent variables included socio-demographic determinants, structure, process and outcome-related determinants and the meeting of expectations. Satisfaction with the screening was high. Parents who perceived the screener as competent, had enough time to ask questions, perceived the proceeding as fluent, perceived a low burden on their infant and whose expectations were met, were more likely to be satisfied. Satisfaction was influenced by process-related factors and not by factors related to the structure and the outcome of the screening. Good information provision before the screening and communication during the screening are means by which parental satisfaction can be influenced positively.

The use of ultrasound (US) screening for developmental dysplasia of the hip (DDH) is an innovation in preventive child health care in the Netherlands. What is not known is whether parents will accept this screening method and will actually participate in it. It is widely known that health behaviors can be influenced by the framing of information. The objective of this study was to examine the influence of a gain- versus loss-framed brochure on parental participation in US screening for DDH. In total, 4150 parents of infants born between August 2007 and December 2008 received either a gain-framed or a loss-framed brochure. Parents could participate in the screening when their infant was 3 months old. The participation rate in the US screening was 74.3%. In contrast to the predictions of prospect theory, the results indicated that parents who had received the gain-framed message were more likely to participate in the screening compared to parents who had received the loss-framed message. This effect may be explained by the low risk perception of parents and by the possibility that the screening was perceived as a health-affirming behavior rather than an illness-detecting behavior. To increase participation rates, it is recommended that parents be informed about the positive aspects of partaking in screening for DDH.

Objective: The introduction of hematopoietic stem cell transplantation (HSCT) has significantly improved the life-span of Hurler patients (mucopolysaccharidosis type I-H, MPS I-H). Yet, the musculoskeletal manifestations seem largely unresponsive to HSCT. In order to facilitate evidence based management, the aim of the current study was to give a systematic overview of the orthopaedic complications and motor functioning of Hurler's patients after HSCT., Methods: A systematic review was conducted of the medical literature published from January 1981 to June 2010. Two reviewers independently assessed all eligible citations, as identified from the Pubmed and Embase databases. A pre-developed data extraction form was used to systematically collect information on the prevalence of radiological and clinical signs, and on the orthopaedic treatments and outcomes., Results: A total of 32 studies, including 399 patient reports were identified. The most frequent musculoskeletal abnormalities were odontoid hypoplasia (72%), thoracolumbar kyphosis (81%), genu valgum (70%), hip dysplasia (90%) and carpal tunnel syndrome (63%), which were often treated surgically during the first decade of life. The overall complication rate of surgical interventions was 13.5%. Motor functioning was further hampered due to reduced joint mobility, hand dexterity, motor development and longitudinal growth., Conclusion: Stem cell transplantation does not halt the progression of a large range of disabling musculoskeletal abnormalities in Hurler's disease. Although prospective data on the quantification, progression and treatment of these deformities were very limited, early surgical intervention is often advocated. Prospective data collection will be mandatory to achieve better evidence on the effect of treatment strategies.

Introduction: Bisphosphonates are currently the medical treatment most often used in children with osteogenesis imperfecta (OI). The purpose of this retrospective pre-post study was to evaluate the efficacy of treatment with bisphosphonates. We measured the effect by evaluating the number of outpatient department consultations and operative interventions before and after treatment with bisphosphonates in children with OI., Methods and Materials: Outpatient department consultation and operative intervention frequencies before and after treatment with bisphosphonates were registered. Children who had at least 2 years of medical records before treatment and at least 2 years after treatment were used in this study., Results: Of 118 children who were treated with bisphosphonates, 51 (23 boys and 28 girls) fulfilled the inclusion criteria. Statistical analysis revealed a significant decrease in outpatient department consultations (P < 0.000) and operative intervention (P < 0.003) before and after bisphosphonate treatment., Conclusion: The pre-post design of our study shows a significant reduction of the number of outpatient department consultations and operative interventions in patients with OI after treatment with bisphosphonates.

Background: Transinguinal sonography can be used to demonstrate the position of the femoral head after reduction of a dislocated hip., Objective: To determine whether transinguinal sonography can replace radiography and CT in the follow-up after reduction of a hip dislocation?, Materials and Methods: Thirty-three children with 39 dislocated hips were followed up with sonography after reduction and immobilization in a spica cast. In cases of an abnormal position a CT scan was advised. A pelvic radiograph at the end of treatment served as an indicator that no dislocations were missed during the previous sonographic examinations., Results: The repositioned hips were examined on 138 occasions. Twenty-four examinations were abnormal and CT scanning was performed on 11 occasions. In four children additional CT was done because a recurrent dislocation was suspected or because sonography was difficult to perform. No dislocations were demonstrated. In five children a recurrent dislocation was suspected, on one or more occasions. In all but one child a CT scan was performed that confirmed the dislocation., Conclusion: Transinguinal sonography is well-suited to demonstrate a normal position of the femoral head in a spica cast. Transinguinal sonography decreases the number of radiographs and CT scans and reduces the exposure to ionizing radiation.

