Localized chondro-ossification underlies joint dysfunction and motor deficits in the Fkbp10 mouse model of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a genetic disorder that features wide-ranging defects in both skeletal and nonskeletal tissues. Previously, we and others reported that loss-of-function mutations in FK506 Binding Protein 10 (FKBP10) lead to skeletal deformities in conjunction with joint contractures. However, the pathogenic mechanisms underlying joint dysfunction in OI are poorly understood. In this study, we have generated a mouse model in which Fkbp10 is conditionally deleted in tendons and ligaments. Fkbp10 removal substantially reduced telopeptide lysyl hydroxylation of type I procollagen and collagen cross-linking in tendons. These biochemical alterations resulting from Fkbp10 ablation were associated with a site-specific induction of fibrosis, inflammation, and ectopic chondrogenesis followed by joint deformities in postnatal mice. We found that the ectopic chondrogenesis coincided with enhanced Gli1 expression, indicating dysregulated Hedgehog (Hh) signaling. Importantly, genetic inhibition of the Hh pathway attenuated ectopic chondrogenesis and joint deformities in Fkbp10 mutants. Furthermore, Hh inhibition restored alterations in gait parameters caused by Fkbp10 loss. Taken together, we identified a previously unappreciated role of Fkbp10 in tendons and ligaments and pathogenic mechanisms driving OI joint dysfunction.

Heterotopic Ossification After Prestige-LP Cervical Disc Arthroplasty Is Related to Insufficient Sagittal Coverage of the Endplate By the Prosthesis.

BACKGROUND Heterotopic ossification (HO) is a major complication after cervical disc arthroplasty (CDR) that has attracted the attention of spine surgeons. There remains a great deal of controversy regarding the surgical risk factors. The present study investigated the correlation between insufficient sagittal coverage of the prosthesis-endplate and HO after CDR and explored strategies to prevent it. MATERIAL AND METHODS We included 73 patients who underwent Prestige-LP arthroplasty. Patients were divided into HO and non-HO groups. Related data, including radiological, clinical information, were collected. HO was graded using the McAfee classification. Analysis was performed to correlate HO to the surgical segmental range of motion (ROM) at last follow-up. To evaluate the insufficient sagittal coverage of the prosthesis-endplate and other factors for developing HO, receiver operating characteristic (ROC) curves were analyzed for insufficient sagittal coverage. RESULTS Among 73 patients, 24 patients had HO at the last follow-up (HO incidence: 32.9%). The ROM in the HO group was significantly lower (P<0.001). The insufficient sagittal coverage of the upper and lower prosthesis-endplate, the height of intervertebral space, and the preoperative and postoperative ROM were related to HO (P<0.05). Multivariate logistic regression analysis showed that only insufficient sagittal coverage of the upper prosthesis-endplate was related to HO (P=0.023), and ROC curve analysis revealed that HO was more likely to occur with insufficient sagittal coverage distance ≥2.5 mm. CONCLUSIONS HO after CDR causes a reduction in ROM, the occurrence of which is associated with insufficient sagittal coverage of the prosthesis-endplate. HO was more likely to occur with insufficient sagittal coverage distance ≥2.5 mm.

When the Nervous System Turns Skeletal Muscles into Bones: How to Solve the Conundrum of Neurogenic Heterotopic Ossification.

PURPOSE OF REVIEW: Neurogenic heterotopic ossification (NHO) is the abnormal formation of extra-skeletal bones in periarticular muscles after damage to the central nervous system (CNS) such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke, or cerebral anoxia. The purpose of this review is to summarize recent developments in the understanding of NHO pathophysiology and pathogenesis. Recent animal models of NHO and recent findings investigating the communication between CNS injury, tissue inflammation, and upcoming NHO therapeutics are discussed. RECENT FINDINGS: Animal models of NHO following TBI or SCI have shown that NHO requires the combined effects of a severe CNS injury and soft tissue damage, in particular muscular inflammation and the infiltration of macrophages into damaged muscles plays a key role. In the context of a CNS injury, the inflammatory response to soft tissue damage is exaggerated and persistent with excessive signaling via substance P-, oncostatin M-, and TGF-ß1-mediated pathways. This review provides an overview of the known animal models and mechanisms of NHO and current therapeutic interventions for NHO patients. While some of the inflammatory mechanisms leading to NHO are common with other forms of traumatic and genetic heterotopic ossifications (HO), NHOs uniquely involve systemic changes in response to CNS injury. Future research into these CNS-mediated mechanisms is likely to reveal new targetable pathways to prevent NHO development in patients.

