Validity of parental recall of children's fracture: implications for investigation of childhood osteoporosis.

UNLABELLED: Fracture history is an important component of osteoporosis diagnosis in children. One in six parentally reported lifetime fractures in children were not confirmed on review of radiographs. Care should be taken to avoid unnecessary investigations for possible osteoporosis due to parental over-reporting of soft tissue injuries as fractures. INTRODUCTION: The diagnosis of osteoporosis in children requires either a vertebral compression fracture, or a significant fracture history (defined as ≥2 long bone fractures <10 years or ≥3 long bone fractures <19 years, excluding high impact fractures) and low bone mineral density. As children with frequent fractures might benefit from further evaluation, we determined whether parental reports of lifetime fracture were accurate compared to radiological reports and if they appropriately selected children for further consideration of osteoporosis. METHODS: Parents of children (<18 years) with a musculoskeletal injury completed a questionnaire on their child's fracture history, including age, site and mechanism of previous fracture(s). Radiological reports were reviewed to confirm the fracture. RESULTS: Six hundred sixty parents completed the questionnaire and reported 276 previous fractures in 207 children. An injury treated at our hospital was recorded in 214 of the 276 parentally reported fractures. Thirty-four of 214 (16 %) were not a confirmed fracture. An injury was recorded for all parentally reported fractures in 150 children, but for 21 % children, there were inaccurate details (no evidence of fracture, incorrect site or forgotten fractures) on parent report. Eighteen of 150 children had a significant fracture history on parental report alone, but following review of radiology reports, 2 of 18 (11 %) did not have clinically significant fracture histories. CONCLUSIONS: Approximately one in six fractures reported by parents to have occurred in their child's lifetime had not resulted in a fracture. One in nine children with a significant fracture history could have been investigated unnecessarily.

What is the incidence of late detection of developmental dysplasia of the hip in England?: a 26-year national study of children diagnosed after the age of one.

AIMS: The aim of this study was to establish the incidence of developmental dysplasia of the hip (DDH) diagnosed after one-year of age in England, stratified by age, gender, year, and region of diagnosis. PATIENTS AND METHODS: A descriptive observational study was performed by linking primary and secondary care information from two independent national databases of routinely collected data: the United Kingdom Clinical Practice Research Datalink and Hospital Episode Statistics. The study examined all children from 1 January 1990 to 1 January 2016 who had a new first diagnostic code for DDH aged between one and eight years old. RESULTS: The incidence of late-diagnosed DDH was 1.28 per 1000 live births. Within the study population, 754 children were identified with a diagnosis of DDH after one-year of age. Of all late diagnoses, 536 (71.1%) were detected between one to two years of age. There were 608 female patients (80.6%) and 146 male patients (19.4%), giving a female-to-male ratio of 4.2:1. Distribution was evenly spread throughout England. CONCLUSION: The incidence of late-diagnosed DDH has not been reduced from that reported 35 years ago, prior to the introduction of the national selective screening programme for DDH. Cite this article: Bone Joint J 2019;101-B:281-287.

Osteonecrosis following treatment for childhood acute lymphoblastic leukaemia: The Southampton Children's Hospital experience.

Purpose: To determine the prevalence of osteonecrosis (ON) in children following treatment of acute lymphoblastic leukaemia (ALL), characterise these cases and review treatment methods. Methods: All children diagnosed and treated for ALL between 01 January 2003 and 31 December 2013 at our centre were retrospectively reviewed. Logistic regression was used to investigate risk factors for ON occurrence. Results: Of 235 children treated for ALL, 48/235 (20.4%) children suffered musculoskeletal symptoms necessitating radiological investigation. A total of 13 (5.5%) had MRI-diagnosed ON, with a median diagnosis time of 12 months (interquartile range 10 to 14) following initiation of chemotherapy.ON affected 40 joints in 13 children. The most commonly involved joints were hips (14 joints in eight patients) and knees (12 joints in seven patients).Older age at ALL diagnosis was associated with significantly increased risk of development of ON per year (odds ratio 1.35, 95% confidence interval 1.17 to 1.57, p < 0.001).Eight children underwent at least one surgical intervention. Joint arthroplasty was undertaken in nine joints of four children at a mean age of 18.3 years. All patients who underwent hip arthroplasty had previously received core decompression, with a mean time of 27.8 months (18 to 33) between treatments. Conclusions: ON is a significant complication of ALL treatment. Our results suggest risk stratification for development of ON by age, and targeted monitoring of high-risk joints is possible. ON treatment is varied with little evidence base.