Background: A research study in the Netherlands showed that general ultrasound (US) screening was cost-effective in the detection of developmental dysplasia of the hip (DDH). This study was followed by a pilot implementation study. Part of this pilot implementation study is to investigate whether professionals of the infant health care (IHC) system, with no previous US experience, would be able to perform US of the hip., Objective: This study looks at health care worker ability to classify US images into a modified Graf system., Materials and Methods: After theoretical and practical training, seven nurses and physicians of the participating IHC centers reported their findings on sonographic images of 80 children. This was repeated five months later. From the two evaluation moments the intraobserver agreement and the interobserver agreement was determined., Results: The average estimated interobserver Cohen's kappa for both sessions was for nurses 0.6 and for physicians 0.5. The second evaluation showed a decrease from an average of 4.3% missed cases per screener to 2.3% and an increase of an average of 5% false positives per screener to 9.1%., Conclusion: The inter- and intra-observer agreement is comparable to similar studies in which the participants had a professional background in US examination. The level of agreement of the trainees in the perspective of the screening process was considered sufficient for the pilot implementation project.

Background: Implementation of medical interventions may vary with organization and available capacity. The influence of this source of variability on the cost-effectiveness can be evaluated by computer simulation following a carefully designed experimental design. We used this approach as part of a national implementation study of ultrasonographic infant screening for developmental dysplasia of the hip (DDH)., Methods: First, workflow and performance of the current screening program (physical examination) was analyzed. Then, experimental variables, i.e., relevant entities in the workflow of screening, were defined with varying levels to describe alternative implementation models. To determine the relevant levels literature and interviews among professional stakeholders are used. Finally, cost-effectiveness ratios (inclusive of sensitivity analyses) for the range of implementation scenarios were calculated., Results: The four experimental variables for implementation were: 1) location of the consultation, 2) integrated with regular consultation or not, 3) number of ultrasound machines and 4) discipline of the screener. With respective numbers of levels of 3,2,3,4 in total 72 possible scenarios were identified. In our model experimental variables related to the number of available ultrasound machines and the necessity of an extra consultation influenced the cost-effectiveness most., Conclusions: Better information comes available for choosing optimised implementation strategies where organizational and capacity variables are important using the combination of simulation models and an experimental design. Information to determine the levels of experimental variables can be extracted from the literature or directly from experts.

Background: It is increasingly recognized that healthcare is a complex system with limited resources and many interacting sources of both positive and negative feedback. Discrete-event simulation (DES) is a tool that readily accommodates questions of capacity planning, throughput management and interacting resources. As a result the use of DES in informing healthcare decision making is increasing. However, understanding when and how to build a DES model and use it for policy making is not yet a common knowledge., Methods: The steps in building a DES model will be demonstrated using a real-world example, i.e., pediatric ultrasound screening for hip dysplasia. The main components of a DES model such as entities, resources and queues will be introduced and we will examine questions such as referral schedule, number of ultrasound machines and type of screeners and how these entities interact. Finally a review of the statistical techniques appropriate to DES will be provided., Conclusion: Discrete-event simulation is a valuable tool in the policymakers armentarium. It can be used effectively to analyze and understand complex healthcare systems and policy problems such as population screening.

Lysosomal storage disorders (LSDs), a heterogeneous group of inborn metabolic disorders, are far more common than most doctors presume. Although patients with a severe LSD subtype are often readily diagnosed, the more attenuated subtypes are frequently missed or diagnosis is significantly delayed. The presenting manifestations often involve the bones and/or joints and therefore these patients are frequently under specialist care by (paediatric) rheumatologists, receiving inadequate treatment. Since effective disease-specific treatments, including enzyme replacement therapy and stem cell transplantation, have become available for certain LSDs and timely initiation of these treatments is necessary to prevent the development of severe, disabling and irreversible manifestations, early diagnosis has become essential. The challenge is to raise awareness for better recognition of the presenting signs and symptoms of LSDs by all doctors who may encounter these patients, including rheumatologists.

Unlabelled: In this double-blind randomised placebo-controlled trial it was investigated during a two-year follow-up whether oral bisphosphonates (Olpadronate 10 mg/m2/day) influence quality of life in children with osteogenesis imperfecta (OI). Thirty-four children with OI (classified according to Sillence criteria), aged 3 to 18 years of age, with a restricted level of ambulation were included. Randomisation was performed using a list of computer generated random numbers to allocate patients to receive Olpadronate or placebo. Quality of life was measured using self-perception profile for children (SPPC) and health-utility index (HUI). Differences between baseline measurements and measurements at two years follow-up were analysed within the Olpadronate and placebo group using a student's t-test. Differences in HUI and SPPC regression coefficients were analysed by random-effects repeated measures analysis (SAS, Proc Mixed, version 8.2), adjusted for age, gender and type of OI. Within the Olpadronate group there was a significant decrease in pain utility; however, difference in six months' regression coefficients between the placebo and Olpadronate group were not significant. Within the placebo group there was a significant increase in scholastic competence and behavioural conduct. The item behavioural conduct showed a steeper annual regression coefficient favourable for the placebo group. In the other SPPC items none of the annual regression coefficients showed a significant difference between the Olpadronate and the placebo group., Conclusion: We found only slight differences in quality of life in favour of the bisphosphonate group. A small but not significant decrease in pain was detected in the bisphosphonate group.