A Comparison of 2 Anterior Hybrid Techniques for 3-Level Cervical Degenerative Disc Disease.

BACKGROUND Novel hybrid surgical techniques that incorporate anterior cervical discectomy and fusion with total disc replacement are widely used. Based on the number of implanted discs, 3-level hybrid surgery can be classified as single fusion combined with double replacement and single replacement combined with double fusion. Few studies to date have directly compared these hybrid techniques. The present study compared the clinical and radiological outcomes of these methods and assessed their characteristics and benefits. MATERIAL AND METHODS Clinical and radiological outcomes were retrospectively evaluated in 64 consecutive patients who underwent 3-level hybrid surgery by single fusion combined with double replacement or single replacement combined with double fusion. RESULTS Significant differences between the 2 groups were observed in postoperative range of motion of C2-C7. C2-C7 cervical lordosis assessed preoperatively and at final follow-up differed significantly in patients who underwent single replacement combined with double fusion. This group showed a higher incidence of heterotopic ossification than patients who underwent double replacement combined with single fusion. CONCLUSIONS Both types of hybrid surgery are safe and effective in treating 3-level cervical degenerative disc diseases. Single replacement combined with double fusion showed greater accuracy in correcting cervical lordosis, but was associated with a higher incidence of heterotopic ossification. In contrast, single fusion combined with double replacement was superior in maintaining cervical range of motion.

Heterotopic Ossification After an Achilles Tendon Rupture Cannot Be Prevented by Early Functional Rehabilitation: A Cohort Study.

BACKGROUND: Tendon loading might play a role in the development of heterotopic ossification after Achilles tendon ruptures. Early heavy loading on a healing tendon in animals has been shown to prolong the proinflammatory response, and inflammatory cells are thought to drive heterotopic ossification formation. Taken together, this suggests that early rehabilitation might influence heterotopic ossification development. QUESTIONS/PURPOSES: The purposes of this study were to investigate (1) whether the presence of heterotopic ossification after Achilles tendon ruptures influences clinical outcome and (2) whether early mobilization or weightbearing prevents the development of heterotopic ossification. METHODS: This was a retrospective analysis of 69 patients from a previous clinical trial. All patients were treated surgically, but with three different early rehabilitation protocols after surgery: late weightbearing and ankle immobilization, late weightbearing and ankle mobilization, and early weightbearing and ankle mobilization. Plain radiographs taken 2, 6, 12, 26, and 52 weeks postoperatively were analyzed for heterotopic ossification, which was detected in 19% of patients (13 of 69) at 52 weeks. Heterotopic ossification was measured, scored, and correlated to clinical outcomes; heel-raise index (HRI), ankle joint ROM, tendon strain, Achilles tendon rupture score (ATRS), and Victorian Institute of Sport Assessment-Achilles (VISA-A) questionnaire scores at 26 and 52 weeks postoperatively. RESULTS: Heterotopic ossification had no adverse effects on patient-reported outcomes (ATRS or VISA-A), tendon strain, or ROM. In fact, patients with heterotopic ossification tended to have a better HRI at 52 weeks compared with patients without (mean difference 14% [95% CI -0.2 to 27]; p = 0.053). Neither the occurrence (heterotopic ossification/no heterotopic ossification) nor the heterotopic ossification severity (ossification score) differed between the three rehabilitation groups. Seventeen percent of the patients (four of 24) with early functional rehabilitation (early weightbearing and ankle joint mobilization exercise) had heterotopic ossification (score, 2-3) while late weightbearing and immobilization resulted in heterotopic ossification in 13% of the patients (score, 3-4). CONCLUSIONS: Heterotopic ossification occurs relatively frequently after Achilles tendon ruptures but appears to have no adverse effects on functional outcomes. Furthermore, heterotopic ossification develops during the first 6 weeks after rupture, and weightbearing or ankle-joint mobilization does not prevent this from occurring. LEVEL OF EVIDENCE: Level III, prognostic study.

