siRNA Mediate RNA Interference Concordant with Early On-Target Transient Transcriptional Interference.

Exogenous siRNAs are commonly used to regulate endogenous gene expression levels for gene function analysis, genotype-phenotype association studies and for gene therapy. Exogenous siRNAs can target mRNAs within the cytosol as well as nascent RNA transcripts within the nucleus, thus complicating siRNA targeting specificity. To highlight challenges in achieving siRNA target specificity, we targeted an overlapping gene set that we found associated with a familial form of multiple synostosis syndrome type 4 (SYSN4). In the affected family, we found that a previously unknown non-coding gene TOSPEAK/C8orf37AS1 was disrupted and the adjacent gene GDF6 was downregulated. Moreover, a conserved long-range enhancer for GDF6 was found located within TOSPEAK which in turn overlapped another gene which we named SMALLTALK/C8orf37. In fibroblast cell lines, SMALLTALK is transcribed at much higher levels in the opposite (convergent) direction to TOSPEAK. siRNA targeting of SMALLTALK resulted in post transcriptional gene silencing (PTGS/RNAi) of SMALLTALK that peaked at 72 h together with a rapid early increase in the level of both TOSPEAK and GDF6 that peaked and waned after 24 h. These findings indicated the following sequence of events: Firstly, the siRNA designed to target SMALLTALK mRNA for RNAi in the cytosol had also caused an early and transient transcriptional interference of SMALLTALK in the nucleus; Secondly, the resulting interference of SMALLTALK transcription increased the transcription of TOSPEAK; Thirdly, the increased transcription of TOSPEAK increased the transcription of GDF6. These findings have implications for the design and application of RNA and DNA targeting technologies including siRNA and CRISPR. For example, we used siRNA targeting of SMALLTALK to successfully restore GDF6 levels in the gene therapy of SYNS4 family fibroblasts in culture. To confidently apply gene targeting technologies, it is important to first determine the transcriptional interference effects of the targeting reagent and the targeted gene.

Craniofacial disorders.

The complexity of the craniofacial patient mandates the cooperation of a multidisciplinary team that can systematically evaluate each individual and ensure that a protocol-driven pathway is undertaken for the best patient care. Oral and maxillofacial surgeons contribute to surgical care in this setting with specific knowledge of growth and development of the face. This enables optimum timing for early skeletal correction where appropriate, and definitive surgery following the cessation of growth to maximize function and aesthetics. This chapter will describe the major principles in managing patients with specific craniofacial anomalies and provide examples of the outcomes possible.

Carpal Coalitions and Metacarpal Synostoses: A Review.

Background: Carpal coalition and metacarpal synostosis are uncommon congenital anomalies of the carpus and hand. Methods: A comprehensive review of the literature was performed to help guide surgical and non-surgical treatment of carpal coalition and metacarpal synostosis. Results: The embryology, epidemiology, medical and surgical management, and associated outcomes are detailed. Conclusions: Most patients with these disorders will likely benefit from conservative measures. Surgery should be considered in patients with pain and limitations in wrist and hand function.

Successful Bone Healing of Nonunion After Ulnar Shortening Osteotomy for Smokers Treated With Teriparatide.

Ulnar shortening osteotomy is widely performed as the standard surgical treatment for ulnar impaction syndrome and has a high percentage of success for pain relief. However, delayed union and nonunion of the osteotomy site remain the most concerning complications. In particular, smokers have a higher incidence of nonunion, which amounts to 30% of cases. For the treatment of nonunion, secondary surgical interventions such as bone grafting will be necessary but are extremely challenging. Recently, teriparatide (recombinant human parathyroid hormone [PTH 1-34]) administration has been reported in several clinical studies as a noninvasive pharmacological systemic treatment for fracture healing or nonunion. The authors present 2 cases of smokers, a 62-year-old man and a 42-year-old woman, with nonunion after ulnar shortening osteotomy and fixation with 6-hole non-locking plate for ulnar impaction syndrome. For treatment of nonunion, noninvasive therapy with teriparatide (20-µg, subcutaneous injection) in addition to low-intensity pulsed ultrasound was underwent. In both cases, partial bone union began to be observed on radiographs after the first 4 weeks of teriparatide administration and successful bone healing without additional surgical interventions was achieved after 10 and 6 months of treatment with teriparatide, respectively. The current case reports showed that non-invasive combination therapy of teriparatide and low-intensity pulsed ultrasound were a possible alternative to surgical intervention. In the future, teriparatide therapy might be applied actively to patients who have risk factors for delayed union, such a heavy smoking habit, and are expected to experience nonunion after ulnar shortening osteotomy.