Objective: To study in children with achondroplasia the response to exercise and muscle strength compared with healthy peers and to describe the relation between exercise capacity, anthropometric factors, and physical activity., Study Design: Patients (7 boys and 10 girls; mean age, 11.8 +/- 3.3 years) with achondroplasia performed a maximal treadmill exercise test. Anthropometric variables and muscle strength were measured and compared with the general population. The level of everyday physical activity was measured by using a diary. Functional ability was measured by using the Activity Scale for Kids., Results: The exercise capacity of the children with achondroplasia was significantly reduced compared with reference values. All anthropometrical measurements differed significantly from reference values. There was a decrease in muscle strength in almost all muscle groups. We found a reduced physical activity level and impairments in functional ability., Conclusions: Cardiopulmonary exercise capacity and muscle strength in children with achondroplasia was reduced compared with reference values. Children with achondroplasia have a unique response to exercise. Clinicians should take these characteristic differences into account when the exercise capacity of subjects with achondroplasia is being tested.

Objective: To describe the clinical features, osseal characteristics, and collagen biochemistry in children who attended our clinic with predominantly generalized hypomobility of the joints, in combination with musculoskeletal complaints or abnormal walking, and no known syndrome or known rheumatic, neurologic, skeletal, metabolic, or connective tissue disorder was present., Methods: Nineteen children who attended the Children's Hospital of the University Medical Center Utrecht for generalized hypomobility of the joints (mean age: 11.6; standard deviation: 2.7), in combination with musculoskeletal complaints or abnormal walking as primary complaints (symptomatic generalized hypomobility [SGH]), were compared with an age-matched reference group of 284 healthy children with normal mobility of the joints. Anthropometrics, range of joint motion, muscle strength, exercise tolerance, motor development, quantitative ultrasound measurements of bone, and degradation products of collagen in urine were studied. Collagen modifications were determined in skin biopsies of 3 children and in hypertrophic scar tissue of another child, all with SGH., Results: The range of joint motion was significantly decreased in almost all joints of all 19 children and after adjustment for age, gender, body weight, and height, significantly lower than that of the reference group (-108.3 degrees; 95% confidence interval [CI]: -136.9 to -79.8). Quantitative ultrasound measurements as well as urinary pyridinoline cross-link levels were, after adjustment for possible confounders, significantly lower in SGH children (broad-band ultrasound attenuation: -9.6 dB/MHz [95% CI: -17.4 to -1.9]; speed of sound: -25.0 m/s [95% CI: -39.7 to -10.3]; hydroxylysylpyridinoline: -50.1 micromol/mmol [95% CI: -87.6 to -12.6], lysylpyridinoline: -21.3 micromol/mmol [95% CI: -34.0 to -8.6]). An increased amount of pyridinoline cross-links per collagen molecule was observed in skin and hypertrophic scar tissue, in combination with increased amounts of collagen., Conclusion: SGH in children is considered a new clinical entity with specific clinical characteristics and might be related to an increased stiffness of connective tissue as a result of higher amounts of collagen with increased cross-linking.

Objective: Glucocorticoid treatment of children often leads to growth retardation, and the precise target(s) in the growth plate responsible for this effect are unknown. Angiogenesis is an important part of the endochondral ossification process, and VEGF expressed in the growth plate is essential for proper angiogenesis to occur. Since glucocorticoid treatment down-regulates VEGF expression in cultured chondrocytes, we hypothesized that in vivo glucocorticoid treatment could result in VEGF down-regulation in the growth plate and disturbed angiogenesis, thus contributing to the growth retardation., Design: We treated 6-week-old prepubertal piglets (10 kg) for 5 days with prednisolone (50 mg/day). Tibial growth plate sections were studied for apoptosis and the expression of VEGF protein and mRNA and MMP-9 protein. Capillaries in the metaphysis were visualized by CD31 immunostaining. Growth plate morphology (width of various zones) was determined by interactive measurements on hematoxylin/eosin stained sections and apoptotic cells were detected by TUNEL assay., Results: In the prednisolone-treated animals, the total width of the growth plate decreased to 81% of controls (P<0.02), which was explained by a decrease of the width of the proliferative zone to 73% (P<0.05). The treatment had no effect on the orderly organization of the chondrocyte columns. In the growth plates of control animals, apoptosis was shown in 5.8% of the hypertrophic chondrocytes and was limited to the terminal hypertrophic chondrocytes. In prednisolone-treated animals, 40.5% of the hypertrophic chondrocytes was apoptotic (P<0.02), with apoptotic chondrocytes also appearing higher in the hypertrophic zone. We observed fewer capillaries and loss of their parallel organization in the metaphysis in the prednisolone-treated animals. The capillaries were shorter and chaotic in appearance. In contrast to controls, in prednisolone-treated animals VEGF mRNA and protein could not be detected in the hypertrophic zone of the growth plate. Trabecular bone length in the primary spongiosa was also diminished by the treatment. No changes were observed in the expression pattern of MMP-9, a matrix metalloproteinase, which is also important for angiogenesis and bone formation., Conclusions: These results indicate that short-term glucocorticoid treatment of growing piglets severely disturbs the width of the growth plate, apoptosis of chondrocytes, VEGF expression by hypertrophic chondrocytes, the normal invasion of blood vessels from the metaphysis to the growth plate and bone formation at the chondro-osseous junction. These effects could alter the dynamics of endochondral ossification and thus contribute to glucocorticoid-induced growth retardation.

