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Chilbule S.K.,Paediatric Orthopaedics Unit | Madhuri V.,Paediatric Orthopaedics Unit
Journal of Children's Orthopaedics

Purpose: Pamidronate, used for the treatment of paediatric osteoporosis, reduces the fracture rate and improves ambulatory status. Intravenous pamidronate therapy has known complications which have not been stratified based on its dose and distribution. This study aims to assess the early minor and major medical and late surgical complications and the effect of the dose and regimen of infusion on these events in paediatric osteoporosis. Study design: Retrospective cohort. Materials and methods: Three regimens for pamidronate infusion were followed in sequential periods in 10 years. Regimen A delivered 1.5 mg/kg/day as a single dose once in 3 months. Regimen B delivered 2 mg/kg/day for 3 days twice a year, while regimen C delivered 1 mg/kg/day for 3 days every 3-4 months. Adverse events were classified as early (major and minor) or late (surgical). Results: Forty-eight children received 158 infusions using one of the three regimens. Twenty-nine complications occurred in 24 children. A significant difference in the complication rate was present among the three regimens (P = 0.005). Nineteen children had minor complications, mainly febrile reaction or asymptomatic hypocalcaemia. Four major complications consisting of one seizure, one respiratory distress and two hypocalcaemic tetany were encountered, all with regimen B. Intraoperative complication faced was loss of position due to splintering of the cortex while rush rodding. This was seen in 20% of the long bone segments operated in those who received pamidronate as compared to 4.4% of the segments which were operated prior to the initiation of pamidronate therapy; the odds of splintering were 5.4 times higher for those patients who were bone segment rodded after pamidronate therapy. Discussion: Intravenous pamidronate is associated with complications in 50% of children with paediatric osteoporosis, with a dose-dependent significant difference. Major complications are not uncommon with higher doses and can be avoided by increasing the number of doses per year and decreasing the dose per cycle. Surgical difficulty, when possible, can be avoided by correcting any major deformities at presentation prior to the induction of pamidronate therapy. © 2012 EPOS. Source

Madhuri V.,Paediatric Orthopaedics Unit | Madhuri V.,Center for Stem Cell Research | Santhanam M.,Center for Stem Cell Research | Sugumar L.K.,Center for Stem Cell Research | And 2 more authors.
Annals of Human Genetics

Fibrodysplasia Ossificans Progressiva (FOP) is a rare debilitating disorder characterized by congenital deformity of the great toes from infancy and postnatal heterotopic ossification. Activating mutations in the activin A receptor type 1 (ACVR1) gene are responsible for the disease. The most common allelic variant leading to FOP is c.617 G>A; p.R206H, however, other alleles have been reported with atypical phenotypes. We report 14 cases presenting to a referral institution in South India over a 3-year period. The patients were clinically diagnosed based on foot abnormality or abnormal ectopic ossification and were screened for ACVR1. The genetic analysis of ACVR1 identified the recurrent allelic variant in 12 of 14 patients. One of the remaining patients had a previously reported allele c.1067G>A; p.G356D in the 9th exon and the second allele c.983G>A; p.G328E in the 8th exon of ACVR1. The most common recurrent allele c.617 G>A; p.R206H is also the most common in Indian patients with FOP. © 2015 John Wiley & Sons Ltd/University College London. Source

Rajagopal K.,Paediatric Orthopaedics Unit | Dutt V.,Paediatric Orthopaedics Unit | Manickam A.S.,Christian Medical College | Madhuri V.,Paediatric Orthopaedics Unit
Indian Journal of Orthopaedics