Post-traumatic humero-ulnar synostosis.

A humero-ulnar synostosis is a bony connection between the humerus and the ulna. This is a very rare finding and it results in a serious disability of the elbow. Usually, a synostosis of the elbow occurs as a congenital anomaly. In this case, a 6-year-old girl was seen with a post-traumatic humero-ulnar synostosis, which has never been reported in the literature before. Surgical resection of the humero-ulnar synostosis was performed. Along with rapid intensive physical therapy, almost full recovery of function was achieved. The short-term result is very satisfactory, but the long-term results and recurrence rate are still unknown.

Inherited thrombocytopenias: an approach to diagnosis and management.

Inherited thrombocytopenias vary in their presentation, associated features, and molecular etiologies. An accurate diagnosis is important to provide appropriate therapy as well as counseling for the individual and their family members. As the genetic basis of more disorders is understood, it will be possible to diagnose a greater fraction of patients as well as learn more about the process of megakaryopoiesis and platelet production.

Management of posttraumatic radioulnar synostosis.

Posttraumatic radioulnar synostosis is a rare complication following fracture of the forearm and elbow. Risk factors for synostosis are related to the initial injury and surgical management of the fracture. Typically, patients present with complete loss of active and passive forearm pronation and supination. Evidence of bridging heterotopic bone between the radius and ulna can be seen on plain radiographs. Although nonsurgical management is sufficient in some cases, surgical excision is typically required. The timing of surgical intervention remains controversial. However, early resection between 6 and 12 months after the initial injury can be performed safely in patients with radiographic evidence of bony maturation. Surgical management consists of complete resection of the synostosis with optional interposition of biologic or synthetic materials to restore forearm rotation. A low recurrence rate can be achieved following primary radioulnar synostosis excision without the need for routine adjuvant prophylaxis.

Prevention of recurrent radioulnar heterotopic ossification by combined indomethacin and a dermal/silicone sheet implant: case report.

A 27-year-old, right-handed man developed severe radioulnar synostosis at the distal radius 7 months after open reduction and internal fixation of his distal radius fracture. Heterotopic ossification formed at the radius fracture site, requiring excision of the heterotopic bone and plate removal. A bilayer, dermal substitute and silicone sheet was placed between the radius and ulna in the interosseous space to prevent recurrence of the heterotopic ossification. After surgery, the patient was treated with indomethacin 25 mg orally 3 times daily for 6 weeks. At 1 year after surgery, he has retained full pronation and near normal supination. Radiographs demonstrate no new heterotopic bone formation.

Miscellaneous conditions about the elbow in athletes.

This article reviews some of the conditions about the elbow in athletes or active individuals. The conditions discussed are synovial plica of elbow, radiocapitellar arthritis, congenital dislocation of the radial head, radio-ulnar synostosis, hemophilia and rheumatoid arthritis. In the past, people who had these conditions were instructed to avoid athletic activities; however, they are now being counseled to remain active and to try to exercise on a regular basis.

A neonate with severe thrombocytopenia and radio-ulnar synostosis.

Bone marrow failure syndromes can be associated with abnormalities of the forearms. We observed a neonate with congenital thrombocytopenia who had bilateral radio-ulnar synostosis and fifth finger clinodactly. We performed an evaluation of the mechanism causing the thrombocytopenia using a combination of direct and indirect measures of thrombopoiesis. These tests indicated decreased platelet production. This entity of congenital hyporegenerative thrombocytopenia with bilateral radio-ulnar synostosis and fifth-finger clinodactly is an uncommon but easily recognizable form of congenital amegakaryocytic thrombocytopenia (CAMT). This entity can be distinguished from the TAR syndrome (thrombocytopenia and absent radii) by the distinctive orthopedic issues, different underlying genetic mutations, and a more worrisome prognosis for CAMT than for TAR.

Coalition of bilateral first cuneometatarsal joints: a case report.

The most common types of tarsal coalition are talocalcaneal and calcaneonavicular coalition. This report presents a case of a patient with middle foot pain who was diagnosed as having first cuneometatarsal coalition.

An aetiological classification for developmental synostoses at the elbow.