Clinical studies with bisphosphonates in children with osteogenesis imperfecta (OI) show an increase in BMD and a decrease in fracture rate. Bone strength in children with OI is not only influenced by changes in BMD but also by changes in collagen I structure of the organic bone matrix. Therefore, we studied the interaction between these two factors in a cross-sectional, single center study including 54 children. We assumed that vertebral deformities in OI represent an unbalance between load and bone strength. Body weight was considered to be a well quantifiable load on vertebral bodies. BMD served as a marker, representing the amount of bone tissue available for vertebral load bearing, and the Sillence classification, either type I or III/IV, as a marker representing the quality of the organic bone matrix. Independent associations were observed between the prevalence of vertebral deformities and (1) Sillence type (OR: 5.7, 95%Cl:1.2-26.8), (2) BMD (OR: 0.003, 95%Cl: 0-0.25) and (3) body weight (OR: 1.15, 95%Cl: 1.05-1.25). Regarding the anthropometrical differences among the different types of OI, the BMD/body weight ratio was introduced to evaluate the BMD in relation to body size. Prevalent vertebral deformities were associated with low BMD/body weight ratios (OR: 0.04, 95%Cl: 0.008-0.2) in OI type I, but no association was found in type III/IV. It was concluded that BMD and Sillence type have independent relationships with vertebral deformities. The BMD/body weight ratio correlates with vertebral deformities in children with OI type I. Its meaning in types III/IV needs further research with larger samples because of the relatively high prevalence of vertebral deformities in this group.

Background: Blood pressure, particularly pulse pressure, is associated with arterial wall stiffness, but little is known about its relation to stiffness of other parts of the body. We examined the extent to which blood pressure levels in young healthy children are related to stiffness of various tissues., Methods: In November 2000, we studied 95 healthy prepubertal children (41 boys and 54 girls, within age range 8-10 years) from two primary schools in the city of Zeist, The Netherlands. Systolic and diastolic blood pressure and pulse pressure were analyzed in relation to various tissue indicators of stiffness, including active joint mobility and skin extensibility. All results were adjusted for age, sex, body height, body weight and muscle strength as possible confounders., Results: Diastolic blood pressure was lower with increased active joint mobility (multivariate generalized linear regression coefficient = -4.5 mmHg per standard deviation [SD] joint mobility; 95% confidence interval [CI] = -7.8 to -1.2). Pulse pressure was lower with increased skin extensibility (-3.2 mmHg per SD skin extensibility; CI = -5.2 to -1.1), through a higher diastolic blood pressure (2.0 mmHg per SD skin extensibility; CI = 0.2-3.9) and possibly lower systolic blood pressure (-0.8 mmHg per SD skin extensibility; CI = -3.5 to 1.9). These associations were mutually independent. Additional adjustment for reported musculoskeletal problems or physical activity levels did not materially change the findings., Conclusions: Our findings support the hypothesis that constitutional stiffness of body tissues may be associated with blood pressure levels and eventually cardiovascular risk.