Molecular characterization of known and novel ACVR1 variants in phenotypes of aberrant ossification.

Diffuse idiopathic skeletal hyperostosis (DISH) is a disorder principally characterized by calcification and ossification of spinal ligaments and entheses. Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disabling disorder characterized by progressive ossification of skeletal muscle, fascia, tendons, and ligaments. These conditions manifest phenotypic overlap in the ossification of tendons and ligaments. We describe herein a patient with DISH, exhibiting heterotopic ossification of the posterior longitudinal ligament where clinical whole exome sequencing identified a variant within ACVR1, a gene implicated in FOP. This variant, p.K400E, is a novel variant, not identified previously, and occurs in a highly conserved region across orthologs. We used sequence-based predicative algorithms, molecular modeling, and molecular dynamics simulations, to test the potential for p.K400E to alter the structure and dynamics of ACVR1. We applied the same modeling and simulation methods to established FOP variants, to identify the detailed effects that they have on the ACVR1 protein, as well as to act as positive controls against which the effects of p.K400E could be evaluated. Our in silico molecular analyses support p.K400E as altering the behavior of ACVR1. In addition, functional testing to measure the effect of this variant on BMP-pSMAD 1/5/8 target genes was carried out which revealed this variant to cause increased ID1 and Msx2 expression compared with the wild-type receptor. This analysis supports the potential for the variant of uncertain significance to contribute to the patient's phenotype.

Special considerations for clinical trials in fibrodysplasia ossificans progressiva (FOP).

Clinical trials for orphan diseases are critical for developing effective therapies. One such condition, fibrodysplasia ossificans progressiva (FOP; MIM#135100), is characterized by progressive heterotopic ossification (HO) that leads to severe disability. Individuals with FOP are extremely sensitive to even minor traumatic events. There has been substantial recent interest in clinical trials for novel and urgently-needed treatments for FOP. The International Clinical Council on FOP (ICC) was established in 2016 to provide consolidated and coordinated advice on the best practices for clinical care and clinical research for individuals who suffer from FOP. The Clinical Trials Committee of the ICC developed a focused list of key considerations that encompass the specific and unique needs of the FOP community - considerations that are endorsed by the entire ICC. These considerations complement established protocols for developing and executing robust clinical trials by providing a foundation for helping to ensure the safety of subjects with FOP in clinical research trials.

Therapeutic advances for blocking heterotopic ossification in fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease in which heterotopic bone forms in muscle and soft tissue, leading to joint dysfunction and significant disability. FOP is progressive and many patients are wheelchair-bound by the 3rd decade of life. FOP is caused by an activating mutation in the ACVR1 gene, which encodes the activin A Type 1 receptor. Aberrant signalling through this receptor leads to abnormal activation of the pSMAD 1/5/8 pathway and triggers the formation of bone outside of the skeleton. There is no curative therapy for FOP; however, exciting advances in novel therapies have developed recently. Here, we review the clinical and translational pharmacology of three drugs that are currently in clinical trials (palovarotene, REGN 2477 and rapamycin) as well as other emerging treatment strategies for FOP.

Union Rates and Reported Range of Motion Are Acceptable After Open Forearm Fractures in Military Combatants.