Synostoses at the elbow joint are rare. The literature divides them into three groups based on the nature of bony ankylosis; the commonest are humeroradial synostoses. Approximately 150 cases have been reported. There are 29 reported cases of humeroradioulnar synostosis and five of humeroulnar synostosis. An anatomical classification was previously described for humeroradial synostoses. Due to significant phenotypic variability we believe a classification based solely on anatomical characteristics will in some cases be misleading. No classification exists for humeroradioulnar and humeroulnar synostosis. By re-examining the literature we have produced a combined classification for all elbow synostoses which more accurately predicts causes. Congenital elbow synostoses often cause little functional disability. Treatment by soft tissue release and osteotomy has been attempted, but although range of movement is initially, improved re-ossification is the norm. Investigation is more complicated and may be helped by classification which identifies syndrome association, risk of organ anomaly, and inheritance pattern.

[Congenital synostoses of the tarsus. Concept, classification, diagnosis and therapeutic approach]. / Sinostosis congénitas del tarso. Concepto, clasificación, diagnóstico y planteamiento terapéutico.

The incidence of congenital tarsal coalition is about 1%. It is recognized as the main etiology of painful, rigid flatfoot in the pediatric population. Talonavicular (50%) and talocalcaneal (40%) coalition are the most common presentation. We must suspect a tarsal coalition in a child with mechanical pain and shoes deformity. Rigid and painful planovalgus deformity are found in physical exam which led to describe in the pass this entity as peroneal spastic flatfoot. Lateral and oblique (35 degrees-45 degrees) radiographs must be practice to observe the coalition. The presence of a beak in the head of the talus or a half moon condensation image as the result of the superposition of the talus over the calcaneus are commonly described. CT-scan is also useful to delineate the size of the coalition and its location. Resection of the bar is the surgical treatment of choice. Excision of the coalition and interposition of fat or a graft must be tried in young patients in order to preserve foot biomechanical properties and to avoid long term problems associated with arthrodesis. Triple arthrodesis or subtalar arthrodesis must be used in older patients with degenerative signs in radiographs or in those cases of multiple coalition or if resection has failed.

Occipital plagiocephaly.

The diagnosis of occipital plagiocephaly has remained a complex and controversial issue in the field of craniofacial surgery. Over the past 30 years, numerous studies have been published describing the management and treatment for 'posterior plagiocephaly', 'plagiocephaly without synostosis', 'deformational plagiocephaly' and 'occipital plagiocephaly', with surgical 'correction' being chosen as the primary modality of treatment irrespective of the patency status of the lambdoid sutures. Two hundred and four patients with unilateral occipital plagiocephaly have been seen at the Australian Craniofacial Unit over the past 16 years. Each patient was evaluated by a craniofacial surgeon, paediatric neurosurgeon and paediatric geneticist. All children underwent plain radiographs of the skull to define the sutural anatomy. In those patients where the sutural anatomy was equivocal, 2-D and 3-D CT scans were performed. Only two of the 204 patients (approximately 1%) manifested the clinical, radiographic and pathological features of true unilambdoid synostosis. There was radiographic evidence of sutural fusion on plain films, 2-D and 3-D CT scans. Pathology specimens showed bony sutural fusion. Two hundred and two patients presented with unilateral occipital deformities and patent sutures on radiography. These patients with occipital plagiocephaly in the absence of true synostosis were initially managed conservatively (head positioning, and physiotherapy in those patients with torticollis). Those patients who underwent surgical correction in infancy (21/204) included patients with severe plagiocephaly not responding to conservative therapy (19/204) and the two patients with true unilambdoid synostosis (2/204).One hundred and ninety-one of the total patients (94%) were noted by their parents to have acceptable improvement in their head shape. Thirteen patients were seen within the past year and are too early to assess. Two surgical patients (one fronto-orbital advancement, one occipital craniectomy) and one patient followed conservatively were judged by their parents to be without notable improvement. In our series it is apparent that the majority of cases of occipital plagiocephaly are not secondary to true synostosis and can be managed by conservative positional measures.

Congenital talonavicular coalition. Review of the literature, case report, and orthotic management.

Talonavicular coalition is a rare entity and is often discovered as a secondary radiographic finding. Today, orthoses are as varied as the patients for whom they are prescribed; however, in cases of symptomatic talonavicular fusion, the use of a shallow U-shaped dispersion within the high medial flange of an orthosis can prove beneficial to the pediatric patient. This article encourages podiatric physicians to return to utilizing basic diagnostic tools (gait analysis, biomechanical examination, and radiographs) to detect and treat talonavicular coalition, a significant but rare anomaly of the foot.