Objectives: Children with generalized hypermobility of the joints and musculoskeletal complaints frequently visit pediatric clinics, but many show no currently known collagen or other possibly related diseases. Whether the symptoms are confined to the musculoskeletal system is unknown. We assessed whether such children have detectable differences in laxity of connective tissue present in organ systems other than joints. We also assessed whether children with generalized joint hypermobility and musculoskeletal complaints have more profound systemic changes in connective tissue of various organ systems as compared with children with generalized joint hypermobility without musculoskeletal complaints., Methods: Anthropometrics, range of joint motion, muscle strength, skin extensibility, blood pressure, quantitative ultrasound measurements of bone, and degradation products of collagen were studied in 15 prepubertal children with generalized joint hypermobility and musculoskeletal complaints and compared with a population-based reference group of 95 nonsymptomatic prepubertal children. Symptomatic hypermobile children were also compared with children of the population-based reference group who had asymptomatic hypermobility of the joints (n = 16)., Results: Children with symptomatic generalized joint hypermobility had significantly higher skin extensibility (5.6 mm/15 kPa, 95% confidence interval [CI]: 4.0-7.1), lower quantitative ultrasound measurements (speed of sound: -26.8 m/s; 95% CI: -41.1 to -12.6) in bone, and lower systolic and diastolic blood pressure (-8.0 mmHg, 95% CI: -13.3 to -2.8; and -6.0 mmHg, 95% CI: -10.0 to -2.2, respectively) as compared with the total reference group. Also, they had significantly lower excretion of urinary hydroxylysylpyridinoline cross-links (mean difference: -51.3 micro mol/mmol; 95% CI: -92.2 to -10.4) as well as lysylpyridinoline cross-links (-18.7 micro mol/mmol; 95% CI: -36.9 to -0.5). Age, gender, body weight, height, and particularly cross-links excretion did not explain group differences in clinical and bone characteristics. After adjustment for age, gender, body weight, and height, children with symptomatic generalized joint hypermobility (n = 15) had significantly higher total range of joint motion (117.8 degrees; 95% CI: 77.7-158.0), skin extensibility (3.5 mm/15 kPa; 95% CI: 1.6-5.3), lower quantitative ultrasound measurements in bone (speed of sound: -27.9 m/s; 95% CI: -48.4 to -7.5), borderline lower diastolic blood pressure (-4.9 mmHg; 95% CI: -10.7-0.9), and significantly higher degradation products in urine (hydroxyproline/creatinine: 21.2 micro mol/mmol; 95% CI: 2.3-40.1) as compared with asymptomatic hypermobile children of the total reference group (n = 16). After adjustment for possible confounders, children with generalized joint hypermobility without musculoskeletal complaints had a significantly higher total range of joint motion and more profound skin extensibility, as compared with the reference group (n = 79)., Conclusions: Clinically manifested symptoms in otherwise healthy children with generalized joint hypermobility are accompanied by increases in the laxity of other body tissues. Thus, generalized joint hypermobility with musculoskeletal symptoms does not seem to be restricted to joint tissues. In symptomatic hypermobile children, a more systemic derangement was also present as compared with asymptomatic hypermobile children.

In this prospective study of 18 hips we compared the efficacy of ultrasound with CT in determining the position of the femoral head in a spica cast after closed or open reduction in children with developmental dysplasia of the hip. Ultrasound was performed through the perineal opening of the cast. With a transinguinal approach, the superior ramus of the pubis, the acetabulum, the femoral head and the femoral neck can be depicted in one plane. The CT and ultrasound images were blinded and reviewed by two of the authors. Ultrasound was inconclusive in the first two reductions since the perineal opening was too small to see all the landmarks in one plane. In the following 16 reductions the landmarks were well defined and interpretation of the CT and ultrasound was similar. The perineal opening in the spica cast should be made in such a way that the ultrasound probe can be positioned in the groin so that the landmarks can be shown in one plane.

A 40 year old man with hereditary multiple exostoses (HME), affecting predominantly his left proximal tibia, distal femur, and proximal femur, underwent resection of an osteochondroma near the trochanter major of his left proximal femur because of malignant transformation of the cartilaginous cap towards secondary peripheral chondrosarcoma. The patient had a history of a papillary thyroid carcinoma four years previously. At examination of the resected specimen, a third malignant tumour, an intermediate grade osteosarcoma (grade II/IV), was found in the osseous stalk of the osteochondroma. Although no mutations were found in the EXT1 and EXT2 genes, the genes involved in HME, or in exons 5-8 of the p53 gene, the development of three malignancies before the age of 40 suggests that this patient is genetically prone to malignant transformation.

Although >80% of the mineral in mammalian bone is present in the collagen fibrils, limited information is available about factors that determine a proper deposition of mineral. This study investigates whether a specific collagen matrix is required for fibril mineralization. Calcifying callus from dog tibias was obtained at various times (3-21 weeks) after fracturing. At 3 weeks, hydroxylysine (Hyl) levels were almost twice as high as in control bone, gradually reaching normal levels at 21 weeks. The decrease in Hyl levels can only be the result of the formation of a new collagen network at the expense of the old one. The sum of the cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) in callus matched that of bone at all stages of maturation. However, the ratio HP/LP was 2.5-4.5 times higher in callus at 3-7 weeks than in normal bone and was normalized at 21 weeks. Some 40% of the collagen was nonmineralized at the early stages of healing, reaching control bone values (approximately 10%) at 21 weeks. In contrast, only a small increase in callus mineral content from 20.0 to 22.6 (% of dry tissue weight) from week 3 to 21 was seen, indicating that initially a large proportion of the mineral was deposited between, and not within, the fibrils. A strong relationship (r = 0.80) was found between the ratio HP/LP and fibril mineralization; the lower the HP/LP ratio, the more mineralized the fibrils were. Because the HP/LP ratio is believed to be the result of a specific packing of intrafibrillar collagen molecules, this study implies that mineralization of fibrils is facilitated by a specific orientation of collagen molecules in the fibrils.