BACKGROUND: High-energy open forearm fractures are unique injuries frequently complicated by neurovascular and soft tissue injuries. Few studies have evaluated the factors associated with nonunion and loss of motion after these injuries, particularly in the setting of blast injuries. QUESTIONS/PURPOSES: (1) In military service members with high-energy open forearm fractures, what proportion achieved primary or secondary union? (2) What is the pronation-supination arc of motion as stratified by the presence or absence of heterotopic ossification (HO) and synostosis? (3) What are the risks of heterotopic ossification and synostosis? (4) What factors may be associated with forearm fracture nonunion? METHODS: A retrospective study of all open forearm fractures treated at a tertiary military referral center from January 2004 to December 2014 was performed. In all, 76 patients were identified and three were excluded, leaving 73 patients for inclusion. All 73 patients had serial radiographs to assess for HO and union. Only 64 patients had rotational range of motion (ROM) data. All patients returned to the operating room at least once after initial irrigation and débridement to ensure the soft tissue envelope was stable before definitive fixation. The indication for repeat irrigation and débridement was determined by clinical appearance. Patient demographics, fracture and soft tissue injury patterns, surgical treatments, neurovascular status at the time of injury, incidence of infection, heterotopic ossification (defined as the presence of heterotopic bone visible on serial radiographs), radioulnar synostosis, bony status after initial definitive treatment (union, nonunion, or amputation), and forearm rotation at final followup were retrospectively obtained from chart review by someone other than the operating surgeon. Seventy-six open forearm fractures in 76 patients were reviewed; 73 patients were examined for osseous union as three went on to early amputation, and 64 patients had forearm ROM data available for analysis. Union was determined by earliest radiology or orthopaedic staff official dictation stating the fracture was healed. Nonunion was defined as the clinical determination by the orthopaedist for a repeat procedure to achieve bony union. Secondary union was defined as union after reoperation to achieve bony union, and final union was defined as overall percentage of patients who were healed at final followup. Of the patients analyzed for union, 20 had less than 1 year of followup, and of these, none had nonunion. Of the patients analyzed for ROM, eight patients had less than 6 months of followup (range, 84-176 days). Of these, one patient had decreased ROM, none had a synostosis, and the remaining had > 140° of motion. RESULTS: Initial treatment resulted in primary union in 62 of 73 patients (85%); secondary union was achieved in eight of 11 patients (73%); and final union was achieved in 70 of 73 patients (96%). Although pronation-supination arc in patients without HO was 140° ± 35°, a limited pronation-supination arc was primarily associated with synostosis (arc: 40° ± 40°; mean difference from patients without HO: 103° [95% confidence interval {CI}, 77°-129°], p < 0.001); patients with HO but without synostosis had fewer limitations to ROM than those with synostosis (arc: 110° ± 80°, mean difference: 77° [35°-119°], p < 0.001). Heterotopic ossification developed in 40 of 73 patients (55%), including a radioulnar synostosis in 14 patients (19%). Bone loss at the fracture site (relative risk (RR) 6.2; 95% CI, 1.8-21) and healing complicated by infection (RR, 9.9; 95% CI, 4.9-20) were associated with the development of nonunion after initial treatment. Other potential factors such as smoking status, vascular injury, both-bone involvement, need for free flap coverage and blast mechanism were not associated. CONCLUSIONS: Despite a high-energy mechanism of injury and high rate of soft tissue defects, the ultimate probability of fracture union in our series was high with a low infection risk. Nonunions were associated with bone loss and deep infection. Functional motion was achieved in most patients despite increased burden of HO and synostosis compared with civilian populations. However, if synostosis did not develop, HO itself did not appear to interfere with functional ROM. Future investigations may provide improved decision-making tools for timing of fixation and prophylactic means against HO synostosis. LEVEL OF EVIDENCE: Level III, therapeutic study.

Loss of pronation-supination in patients with heterotopic ossification around the elbow.

BACKGROUND: Heterotopic ossification (HO) is a well-recognized cause of limited flexion-extension, but it can also limit pronation-supination. There is a paucity of literature concerning restriction of pronation-supination due to HO. METHODS: We conducted a retrospective review of patients who had undergone elbow surgery for HO removal between January 1, 2003, and September 27, 2013. Computed tomography scans were reviewed to determine the presence of HO restricting forearm rotation and were rated independently by 4 observers. Each elbow was given 1 of 4 scores according to the likelihood that HO was restricting forearm rotation. Agreement was achieved when 3 or 4 observers thought that HO definitely or probably caused a loss of pronation-supination. RESULTS: Of 132 post-traumatic patients undergoing HO excision for restricted elbow motion, 61 (46%) also lacked a functional arc of pronation and supination (50° and 50°, respectively). Of these 61 patients, 32 (53%) were considered to have lost forearm rotation because of HO. The remaining 29 patients (47%) were thought to have restricted forearm rotation for reasons unrelated to HO. DISCUSSION: In this study, loss of pronation-supination affected almost half of the patients (61 of 132 [46%]) undergoing HO excision around the elbow. Of these 61 patients, 32 (52%) had HO extending into the proximal forearm and affecting rotation. From our data, one can expect that about one-quarter (24% of patients in this study, or 32 of 132) with post-traumatic HO of the elbow will have a significant functional loss of pronation-supination due to HO extending into the forearm.