[Too long antero-medial process of the calcaneus. A study of 59 cases in 37 children and adolescents]. / Processus antéro-interne du calcanéum trop long. Expérience de 59 cas chez 37 enfants et adolescents.

PURPOSE OF THE STUDY: In 1983, we reported 5 cases of a type of tarsal abnormality which often went unrecognized in children and adolescents, the so-called "too long antero-medial process of the calcaneus" (TLAP). This report analyzes 59 such abnormalities observed in 37 children and adolescents. Treatment of the 48 symptomatic cases is presented. MATERIAL: A retrospective study was done on the files of all patients in whom oblique foot radiographs, CT scan or MRI of the foot showed an abnormal antero-medial process of the calcaneus. Of this group, patients were re-examined and radiographs of both feet (AP, lateral and oblique views) were obtained. METHODS: Gender, age at occurrence of symptoms, diagnosis and follow-up, patient complaints and successive treatment were assessed. Final clinical results were graded according to patient's complaints of pain and functional limitation as well as clinical evaluation of subtalar motion. RESULTS: Fifty-nine TLAPs have been found in 37 patients, 30 girls and 7 boys of 11.6 years on average at the first symptoms. Delay of diagnosis from onset of symptoms to final diagnosis averaged 2 years. First symptoms were so-called ankle sprains in 19 patients, ankle instability with tarsal pain in 17, pain and tarsal stiffness in 11, spastic flat foot in 1. In 11 patients, the abnormality was found on the opposite foot. In 2 patients, the TLAP was combined to a calcaneo-navicular bridge of the other foot. Eleven strapping managements resulted in 11 failures, 36 plaster immobilizations led to 12 good, 2 fair and 22 poor results; 25 resections gave 23 good, 1 fair and 1 poor result at a 4.6 years follow-up on average. DISCUSSION: In some people, the antero-medial process of the calcaneus is elongated and becomes interposed between the head of the talus and the cuboïd, far enough to cause impingement on the navicular. Because of the elongation, supination produces a "nutcracker" phenomenon with compression of the process between the talus and the cuboïd; this may result in a chondral injury of the talus head at its inferior and lateral part which faced the TLAP. Authors suggest that calcaneo-navicular coalition and TLAP represent a spectrum of types of errors in embryologie mesenchymal formation with lack of normal joint formation of the tarsal ossicles during fetal life. Immobilization treatment as primary management was particularly unsuccessful in the group with recurrent ankle sprains and persistent pain. Process resection proved a highly successful technique in management of those patients who failed to achieve good results with plaster immobilization. CONCLUSION: The "too long antero-medial process of the calcaneus" should be considered when assessing possible causes of recurrent ankle sprain or persistent tarsal pain in adolescents. An oblique X-ray is usually satisfactory for diagnosis. In patients who failed a conservative management, resection of the process produced good results and painless, supple feet.

[Congenital tarsal synostosis]. / Les synostoses congénitales du tarse.

Tarsal coalition results from the fusion of at least two tarsal bones. The clinical and radiological pictures depend on the anatomic location of the coalition. Calcaneonavicular and talonavicular coalitions are the most frequent features which may result in peroneal spastic flat foot; however they are symptomless in most cases. Tarsal coalitions are usually evident on plain X-ray films using appropriate incidences. In selected cases, partial talocalcaneal coalition requires CT scan or MRI. No treatment is needed for asymptomatic conditions. Painful spastic flat foot must be treated conservatively by limiting sport activity as a first step treatment. In case of persistent symptoms, cast with correction of deformities under general anesthaesia is recommended. Surgery is needed only in case of failure of previous treatment, requiring resection of the bony bridge and sometimes triple foot arthrodesis.

Management of antebrachial deformity and shortening secondary to a synostosis in a dog.

A nine-week-old labrador was presented with a deformed left forelimb causing obvious lameness. Radiographs suggested that the dog had suffered a fracture involving the radius and ulna which had healed resulting in a synostosis. There was a concurrent radial physeal injury. The dog was treated initially by osteotomy of the radius and ulna stabilised using a static external skeletal fixator. At a subsequent surgery lengthening of the limb was achieved by using an Ilizarov apparatus. Worsening carpal hyperflexion was managed by bandaging in forced extension. A successful outcome was achieved with a final result of a 24 per cent discrepancy in length between the two radii at 17 months of age. An increase in length of the ipsilateral humerus was seen in association with the shortened forelimb.