The brittleness of bone in patients with osteogenesis imperfecta (OI) has been attributed to an aberrant collagen network. However, the role of collagen in the loss of tissue integrity has not been well established. To gain an insight into the biochemistry and structure of the collagen network, the cross-links hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) and the level of triple helical hydroxylysine (Hyl) were determined in bone of OI patients (types I, III, and IV) as well as controls. The amount of triple helical Hyl was increased in all patients. LP levels in OI were not significantly different; in contrast, the amount of HP (and as a consequence the HP/LP ratio and the total pyridinoline level) was significantly increased. There was no relationship between the sum of pyridinolines and the amount of triple helical Hyl, indicating that lysyl hydroxylation of the triple helix and the telopeptides are under separate control. Cross-linking is the result of a specific three-dimensional arrangement of collagens within the fibril; only molecules that are correctly aligned are able to form cross-links. Inasmuch as the total amount of pyridinoline cross-links in OI bone is similar to control bone, the packing geometry of intrafibrillar collagen molecules is not disturbed in OI. Consequently, the brittleness of bone is not caused by a disorganized intrafibrillar collagen packing and/or loss of cross-links. This is an unexpected finding, because mutant collagen molecules with a random distribution within the fibril are expected to result in disruptions of the alignment of neighboring collagen molecules. Pepsin digestion of OI bone revealed that collagen located at the surface of the fibril had lower cross-link levels compared with collagen located at the inside of the fibril, indicating that mutant molecules are not distributed randomly within the fibril but are located preferentially at the surface of the fibril.

Polyactive(R) [polyethylene oxide-polybuthylene terephtalate (PEO-PBT)] refers to a group of copolymers with bone-bonding properties. In reference to these properties, PEO-PBT copolymers are currently being investigated for their possible use in orthopedic surgery and dentistry. PEO-PBT copolymers exhibit hydrogel behavior. When swelling in fluid is prohibited by mechanical confinement, the copolymers exert a swelling pressure on surrounding structures. In the first part of this study, these swelling pressures were measured in vitro. Polymers with different ratios of PEO-PBT exerted a swelling pressure of more than 2 MPa when tested in fluid between the cross-heads of a Hounsfield test-bench. In the second part of the study, the biocompatibility of PEO-PBT 55-45 and the effect of continuous intramedullary pressure of these copolymers on bone was investigated. Large cylinders of dry PEO-PBT 55-45 were implanted with a tight fit in the distal part of goat femora. Preswollen cylinders of PEO-PBT implanted in the opposite femur served as a control. Although it was assumed that the pressure of dry PEO-PBT on the bone would reach more than 2 MPa with press-fit insertion, no immediate hazardous effects of the expanding polymer were noticed within the first days postoperatively. The goats were sacrificed after 3, 9, and 25 weeks. Histological examination showed good implant-bone contact at different follow-up times in the distal femora with the dry implanted implants. The femora in which the preswollen cylinders had been implanted showed a thin layer of soft tissue between the PEO-PBT implant and bone. The swelling pressure exerted by dry press-fit implanted PEO-PBT implants is an important factor in creating a strong interface bond between PEO-PBT and bone., (Copyright 2000 John Wiley & Sons, Inc.)

Purpose: Exposure of human cells to heat leads to denaturation and aggregation of proteins. Within the nucleus, it has been suggested that protein aggregation is linked to the selective inhibition by hyperthermia of nucleotide excision repair in transcriptionally active genes. In this study it was investigated in detail whether and how the inhibition of repair of transcriptionally active genes might be related to alterations in their association with the nuclear-matrix., Material and Methods: Different protocols for nuclear-matrix isolation (high salt and lithium 3',5'-diiodosalycilate [LIS] extraction of nuclei) were used to compare DNA loop organization and positioning of transcriptionally active genes in both heated and non-heated cells., Results: DNaseI digestion of total genomic DNA in Cu2+ -stabilized LIS-extracted nuclei revealed that heat shock perturbed the formation of nuclear-matrix attachment sites. Specific labelling of active genes indicated that the number of nuclear-matrix attachment sites in transcriptionally active DNA was increased due to the heat shock. At the level of individual genes, heat treatment led to stabilization of the 5' matrix attachment site (MAR) in the transcriptionally active adenosine deaminase (ADA) housekeeping gene. Moreover, heat shock resulted in the formation of an additional MAR at the 3' end of the ADA gene. The inactive 754 locus was unassociated, irrespective of a heat shock., Conclusions: The reported changes in chromatin structure might underlie the selective inhibition of repair in transcriptionally active genes and consequently may be mechanistically linked to the sensitization of heated cells to ionizing radiation.

This a well-documented case of a 13-year-old girl with unilateral pseudarthrosis of the left clavicle without the presence of cervical ribs or dextrocardia. Magnetic resonance imaging could not detect any abnormality that could be related to the left-sided pseudarthrosis.

Polyether-polyester segmented block copolymers (Polyactive) on the basis of polybutylene terephthalate (PBT) and polyethylene oxide (PEO) were mechanically tested. Tensile strength and modulus of elasticity in compressive and tensile deformation were recorded according to ASTM standards. These tests were done in vitro under dry and wet conditions, and after 3, 9 and 25 wk subcutaneous implantation of these materials in goats. Strength and modulus of elasticity were higher with increased contents of PBT in the copolymers. After water uptake, the polymer displayed a lower strength and stiffness. Disintegration of the materials with 70% PEO content and dumb-bell shape was noted at 3 wk. Disintegration of the cylinders of the same material was seen after 25 wk implantation. Of the materials with 60% PEO content, only four of the five dumb-bells had disintegrated after 25 wk implantation. The in vivo test results of all other implants did not show a clinically relevant decrease of strength and stiffness with time after implantation of the copolymers in the goats. Mechanical behavior of the various copolymers seemed mainly determined by the amount and integrity of the PBT phase.