"Cell paralysis" as an intermediate stage in the programmed cell death of epiphyseal chondrocytes during development.

The efficient elimination of apoptotic cells depends on heterophagocytosis by other cells, which is difficult or impossible when the dying cells are embedded in an extracellular matrix. This situation is exemplified by the epiphyseal chondrocytes during the development of the chondroepiphyses of long bones. A detailed ultrastructural study identified an unusual type of epiphyseal chondrocyte which contained a very dark nucleus with irregular patches of condensed chromatin and a crenated nuclear membrane. The cytosol consisted of excessively expanded endoplasmic reticulum lumen, containing "islands" of cytoplasm and organelles. Since these cells appeared to be "in limbo," neither viable nor dead, they are referred to as "paralyzed" cells. By studying cells of intermediate morphologies, we were able to demonstrate the sequence of events leading to cell paralysis. It is proposed that the paralysis represents an intermediate state in the physiological cell death of epiphyseal chondrocytes in which destruction is orderly and avoids a inflammatory, potentially locally destructive, reaction. The cell is rendered paralyzed in terms of function but impotent in respect of damaging consequences. Paralysis is compared and contrasted with apoptosis, autophagocytosis, and necrosis and may represent another mode of programmed cell death in situations where cells are immature and/or where phagocytosis by neighboring cells is difficult.

Initiation of the bony epiphysis in long bones: chronology of interactions between the vascular system and the chondrocytes.

Many events occur concurrently during the initiation of the secondary ossification center in the cartilaginous epiphyses of long bones. We have investigated the chronology of interactions between the vascular system and epiphyseal chondrocytes by culturing explanted heads of femurs and humeri from pre- and neonatal rabbits on the chorioallantoic membrane (CAM) of growing chick embryos. We confirmed that, on the whole, the epiphyseal cartilage was resistant to vascular invasion, whereas the physeal growth plate was resorbed. However, new CAM-derived cartilage canals occasionally penetrated through the articular surface. This caused death of those chondrocytes in the immediate vicinity of the canal but no further reaction. If explants already contained a bony epiphysis and were halved prior to culture, CAM-derived vessels were attracted to the spongiosa. From there they pushed into the uncalcified cartilage, indicating that calcification was not a prerequisite for vascular invasion. Where at least two vessels were in apposition, a new pseudo-ossification center was initiated: chondrocytes became hypertrophic and the matrix calcified. This suggests that cumulative release of diffusible factors from more than one vessel was the trigger for chondrocyte hypertrophy, which, in turn, led to the initiation of the bony epiphysis. CAM cultures thus provide an experimental model for both the quiescent angiogenesis of cartilage canal formation and the reactionary angiogenesis associated with chondrocyte hypertrophy. By exploiting the different anatomy of CAM-derived vascularity, events that occur concurrently in vivo can be specially separated in CAM culture.

Human osteoprogenitor growth and differentiation on synthetic biodegradable structures after surface modification.

The ability to generate new bone for skeletal use is a major clinical need. Biomimetic scaffolds that interact and promote osteoblast differentiation and osteogenesis offer a promising approach to the generation of skeletal tissue to resolve this major health-care issue. In this study we examine the ability of surface-modified poly(lactic acid) (PLA) films and poly(lactic-co-/glycolic acid) (PLGA) (75:25) porous structures to promote human osteoprogenitor adhesion, spreading, growth, and differentiation. Cell spreading and adhesion were examined using Cell Tracker green fluorescence and confocal microscopy. Osteogenic differentiation was confirmed with alkaline phosphatase activity as well as immunocytochemistry for type I collagen, core binding factor-1 (Cbfa-1), and osteocalcin. Poor cell growth was observed on nonmodified PLA films and PLGA scaffolds. The polymers were then coupled with RGD peptides [using poly(L-lysine), or PLL] and physical adsorption as well as PLA films presenting adsorbed fibronectin (FN). Both modifications enhanced cell attachment and spreading. On PLA-FN and PLA-PLL-GRGDS films, the osteoblast response was dose dependent (20 pmol/L to 0.2 micromol/L FN and 30 nmol/L to 30 micromol/L PLL-GRGDS) and significant at concentrations as low as 2 nmol/L FN and 30 nmol/L PLL-GRGDS. With optimal concentrations of FN or RGD, adhesion and cell spreading were comparable to tissue culture plastic serum controls. In PLGA (75:25) biodegradable porous scaffolds, coated with FN, PLL-GRGDS, or fetal calf serum for 24 h in alpha MEM alone, prior to growth in dexamethasone and ascorbate-2-phosphate for 4-6 weeks, extensive osteoblast impregnation was observed by confocal and fluorescence microscopy. Cell viability in extended culture was maintained as analyzed by expression of Cell Tracker green and negligible ethidium homodimer-1 (a marker of cell necrosis) staining. Alkaline phosphatase activity, type I collagen, Cbfa-1, and osteocalcin expression were observed by immunocytochemistry. Mineralization of collagenous matrix took place after 4 weeks, which confirmed the expression of the mature osteogenic phenotype. These observations demonstrate successful adhesion and growth of human osteoprogenitors on protein- and peptide-coupled polymer films as well as migration, expansion, and differentiation on three-dimensional biodegradable PLGA scaffolds. The use of peptides/proteins and three-dimensional structures that provide positional and environmental information indicate the potential for biomimetic structures coupled with appropriate factors in the development of protocols for de novo bone formation.