Background: Autologous articular cartilage at present forms the main source of chondrocytes for cartilage tissue engineering. In children, iliac apophysis is a rich and readily accessible source of chondrocytes. This study compares the growth characteristics and phenotype maintenance of goat iliac apophysis growth plate chondrocytes with those sourced from goat articular cartilage, and thereby assesses their suitability for autologous chondrocyte transplantation in immature animals for growth plate and articular cartilage regeneration. Materials and Methods: Four sets of experiments were carried out. Cartilage samples were harvested under aseptic conditions from goat iliac apophysis and knee articular cartilage. The chondrocytes were isolated in each set and viable cells were counted and subsequently cultured as a monolayer in tissue culture flasks containing chondrogenic media at 2.5 × 10 3 cells/cm 2. The growth was periodically assessed with phase contrast microcopy and the cells were harvested on 8 th and 15 th days for morphology, cell yield, and phenotype assessment. Student's t-test was used for comparison of the means. Results: Confluence was reached in the iliac apophysis growth plate chondrocytes flasks on the 10 th day and the articular cartilage chondrocytes flasks on the 14 th day. Mean cell count of growth plate chondrocytes on the 8 th day was 3.64 × 10 5 (SD = 0.601) and that of articular cartilage chondrocytes was 1.40 × 10 5 (SD = 0.758) per flask. The difference in the means was statistically significant (P = 0.003). On the 15 th day, the mean cell number had increased to 1.35 × 10 6 (SD = 0.20) and 1.19 × 10 6 (SD = 0.064) per flask, respectively. This difference was not statistically significant (P = 0.26). The population doubling time on the 8 th day of cell culture was 3.18 and 6.24 days respectively, for iliac apophyseal and articular cartilage chondrocytes, which was altered to 3.59 and 3.1 days, respectively, on the 15 th day. The immunocytochemistry showed 100% retention of collagen 2 positive and collagen 1 negative cells in both sets of cultures in all samples. Conclusion: Iliac apophysis is a rich source of chondrocytes with a high growth rate and ability to retain phenotype when compared to articular cartilage derived chondrocytes. Further in vivo studies may determine the efficacy of physeal and articular repair in children with apophyseal chondrocytes. Source

Madhuri V.,Paediatric Orthopaedics Unit | Dutt V.,Paediatric Orthopaedics Unit | Gahukamble A.D.,Paediatric Orthopaedics Unit | Tharyan P.,Care Network
Evidence-Based Child Health

