A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2-/- phenotype.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α-androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.

[Mid-Term to Long-Term Results of Revision Total Hip Arthroplasty Using the Oval-Shaped Acetabular Cup - TC Type]. / Strednedobé az dlouhodobé výsledky reimplantací totální náhrady kycelního kloubu pri pouzití oválné revizní jamky ­ typ TC.

INTRODUCTION The purpose of our paper is to evaluate the mid-term to long-term results and to confirm the basic criteria of a high-quality revision implant: safe bridging of bone defects, achievement of reliable primary fixation of revision acetabular cup, achievement of good secondary stability with documentable osteointegration of cup and demonstration of remodelling of transplanted bone tissue in the area of defects and in spaces between the implant ribs. MATERIAL AND METHODS Altogether 36 patients (38 cups) were evaluated who had undergone revision hip arthroplasty in the period from 2004 to 2010. The mean follow-up was 8.2 years (5.1-11.6 years after the reimplantation, more than 10 years in 16 patients who underwent surgery). The position and osseointegration of the implant were assessed by digital radiography, the remodelling of transplanted bone tissues in the area of defects and between the implant ribs by computed tomography with reducing artefacts around the metal implant (Aquilion 64 - Toshiba Medical Systems), and for the clinical outcomes the Harris Hip Score was used. RESULTS Preoperatively, the condition of the hip joint based on the Harris Hip Score was in 30 cases evaluated as poor, in 8 patients as satisfactory. At the time of final evaluation, 8 patients achieved excellent results, in 19 patients the condition of the joint was very good (in 2 patients bilaterally), in 6 patients it was considered satisfactory and in 3 patients poor. The mean value for HHS increased from 39.5 to 84.5. Based on the radiography evaluation, in 27 patients (in 2 patients bilaterally) the osseointegration of the revision cup was good, in 8 cases with a radiolucent line of 2-4 mm in width in DeLee zone III, in one case proximal migration of the cup occurred caused by deep infection. The informed consent form for pelvic CT was signed by 25 patients of our cohort. Remodelling of bone tissue in the space between the ribs of the implant was always detected, the presence of bone cysts was not reported, the bone defects following the application of autologous spongioplasty in the monitored patients were healed. In 6 patients, an ingrowth of fibrous tissue of 2-4 mm in width in the convexity of the cup was detected. The mean survival of the revision oval-shaped cup - TC type with a follow-up of 8.2 years after the reimplantation based on Kaplan-Meier analysis was 91.4 %. DISCUSSION The number of revision total hip arthroplasties due to a younger age of patients who undergo alloplasty keeps growing. The choice of a revision implant should always match the intraoperative finding and the bone tissue quality. The standard uncemented implants with osteoactive surface can be opted for when anterior and posterior column of the acetabulum are intact (IIA and IIB according to Paprosky). Starting from type IIC, also the proximal part of acetabulum shall be considered. At our department, preference is given to the revision cup - TC type. The oval shape facilitates a lower degree of bone resection and easier restoration of the anatomical centre of rotation. Careful debridement of granulating and necrotic tissue, thorough treatment of bone defects and osteoactive surface of implants in case of adequate primary fixation of the cup substantially contribute to the quality of its osseointegration. Greater rigidity of fixation verified by pull-out tests enables to insert angular stable screws into the gaps in the proximal part of the cup. There is still room for improvement in treating the bone defect. The application of allogenic bone grafts into the defects and spaces between the ribs of the TC cup is more challenging than the use of augmentation in the systems with trabecular titanium. Based on the evaluation of CT scans, remodelling of the transplanted bone occurs, therefore the defect zone is reduced. CONCLUSIONS The oval-shaped uncemented cup - type TC meets the requirements placed on a state-of the art revision implant, moreover its specific construction helps improve the conditions where another re-operation of acetabulum is necessary. By evaluating mid-term to long-term results of non-homogenous group of 36 patients (38 cups) we have obtained data on joint function comparable to similar groups with revision uncemented implants presented in our and foreign literature. Key words: revision oval-shaped cup, bone remodelling, pull-out tests, angular stable screws, computed tomography.

[Evaluation of Outcomes after Anterior Cruciate Ligament Reconstruction in Children and Adolescents]. / Zhodnocení souboru pacientu po náhrade predního zkrízeného vazu v detském a adolescentním veku.

PURPOSE OF THE STUDY: Treatment for tears of the anterior cruciate ligament (ACL) in paediatric patients has been a long-discussed issue because of complications associated with ligament reconstruction in the presence of growth plates. Various fixation materials and their efficiency as well as ACL techniques are still under investigation. The aim of our study was to find an optimal strategy of treating acute intra-articular ACL injury in childhood. MATERIAL AND METHODS: The paediatric patients treated for primary traumatic ACL injury between 2003 and 2013 were retrospectively evaluated. Only patients with a healthy contralateral knee (with no signs of instability or previous injury) and no record of previous ACL repair were included. A total of 78 patients were assessed; there were 39 girls and 39 boys with an average age of 15.4 years (11 - 16). The physical development of the patients was assessed on the Tanner scale, their satisfaction was recorded on the basis of the IKDC subjective knee evaluation form and the Tegner-Lysholm scoring system. The instrumented Lachman test using a rollimeter was performed to assess knee stability at 12 and 24 months of follow-up. In addition, the range of knee motion in comparison with the other side, complications and the re-rupture rate of reconstructed ACLs were recorded. Four patients with open growth plates were operated on using the transepiphyseal technique, the remaining 74 underwent reconstruction by the standard transphyseal method. RESULTS: The average Tegner-Lysholm scores were 54 (41-62) pre-operatively and 86.1 (74-96) at 24 months post-operatively. The average IKDC score increased from 48 (42-56) points to 91 (73-97) points. The Lachman test was positive in all patients before ACL reconstruction and negative in 96% of them at 12 and 24 months after surgery. The full range of joint motion was restored after ACL surgery, with minimal motion restriction in flexion and extension, in 70 (89.7%) patients. Motion restriction by 15° or less in flexion and 5° or less in extension was recorded in seven (9%) patients and a significant restriction in extension exceeding 10° was found in one (1.3%) patient. No differences in results were found between the two scoring systems. Five patients (6.4 %) sustained a re-tear in the reconstructed ACL due to a trauma. Non-traumatic subjective instability after the primary repair was not recorded. Revision ACL surgery was carried out due to fixation materials protruding from the bone surface in two patients and because of a Cyclops lesion with extension deficit in one patient. No development of deformity or instability was observed at 24 months in the patients in whom the transepiphyseal technique was used. DISCUSSION In the current literature ACL reconstruction by the transphyseal technique has been described in patients older than 15 years of age but no optimal age has been suggested. Animal experiments have shown that tunnels taking up more that 7-9% of the growth plate surface can result in growth restriction or angular deformity. ACL reconstruction in patients with distinct bone immaturity carries a high risk. The effect of growth on the biomechanical properties of a graft and a long-term consequence of surgical intervention in the growth plate is not yet understood. CONSLUSIONS: Although indications for surgical ACL repair and its timing are bound to be different in each patient, we consider the age of over 15 years to be ideal for ACL reconstruction. In patients younger than 15 years, the necessity of surgical treatment is questionable and conservative therapy can give good outcomes. No adverse effect of an applied graft on the post-operative results was demonstrated. The features of an immature skeleton are specific and complicated therefore, in our view, the relevant health care for paediatric patients should be concentrated into specialised institutions.