Factors regulating the rat insulin-like growth factor-binding protein-1 response to octreotide.

Insulin-like growth factor-binding protein-1 (IGFBP-1) production is increased by somatostatin and its analogues. In order to determine the time course and identify possible mechanisms of this increase in vivo we administered octreotide to rats and determined IGFBP-1 concentrations by RIA. After 60 min of anaesthesia, the mean baseline IGFBP-1 concentrations were 166 (95% confidence interval 123 to 225) ng/ml and increased in saline-infused animals to 729 (488 to 1086) ng/ml after 180 min. IGFBP-1 was stimulated transiently in response to octreotide, with circulating IGFBP-1 concentrations peaking at 1605 (1220 to 2111) ng/ml at 105 min during a continuous infusion of octreotide (100 micrograms/kg per h). In conscious chronically cannulated rats, baseline IGFBP-1 concentrations were 22 (18 to 28) ng/ml, 8-fold less than in the anaesthetised state, and were stimulated in the short term after administration of an octreotide bolus (100 micrograms/kg s.c.) to reach 88 (62 to 126) ng/ml at 60 min. A similar response was seen after i.v. administration to conscious rats. Intravenous bolus of octreotide (100 micrograms/kg) in rats anaesthetised for 3 h resulted in an increase in IGFBP-1 to peak at 1556 (1268 to 1910) ng/ml at 60 min. The IGFBP-1 response to octreotide was diminished in high-fat fed hyperinsulinaemic rats. The pattern of disappearance of iodinated IGFBP-1 from the circulation was not influenced by octreotide. The changes in GH, insulin and glucose concentrations alone did not sufficiently account for the patterns of response observed. We conclude that, in rats, octreotide stimulates IGFBP-1 acutely and this response is potentiated by factors related to anaesthesia.

Regulation of insulin-like growth factor-binding protein-3 ternary complex formation in pregnancy.

The IGFs are believed to be important in pregnancy and are implicated in the pathophysiology of pre-eclampsia. In adults the IGFs circulate primarily with IGF-binding protein-3 (IGFBP-3) and an acid-labile glycoprotein (ALS) in a 140 kDa complex which limits IGF bioavailability. Less than 10% of IGFBP-3 is in lower molecular weight forms. We have investigated the developmental regulation of the IGF/IGFBP system in normal and pre-eclamptic pregnancies with particular emphasis on the IGFBP-3 ternary complex. Circulating levels of IGF-I, IGFBP-3 and ALS, and their degree of association in the ternary complex in the fetus increased with gestational age. In neonatal serum from deliveries <35 weeks' gestation IGFBP-3 was predominantly in 30-50 kDa form(s) and ALS was a limiting factor for ternary complex formation. In serum from deliveries >35 weeks both ALS and IGFs were limiting but approximately 25% of IGFBP-3 was unable to form the ternary complex even in the presence of excess ALS and IGF-I. Serum IGFBP-1, -2 and -6 concentrations tended to decrease with increasing gestational age. In pre-eclamptic pregnancies, amniotic fluid IGFBP-2, -3 and -6 levels decreased with gestational age while IGFBP-1 levels did not show the normal decline. We speculate that the endocrine IGF system develops in the fetus during the third trimester of pregnancy when ALS levels increase.

Effect of antimicrobial factors in human milk on rhinoviruses and milk-borne cytomegalovirus in vitro.