Treatment of capitellar and trochlear fractures with posterior comminution: minimum 2-year follow-up.

HYPOTHESIS: This study aimed to evaluate the safety and efficacy of the fixation of Dubberley type B capitellar and trochlear fractures using dorsolateral anatomic plates with support of the distal humerus (DAPSDHs). METHODS: Fifteen patients with Dubberley type B capitellar and trochlear fractures (two type 1B, five type 2B, and eight type 3B) were treated through the extended lateral approach, and fixation was achieved with DAPSDHs. Radiographic evaluation was performed, and range of motion of the elbow and forearm was recorded. Functional outcomes were assessed using the Mayo Elbow Performance Score and Disabilities of the Arm, Shoulder and Hand score. RESULTS: The mean follow-up period was 32.5 months (range, 24-54 months). Fracture union was achieved in all cases. At the final follow-up, range of motion was as follows: flexion, 123.7° ± 8.1° (range, 110°-135°); lack of extension, 11.0° ± 7.1° (range, 5°-30°); pronation, 81.7° ± 5.6° (range, 70°-90°); and supination, 78.7° ± 5.2° (range, 70°-85°). At the final follow-up, the mean Disabilities of the Arm, Shoulder and Hand score was 11.9 ± 4.0 (range, 4.2-20.8) and the mean Mayo Elbow Performance Score was 89.0 ± 7.1 (range, 70-95). The outcome was rated as excellent in 12 patients (80.0%), good in 2 (13.3%), and fair in 1 (6.7%). Avascular necrosis of the capitellum developed in 1 patient. One patient had implant irritation. Heterotopic ossification developed in 1 patient. Ten patients returned to their previous activity levels. CONCLUSION: Capitellar and trochlear fractures with posterior comminution are safely and effectively treated through the extended lateral approach using DAPSDHs, resulting in good radiographic and functional outcomes.

Heterotopic ossification after total elbow arthroplasty: a systematic review.

BACKGROUND: Heterotopic ossification (HO) is a known complication that can arise after total elbow arthroplasty (TEA). In most cases, it is asymptomatic; however, in some patients, it can limit range of motion and lead to poor outcomes. The objective of this review was to assess and report the incidence, risk factors, prophylaxis, and management of HO after TEA. METHODS: A systematic search was conducted using MEDLINE, Embase, and PubMed to retrieve all relevant studies evaluating the occurrence of HO after TEA. The search was performed in duplicate, and a quality assessment of all included studies was performed. RESULTS: A total of 1907 studies were retrieved, of which 45 were included involving 2256 TEA patients. HO was radiographically present in 10% of patients and was symptomatic in 3%. Fewer than 1% of patients went on to undergo surgical excision of HO, with outcomes after surgery reported as good or excellent as assessed by range of motion and the Mayo Elbow Performance Score. HO appears more likely to develop in patients undergoing TEA because of ankylosis, primary osteoarthritis, and distal humeral fractures. Surgical intervention is more likely to be required in patients in whom HO develops after TEA performed for ankylosis and post-traumatic osteoarthritis. CONCLUSION: HO is an uncommon complication after TEA, with most patients in whom HO develops being asymptomatic and requiring no surgical management. Routine HO prophylaxis for TEA is not supported by the literature. The effectiveness of prophylaxis in high-risk patients is uncertain, and future studies are required to clarify its usefulness.

Surgical management of patients with Eagle syndrome.