In order to study bone growth conducting capacities of new biomaterials under standardized conditions, a goat model was developed based on a canine model by Soballe. Titanium alloy implants with and without a hydroxyapatite coating were used as positive and negative controls, and these were implanted with a circumferential gap of one millimeter in the spongious bone of the knee condyles of two groups of four goats. These goats were sacrificed at 6 and 25 weeks. A second experiment was done on two groups of four goats with the same type of titanium alloy and hydroxyapatite-coated implants as controls and with Polyactive 55-45 coated titanium alloy implants for testing. These goats were sacrificed at 9 and 25 weeks, respectively. Qualitative and quantitative differences in gap healing were evaluated through light microscopy, and initiation and direction of bone apposition were determined with fluorescence microscopy. Apposition of bone was seen directly on all hydroxyapatite surfaces and on some of the noncoated titanium alloy surfaces. The difference between the percentage of bone growth on the titanium alloy implants and the hydroxyapatite-coated implants appeared to be divergent in time: the bone growth on the noncoated implants declined after 9 weeks in contrast to the steady increase of bone growth on the hydroxyapatite-coated implants towards the 25 week follow-up time (p = 0.02). No significant difference was found between the first and the second experiment: apposition of bone on the implants differed only 6.6% on a scale of 0% to 100%. Only scarce bone growth was seen on the polyactive-coated implants in this model. The newly tested Polyactive 55-45 coating apparently needs initial bone contact for bone-bonding and therefore showed hardly any direct bone formation on its surface. The clear differences in the reaction of bone to the coated and noncoated implants in this goat study and the reproducibility of these reactions of bone to the different controls indicate the sensitivity of the currently used animal model and its suitability for use as a bioactivity assay.

Hydroxylapatite coatings are under clinical investigation in orthopaedics and dentistry. Bone formation on apatite coatings in the presence of gaps is important for clinical applications. The importance of the stability of the coating is not known at present. By varying the plasma-spray parameters, and by the addition of fluoride, the crystallinity and stability of calcium phosphates can be changed. It is suggested that bone formation is enhanced by dissolution of the apatite coating. We studied apatite coatings of varying stability with regard to their gap-healing characteristics, and we examined what the maximum gap would be that can be bridged if a coating is applied. Ti-6A1-4V implants coated with 62% crystalline hydroxylapatite, 30% crystalline hydroxylapatite or fluorapatite, or noncoated Ti-6A1-4V were implanted in 16 goats. The implants were surrounded by gaps of 1 or 2 mm, and the follow-up period was 6 weeks. Histological examination and histometry revealed that gaps of 1 mm can be bridged by bone if an apatite coating is applied. However, only a minimal amount of bone contact was seen on the apatite coatings with 2 mm gaps. Uncoated implants demonstrated no bone contact at all. Among the three different coatings there were no differences in gap healing. It can be concluded that in the goat, gaps of 2 or more mm between coated implants and host bone tissue inhibit bone deposition on the coating (p < 0.05), but the stability of the coating does not influence gap-healing characteristics.

In normal human fibroblasts, repair of (6-4)PP in the active adenosine deaminase (ADA) gene occurs with similar rate in the transcribed and non-transcribed strand of the ADA gene, and removal of (6-4)PP from the active ADA gene is faster than from the inactive X-chromosomal 754 locus. Heat shock decreased the rate of repair of the active ADA gene down to the level of inactive genes, whereas the rate of repair of the inactive 754 locus was not affected.

Hyperthermia specifically inhibits the repair of UV-induced DNA photolesions in transcriptionally active genes. To define more precisely which mechanisms underlie the heat-induced inhibition of repair of active genes, removal of cyclobutane pyrimidine dimers (CPDs) was studied in human fibroblasts with different repair capacities and different transcriptional status of the adenosine deaminase gene, i.e. normal human cells, human cells carrying an inactive copy of the adenosine deaminase gene and xeroderma pigmentosum complementation group C fibroblasts. The results indicate that repair of active genes is impaired by inhibition of two repair pathways: (i) a global repair system involved in the repair of CPDs in potentially active genes; and (ii) the transcription-coupled repair pathway responsible for the accelerated repair of the transcribed strand. Since X-ray-induced DNA damage is also preferentially removed from the transcribed strand of active genes, selective inhibition of repair of radiation-induced DNA damage in active genes may play a key role in radiosensitization due to hyperthermia.