Various antimicrobial factors present in human milk were tested for in-vitro antiviral activity against three rhinoviruses (two clinical isolates and rhinovirus 2) and an isolate of cytomegalovirus (CMV) from human milk. These factors included the gangliosides GM1, 2 and 3, sialyl-lactose, chondroitin sulphates A, B and C, prostaglandins E2 and F2alpha, monolaurin, vitamin A and the protein lactoferrin. All were tested for their ability to inhibit growth of the viruses in cell culture. Human milk was also tested for antiviral activity against these viruses. Only vitamin A, monolaurin and lactoferrin inhibited the growth of CMV, whereas both prostaglandins enhanced the growth of this virus at least four-fold. CMV infects infants from milk but, nevertheless, the milk-borne CMV isolate showed no special resistance to any of the antiviral factors tested. None of the compounds inhibited or enhanced the growth of the rhinoviruses. However, human milk decreased the growth of some of the rhinoviruses and specific secretory immunoglobulin A (sIgA) neutralised the virus.

Painful sequelae of coxa plana.

Thirty-one patients with an average age of twenty-seven years had painful hips as the result of coxa plana in childhood. The pain was severe enough for surgical relief to be considered. Radiographically the lesions could be subdivided into three groups: severe mushroom deformity of the femoral head, 43 per cent; less severe dysplasia of the hip, 27 per cent; and severe osteoarthritis, 30 per cent. Twenty-three hip operations were done on theses patients. Fifteen hips showed radiographic evidence of definitive premature closure of the femoral capital epiphysis. The series is presented to illustrate that coxa plana may be followed by major disability in the hip within the first three decades of life.

Coxa plana--the fate of the physis.

Eighty patients who had unilateral coxa plana and who had been treated conservatively were followed to a mean age of sixteen and one-quarter years, and their cases were reviewed for radiographic evidence of a disturbance of the femoral capital growth plate. This physeal involvement was inferred by the presence of one or more of five findings: premature physeal closure, overgrowth of the greater trochanter, change in physeal shape, lateral protrusion of the capital nucleus, and medial bowing of the femoral neck. Premature physeal closure, which was more common in the girls than in the boys, occurred in 25 per cent of the affected femoral heads, and 90 per cent of the patients showed some interference with normal physeal growth in the affected femoral head. A direct correlation was found between the severity of the physeal involvement and the ultimate deformity of the femoral head. The possible causes of interference with physeal growth and damage are discussed.

Ultrasound imaging and secondary screening for congenital dislocation of the hip.

We report the preliminary results of a continuing prospective evaluation of a screening programme for congenital dislocation of the hip (CDH) which uses ultrasound imaging to provide delayed selective screening to complement neonatal clinical screening. Of 26,952 births in the Southampton district, 1894 infants were referred for secondary screening because of a clinical abnormality or the presence of a predetermined risk category for CDH. Pavlik harness treatment was required for only 118 infants, giving a treatment rate of 4.4 per 1000 births. Of those referred with clinical instability, 35% did not require treatment. Dislocation or subluxation was detected in 17 of 643 infants referred only because they fell within one of three risk categories: breech presentation, foot deformity and family history. All 17 had normal clinical examinations and cases were discovered in each category. Six children presented with CDH after 12 weeks of age, giving a late presentation rate of 0.22 per 1000 births. All had normal clinical examinations within 24 hours of birth and none was in a risk category. Surgery has been required in ten children, giving a surgical treatment rate of 0.37 per 1000 births. We conclude that, in Southampton, delayed selective secondary screening with ultrasound is more effective than clinical screening alone. It targets treatment to those infants who need it, and reveals a number of dislocated and subluxed hips that would otherwise be missed.

Slipped upper femoral epiphysis. A potential for spontaneous recovery.

Evidence is presented to support the contention that after slipping of the upper femoral epiphysis there is a potential for the bony epiphysis to grow back to its pre-slipped position. A suggestion is made as to how this recovery may occur.

Monitoring the treatment of developmental dysplasia of the hip with the Pavlik harness. The role of ultrasound.

We report the six-year results of a prospective, controlled demographic trial of developmental dysplasia of the hip (DDH) treated in the Pavlik harness using ultrasound supervision. Our aim was to assess the value of ultrasound and its role in monitoring reduction in the harness, in terms of progression or failure of reduction at an early state. From 1988 to 1994, a total of 221 patients with 370 ultrasonographically abnormal hips was treated in the Pavlik harness. This represents a treatment rate for the Southampton district of 5.1 per 1000 live births. Sixteen hips in 12 patients were not reduced in the harness and required surgical treatment; 95.7% were successfully reduced. One case of mild avascular necrosis (0.3%) was identified in those treated by harness alone. Of the 221 patients 87.8% remain under radiological review, with 3.2% of affected hips showing continued, mild acetabular dysplasia. We conclude that ultrasound monitoring has led to an acceptably low level of intervention, a high reduction rate and minimal iatrogenic complications. The trial is continuing.