OBJECTIVE: Eagle syndrome, a spectrum of disease resulting from an elongated styloid process and/or calcified stylohyoid ligament, lacks standardized recommendations regarding indications for surgical intervention and approach. STUDY DESIGN: Retrospective cohort study. SETTING: Single tertiary care institution. SUBJECTS: Patients treated surgically for Eagle syndrome between January 2011 and June 2017. METHODS: Patients were diagnosed with Eagle syndrome based on thorough clinical workup and assessment. The primary outcome was improvement in pain severity following surgery, with complete resolution of pain being considered clinically meaningful. Wilcoxon rank-sum tests and Fisher's exact were used to compare numerical and categorical variables, respectively. RESULTS: Twenty-one patients were diagnosed with Eagle syndrome and underwent surgical resection of the styloid process. Patients most often complained of neck pain (81%), throat pain (62%), and ear pain (48%). Among these patients, 57% of procedures featured a transcervical approach, while the remaining 43% were transoral. The vast majority (90%) of patients experienced improvement in pain severity from a median of 6.0 before surgery to 0.0 afterwards (p < 0.01) as 62% experienced complete resolution. Using multivariable linear regression to model changes in pain severity, neck pain (ß = -1.69, p < 0.01) and jaw pain (ß = -0.93, p = 0.03) predicted greater relief, while headache (ß = 0.82, p = 0.04) predicted an inferior response. Adverse events were uncommon and typically resolved within three months, with 24% experiencing first bite syndrome and 19% reporting numbness. CONCLUSIONS: Transcervical and transoral styloidectomy are effective treatments for Eagle syndrome with minimal adverse effects. Patients with classic symptoms of neck or jaw pain benefit most from surgery.

Genetic advances in craniosynostosis.

Craniosynostosis, the premature ossification of one or more skull sutures, is a clinically and genetically heterogeneous congenital anomaly affecting approximately one in 2,500 live births. In most cases, it occurs as an isolated congenital anomaly, that is, nonsyndromic craniosynostosis (NCS), the genetic, and environmental causes of which remain largely unknown. Recent data suggest that, at least some of the midline NCS cases may be explained by two loci inheritance. In approximately 25-30% of patients, craniosynostosis presents as a feature of a genetic syndrome due to chromosomal defects or mutations in genes within interconnected signaling pathways. The aim of this review is to provide a detailed and comprehensive update on the genetic and environmental factors associated with NCS, integrating the scientific findings achieved during the last decade. Focus on the neurodevelopmental, imaging, and treatment aspects of NCS is also provided.

A preliminary investigation on the effect of extracorporeal shock wave therapy as a treatment for neurogenic heterotopic ossification following traumatic brain injury. Part II: Effects on function.

INTRODUCTION: Neurogenic heterotopic ossification (NHO) occurs as a complication of traumatic brain injury (TBI). Management of clinically significant NHO remains variable. Complications of mature NHO include limitation of mobility. The effect of the extracorporeal shock wave therapy (ESWT) on range of motion at hip and knee, and function in patients with TBI with chronic NHO was investigated. METHODS: A series of single-case studies applying ESWT to chronic NHO at the hip or knee of 11 patients with TBI were undertaken at a rehabilitation hospital. Participants received four applications of high-energy EWST delivered to the affected hip or knee over a period of 8 weeks. Two-weekly follow- up assessments were carried out; final assessments were made 3 and 6 months post-intervention. Range of motion (ROM) and Functional Reach (FR) or Modified Functional Reach (MFR) were measured. RESULTS: Application of high-energy ESWT was associated with significant improvement in ROM (flexion) of the NHO-affected knee (Tau = 0.833, 95% CI 0.391-1.276, p = 0.002) and significant improvement of FR (Overall Tau 0.486, 95% CI 0.141-0.832, p = 0.006); no significant improvement in hip ROM or MFR. CONCLUSIONS: ESWT may improve mobility and balance of patients with TBI who have chronic NHO.

[The results of bilateral cochlear implantation in the children who survived meningitis]. / Rezul'taty bilateral'noi kokhlearnoi implantatsii u detei, perenesshikh meningit.