Background: Fractures of the femoral shaft in children are relatively uncommon but serious injuries that disrupt the lives of children and their carers and can result in significant long-term disability. Treatment involves either surgical fixation, such as intramedullary nailing or external fixation, or conservative treatment involving prolonged immobilisation, often in hospital. Objectives: To assess the effects (benefits and harms) of interventions for treating femoral shaft fractures in children and adolescents. Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (accessed 16 August 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013 Issue 7), MEDLINE (1946 to August Week 1 2013), EMBASE (1980 to 2012 week 9), CINAHL (16 August 2013), clinical trials registries, conference proceedings and reference lists; and contacted trial authors and experts in the field. Selection criteria: Randomised and quasi-randomised controlled trials comparing conservative and surgical interventions for diaphyseal fractures of the femur in children under 18 years of age. Our primary outcomes were functional outcome measures, unacceptable malunion, and serious adverse events. Data collection and analysis: Two authors independently screened and selected trials, assessed risk of bias and extracted data. We assessed the overall quality of the evidence for each outcome for each comparison using the GRADE approach. We pooled data using a fixed-effect model. Main results: We included 10 trials (six randomised and four quasi-randomised) involving a total of 527 children (531 fractures). All trials were at some risk of bias, including performance bias as care provider blinding was not practical, but to a differing extent. Just one trial was at low risk of selection bias. Reflecting both the risk of bias and the imprecision of findings, we judged the quality of evidence to be 'low' for most outcomes, meaning that we are unsure about the estimates of effect. Most trials failed to report on self-assessed function or when children resumed their usual activities. The trials evaluated 10 different comparisons, belonging to three main categories. Surgical versus conservative treatment Four trials presenting data for 264 children aged 4 to 12 years made this comparison. Low quality evidence (one trial, 101 children) showed children had very similar function assessed using the RAND health status score at two years after surgery (external fixation) compared with conservative treatment (spica cast): mean 69 versus 68. The other three trials did not report on function. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up 3 to 24 months) that surgery reduced the risk of malunion (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.15 to 0.59, 4 trials). Assuming an illustrative baseline risk of 115 malunions per 1000 in children treated conservatively, these data equate to 81 fewer (95% CI 47 to 97 fewer) malunions per 1000 in surgically-treated children. Conversely, low quality evidence indicated that there were more serious adverse events such as infections after surgery (RR 2.39, 95% CI 1.10 to 5.17, 4 trials). Assuming an illustrative baseline risk of 40 serious adverse events per 1000 for conservative treatment, these data equate to 56 more (95% CI 4 to 167 more) serious adverse events per 1000 children treated surgically. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with intramedullary nailing than with traction followed by a cast, and that surgery reduced the time taken off from school. Comparisons of different methods of conservative treatment The three trials in this category made three different comparisons. We are very unsure if unacceptable malunion rates differ between immediate hip spica versus skeletal traction followed by spica in children aged 3 to 10 years followed up for six to eight weeks (RR 4.0, 95% CI 0.5 to 32.9; one trial, 42 children; very low quality evidence). Malunion rates at 5 to 10 years may not differ between traction followed by functional orthosis versus traction followed by spica cast in children aged 5 to 13 years (RR 0.98, 95% CI 0.46 to 2.12; one trial, 43 children; low quality evidence). We are very unsure (very low quality evidence) if either function or serious adverse events (zero events reported) differ between single-leg versus double-leg spica casts (one trial, 52 young children aged two to seven years). Low quality evidence on the same comparison indicates that single-leg casts are less awkward to manage by parents, more comfortable for the child and may require less time off work by the caregiver. Comparisons of different methods of surgical treatment The three trials in this category made three different comparisons. Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using elastic stable intramedullary nailing or external fixation (one trial, 19 children). The same applies to the rates of serious adverse events and time to resume full weight-bearing in children treated with dynamic versus static external fixation (one trial, 52 children). Very low quality evidence (one trial, 47 children) means that we do not know if malunion, serious adverse events and time to resume weight-bearing actually differ between intramedullary nailing versus submuscular plating. However, there could be more difficulties in plate removal subsequently. Authors' conclusions: There is insufficient evidence to determine if long-term function differs between surgical and conservative treatment. Surgery results in lower rates of malunion in children aged 4 to 12 years, but may increase the risk of serious adverse events. Elastic stable intramedullary nailing may reduce recovery time. There is insufficient evidence from comparisons of different methods of conservative treatment or of different methods of surgical treatment to draw conclusions on the relative effects of the treatments compared in the included trials. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Source

Ramesh S.,Paediatric Orthopaedics Unit | Rajagopal K.,Paediatric Orthopaedics Unit | Vaikkath D.,Sree Chitra Tirunal Institute for Medical Science and Technology | Nair P.D.,Sree Chitra Tirunal Institute for Medical Science and Technology | Madhuri V.,Paediatric Orthopaedics Unit
Biotechnology Letters

Two encapsulation techniques for rabbit chondrocytes in chitosan/hyaluronic acid gel have been compared. The standard technique involves the cross-linking of chitosan and hyaluronic acid at 2:1 (w/w). In the modified technique, cells were initially added to 33 % of hyaluronic acid dialdehyde and the gelation process was completed with the remaining 67 %. This minimised the cell loss and improved the encapsulation of the cells. By the third week, the modified technique showed better seeding density, with matrix synthesis (per scaffold) of 11 μg as compared to 1.1 μg in the current technique. Relative expression of collagen II with the current technique and the modified technique were 6.4 % and ~1,600 % respectively. The modified technique was superior for matrix synthesis and maintenance of phenotype. © 2014 Springer Science+Business Media Dordrecht. Source

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