Physiological cell death of chondrocytes in vivo is not confined to apoptosis. New observations on the mammalian growth plate.

Chondrocytes at the lower zone of the growth plate must be eliminated to facilitate longitudinal growth; this is generally assumed to involve apoptosis. We attempted to provide definitive electron-microscopic evidence of apoptosis in chondrocytes of physes and chondroepiphyses in the rabbit. We were, however, unable to find a single chondrocyte with the ultrastructure of 'classical' apoptosis in vivo, although such a cell was found in vitro. Instead, condensed chondrocytes had a convoluted nucleus with patchy chromatin condensations while the cytoplasm was dark with excessive amounts of endoplasmic reticulum. These cells were termed 'dark chondrocytes'. A detailed study of their ultrastructure combined with localisation methods in situ suggested a different mechanism of programmed cell death. In addition, another type of death was identified among the immature chondrocytes of the chondroepiphysis. These cells had the same nucleus as dark chondrocytes, but the lumen of the endoplasmic reticulum had expanded to fill the entire non-nuclear space, and all cytoplasm and organelles had been reduced to dark, worm-like inclusions. Since these cells appeared to be 'in limbo', they were termed 'paralysed' cells. It is proposed that 'dark chondrocytes' and 'paralysed cells' are examples of physiological cell death which does not involve apoptosis. It is possible that the confinement of chondrocytes within their lacunae, which would prevent phagocytosis of apoptotic bodies, necessitates different mechanisms of elimination.

Relapse in staged surgery for congenital talipes equinovarus.

Between 1988 and 1995, we studied 91 club feet from a series of 120 recalcitrant feet in 86 patients requiring surgical treatment. There were 48 boys and 20 girls. The mean age at operation was 8.9 months. Surgery consisted of an initial plantar medial release followed two weeks later by a posterolateral release. This strategy was adopted specifically to address the problems of wound healing associated with single-stage surgery and to ascertain the rate of relapse after a two-stage procedure. Immobilisation in plaster was used for three months followed by night splintage. The feet were classified preoperatively and prospectively into four grades according to the system suggested by Dimeglio et al. Grade-1 feet were postural and did not require surgery. All wounds were closed primarily. One superficial wound infection occurred in a grade-4 foot and there were no cases of wound breakdown. The rate of relapse was 20.4% in grade-3 and 65.4% in grade-4 feet. Two-stage surgery for the treatment of club foot seems to be effective in the reduction of wound problems but does not appear to give significantly better results in terms of relapse when performed for more severe deformities.

Recurrent irritable hip in childhood.

Between 1989 and 1992 we admitted 426 children with an irritable hip, 363 (85.2%) once and 63 (14.8%) on 143 occasions. We assessed the records retrospectively to determine whether the groups differed and in particular whether recurrence was followed by pathological sequelae. We identified no feature which distinguished between them at either presentation. The use of bone isotope scans was greatly increased in recurrent cases, without clinical benefit. No relationship between recurrence and subsequent abnormality was identified, with 22 (42%) of the recurrences taking place in the opposite hip. The only difference was a higher incidence of 'psychosocial factors' recorded in the notes of children who presented on more than two occasions. The incidence of recurrent irritable hip is larger than previously indicated and in the presence of normal radiographs and low-grade clinical signs, more detailed investigation on subsequent admission is unlikely to be helpful.

Congenital dislocation of the hip in extrauterine pregnancy.

Only two cases have been reported of congenital dislocation of the hip in infants born after extrauterine pregnancies. We report a further two and discuss the management and the variable outcome. These cases seem to confirm that congenital dislocation of the hip is associated with moulding forces rather than being a teratological abnormality.

Surgical release of the 'snapping iliopsoas tendon'.

We report 22 patients (19 women and three men) of mean age 20.8 years who had painful snapping sensations in the groin. Most were able to reproduce the click by extending the affected hip from a flexed, abducted and externally rotated position and most were tender in the adductor triangle. Plain radiographs and an arthrogram were normal. A clinical diagnosis of subluxation of the iliopsoas tendon was made. Conservative management failed in 14 patients, two of whom had bilateral pain. All 14 had surgical release of the iliopsoas tendon through a medial approach. At follow-up (mean 17 months) the click had resolved in ten hips, was occasional but painless in five and unchanged in one. The syndrome of a painful 'snapping' psoas may result in disproportionately disabling symptoms. It may be diagnosed on clinical grounds and effectively treated, when severe, by release of the iliopsoas tendon.