The objective of the present study was the prospective analysis of the results of bilateral cochlear implantation (CI) in the children presenting with bilateral ossification of the cochlea after they had survived meningitis. A total of 15 patients underwent the surgical intervention. In those exhibiting bilateral ossification of the basal cochlear helix over the 5 mm segment (up to first bend of the cochlear turn) and partial ossification of the second helix (in 6 children), the affected portions were removed with the placement of two choleostomies, the lower one (from the ossified membrane of the cochlear window) and the upper one (toward the second helix). Activation of the speech processors of the CI systems was carried out within 4-6 weeks after surgery. The hearing abilities of the children were evaluated in accordance with the 'Estimation of the auditory perception categories', 'Estimation of the child's apprehension capacity', and 'Analysis of speech intelligibility rating' guidelines. In all the children with ossification over less than 5 mm of the basal cochlear helix, it proved possible to introduce the whole intracochlear electrode grid whereas only half of the electrode array was implanted in the cases of overall ossification of the basal helix. The first results obtained by telemetry and surdopedagogical testing gave evidence of the possibility of identifying various sources of non-verbal and speech stimuli in all the treated children at a small (up to 3 meters) distance.

[The non-damaging method for the insertion of a standard electrode for cochlear ossification].

The objective of the present study was to develop the non-damaging method for the insertion of a standard electrode for cochlear ossification with a view to improving the results of hearing and speech rehabilitation of the patients presenting with grade IV sensorineural impairment of hearing. Twenty preparations of the cadaveric temporal bone were used to investigate topographic and anatomical relationships in the main structures of the middle and internal ears, viz. the second cochlear coil, vestibulum and its windows, processus cochleaformis, spiral lamina, and modiolus. The optimal method for the insertion of a standard electrode into the spiral canal of the cochlea after the removal of the ossified structures is proposed. The optimal site for constructing the second colostomy is determined that allows the spiral plate and modiolus to be maximally preserved. The proposed method was employed to treat 11 patients with grade IV sensorineural impairment of hearing and more than 5 mm ossification of the basal cochlear coil. With this method, it proved possible to insert the maximum number of electrodes into the cochlear spiral canal and thereby to obtain excellent results of hearing and speech rehabilitation in the patients with the ossified cochlea.

Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis.

OBJECTIVES: Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. METHODS AND RESULTS: Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-ß pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10(-5)). CONCLUSIONS: Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-ß/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-ß-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.

Identifying the Cellular Mechanisms Leading to Heterotopic Ossification.

Heterotopic ossification (HO) is a debilitating condition defined by the de novo development of bone within non-osseous soft tissues, and can be either hereditary or acquired. The hereditary condition, fibrodysplasia ossificans progressiva is rare but life threatening. Acquired HO is more common and results from a severe trauma that produces an environment conducive for the formation of ectopic endochondral bone. Despite continued efforts to identify the cellular and molecular events that lead to HO, the mechanisms of pathogenesis remain elusive. It has been proposed that the formation of ectopic bone requires an osteochondrogenic cell type, the presence of inductive agent(s) and a permissive local environment. To date several lineage-tracing studies have identified potential contributory populations. However, difficulties identifying cells in vivo based on the limitations of phenotypic markers, along with the absence of established in vitro HO models have made the results difficult to interpret. The purpose of this review is to critically evaluate current literature within the field in an attempt identify the cellular mechanisms required for ectopic bone formation. The major aim is to collate all current data on cell populations that have been shown to possess an osteochondrogenic potential and identify environmental conditions that may contribute to a permissive local environment. This review outlines the pathology of endochondral ossification, which is important for the development of potential HO therapies and to further our understanding of the mechanisms governing bone formation.

The immunological contribution to heterotopic ossification disorders.

The formation of bone outside the endogenous skeleton is a significant clinical event, rendering affected individuals with immobility and a diminished quality of life. This bone, termed heterotopic ossification (HO), can appear in patients following invasive surgeries and traumatic injuries, as well as progressively manifest in several congenital disorders. A unifying feature of both genetic and nongenetic episodes of HO is immune system involvement at the early stages of disease. Activation of the immune system sets the stage for the downstream anabolic events that eventually result in ectopic bone formation, rendering the immune system a particularly appealing site of early therapeutic intervention for optimal management of disease. In this review, we will discuss the immunological contributions to HO disorders, with specific focus on contributing cell types, signaling pathways, relevant in vivo animal models, and potential therapeutic targets.