A new range of clinically used, biodegradable, bone-bonding copolymers has hydrogel properties. With intramedullary press fit, these polymers generate considerable pressure through swelling caused by water absorption. In total hip arthroplasty, high intramedullary pressures can be attained by insertion of the prosthesis into femora by using methylmethacrylate cement and a cement plug. Because the effects of such intramedullary pressures are not fully known, 10-cm-long segments of the proximal diaphysis of fresh femoral bones from 22 human cadavers were tested for their intramedullary pressure resistance. The intramedullary pressure resistance, calculated burst forces, and stress on the bone were correlated to age, gender, bone mineral content per unit length, and bone mineral density. In most bone segments, a burst fracture occurred just opposite the linea aspera. The hydraulic bursting pressures ranged from 2.3 to 13.4 MPa (age adjusted gender effect [male-female], 2.2 MPa [p = 0.05]). The forces at fracture were calculated to be between 265 and 1361 N (regression coefficient: 247/unit bone mineral content per unit length). The tangential stress appeared to be between 7.54 and 27.54 MPa (regression coefficient: 11.6/unit bone mineral density; bone mineral density adjusted gender difference [male-female], 4.5 MPa [p < 0.05]). Biochemical examination of the bones did not show any abnormalities. The results of this study show that the human femora can resist mechanically an intramedullary pressure of at least 2 MPa. From a mechanical point of view, intramedullary pressures generated by swelling polymers should remain below 2 MPa for safe use.

The effect of hyperthermia on induction and repair of UV-radiation-induced cyclobutane pyrimidine dimers was investigated in the genome overall and in transcriptionally active and inactive genes in confluent human fibroblasts. Hyperthermia treatment (30 min, 45 degrees C) of human fibroblasts resulted in an increase in the protein content of isolated nuclei (protein aggregation) similar to that observed for HeLa S3 cells. The faster rate of disaggregation of nuclear proteins and the higher survival rate of heated fibroblasts in comparison with those for HeLa cells provide further evidence for a possible role of protein aggregation in heat-induced cell killing. Determination of the frequencies of cyclobutane pyrimidine dimers in the genome overall and in restriction fragments of the active adenosine deaminase (ADA) gene and inactive 754 locus revealed that hyperthermia selectively inhibits the induction of cyclobutane pyrimidine dimers in transcriptionally active DNA. Removal of cyclobutane pyrimidine dimers from the ADA gene was strongly delayed during the first 8 h in 10 J/m2 UV-irradiated fibroblasts. Such inhibition of repair of cyclobutane pyrimidine dimers was not observed for the 754 gene, indicating that inhibition of repair by hyperthermia is generally not mediated by inactivation of repair enzymes. It is proposed that the inhibition of induction and repair of cyclobutane pyrimidine dimers in active genes by hyperthermia is related to the heat-induced aggregation of proteins with the nuclear matrix, proximal to which active genes are located. Our results are consistent with a functional compartmentalization of DNA repair at the nuclear matrix.

We performed a histological examination and DNA analysis on samples of tissue from a forty-seven-year-old woman who had a clinical diagnosis of pigmented villonodular synovitis. The histological examination confirmed the diagnosis. The evaluation of the samples of tissue with preferential X-chromosome inactivation analysis (a molecular biological method for the study of clonality in tumors) showed that the lesion was polyclonal in origin. We concluded, therefore, that pigmented villonodular synovitis is more likely to be a reactive process than a true neoplasm.

Magnetic resonance imaging (MRI) studies in two patients with congenital coxa vara revealed a widened growth plate with expansion of cartilage mediodistally between the capital femoral epiphysis and metaphysis. They did not reveal slippage. Histologic studies showed that the growth plate appeared to be composed merely of irregularly and scarcely distributed germinal cartilage cells with abundant matrix. The histologic studies resembled the histopathologic reports of metaphyseal chondrodysplasia Schmid type, but only with regard to the proximal femoral growth plate. Determination of the sulfur concentration of the cartilaginous matrix was within normal range.

In different murine systems, delayed-type hypersensitivity (DTH) swelling responses at 24-48 hr after antigen challenge were preceded by an early 2-hr swelling response. The 24-hr DTH response is thought to depend on this early (DTH-initiating) hypersensitivity response. In this paper we show that in the syngeneic DBA/2-SL2 murine tumour system only an early 2-hr swelling response can be evoked. This early hypersensitivity response was tumour specific and serotonin dependent. The early hypersensitivity response in contact hypersensitivity has been ascribed to antigen-specific T-cell factors. To test whether similar T-cell factors were involved in the early hypersensitivity response in this syngeneic tumour system, we have transferred lymph node, spleen lymphocytes and serum from immunized mice into naive recipients. The serum was fractionated in two fractions, a 50,000-80,000 MW fraction, and a 120,000-190,000 MW fraction. In recipients of lymphocytes, total serum and the 50,000-80,000 MW fraction of the serum, an early hypersensitivity response can be evoked. So, these data suggest the involvement of specific T-cell factors in the development of an early hypersensitivity response against syngeneic tumour cells. Despite the development of an early (DTH initiating) hypersensitivity swelling response these immunized animals cannot develop a classical 24-hr swelling response. This absence of the 24-hr response in the presence of the 2-hr response is discussed in relation to the frequently observed immune suppression in tumour-bearing mice.