Valeriy Shubinets

Distinct requirements for wnt9a and irf6 in extension and integration mechanisms during zebrafish palate morphogenesis

Development of the palate in vertebrates involves cranial neural crest migration, convergence of facial prominences and extension of the cartilaginous framework. Dysregulation of palatogenesis results in orofacial clefts, which represent the most common structural birth defects. Detailed analysis of zebrafish palatogenesis revealed distinct mechanisms of palatal morphogenesis: extension, proliferation and integration. We show that wnt9a is required for palatal extension, wherein the chondrocytes form a proliferative front, undergo morphological change and intercalate to form the ethmoid plate. Meanwhile, irf6 is required specifically for integration of facial prominences along a V-shaped seam. This work presents a mechanistic analysis of palate morphogenesis in a clinically relevant context.

Requirement for frzb and fzd7a in cranial neural crest convergence and extension mechanisms during zebrafish palate and jaw morphogenesis

Regulation of convergence and extension by wnt-frizzled signaling is a common theme in embryogenesis. This study examines the functional requirements of frzb and fzd7a in convergence and extension mechanisms during craniofacial development. Using a morpholino knockdown approach, we found that frzb and fzd7a are dispensable for directed migration of the bilateral trabeculae, but necessary for the convergence and extension of the palatal elements, where the extension process is mediated by chondrocyte proliferation, morphologic change and intercalation. In contrast, frzb and fzd7a are required for convergence of the mandibular prominences, where knockdown of either frzb or fzd7a resulted in complete loss of lower jaw structures. Further, we found that bapx1 was specifically downregulated in the wnt9a/frzb/fzd7a morphants, while general neural crest markers were unaffected. In addition, expression of wnt9a and frzb was also absent in the edn-/- mutant. Notably, over-expression of bapx1 was sufficient to partially rescue mandibular elements in the wnt9a/frzb/fzd7a morphants, demonstrating genetic epistasis of bapx1 acting downstream of edn1 and wnt9a/frzb/fzd7a in lower jaw development. This study underscores the important role of wnt-frizzled signaling in convergence and extension in palate and craniofacial morphogenesis, distinct regulation of upper vs. lower jaw structures, and integration of wnt-frizzled with endothelin signaling to coordinate shaping of the facial form.

Functional Analysis of SPECC1L in Craniofacial Development and Oblique Facial Cleft Pathogenesis

Background: Oblique facial clefts, also known as Tessier clefts, are severe orofacial clefts, the genetic basis of which is poorly understood. Human genetics studies revealed that disruption in SPECC1L resulted in oblique facial clefts, demonstrating that oblique facial cleft malformation has a genetic basis. An important step toward innovation in treatment of oblique facial clefts would be improved understanding of its genetic pathogenesis. The authors exploit the zebrafish model to elucidate the function of SPECC1L by studying its homolog, specc1lb. Methods: Gene and protein expression analysis was carried out by reverse-transcriptase polymerase chain reaction and immunohistochemistry staining. Morpholino knockdown, mRNA rescue, lineage tracing and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assays were performed for functional analysis. Results: Expression of specc1lb was detected in epithelia juxtaposed to chondrocytes. Knockdown of specc1lb resulted in bilateral clefts between median and lateral elements of the ethmoid plate, structures analogous to the frontonasal process and the paired maxillary processes. Lineage tracing analysis revealed that cranial neural crest cells contributing to the frontonasal prominence failed to integrate with the maxillary prominence populations. Cells contributing to lower jaw structures were able to migrate to their destined pharyngeal segment but failed to converge to form mandibular elements. Conclusions: These results demonstrate that specc1lb is required for integration of frontonasal and maxillary elements and convergence of mandibular prominences. The authors confirm the role of SPECC1L in orofacial cleft pathogenesis in the first animal model of Tessier cleft, providing morphogenetic insight into the mechanisms of normal craniofacial development and oblique facial cleft pathogenesis.

Surgically Treated Hernia following Abdominally Based Autologous Breast Reconstruction: Prevalence, Outcomes, and Expenditures.

Background: Donor-site hernia is one of the most feared complications following abdominally based autologous breast reconstruction. The authors aim to assess the incidence of surgically repaired abdominal hernia across different types of abdominally based breast reconstruction, identify predictive perioperative factors, and estimate the health care charges associated with this morbidity. Methods: Using inpatient and ambulatory surgery data from four states in the United States, the authors identified adult women who underwent pedicled transverse rectus abdominis muscle (TRAM), free TRAM, or deep inferior epigastric perforator (DIEP) flap breast reconstruction between 2008 and 2012. The primary outcome was surgical repair of abdominal hernia within 4 years. Multivariate Cox proportional hazards regression modeling was used to compare outcomes between groups. Results: The final sample included 8246 women who underwent pedicled TRAM (29.2 percent), free TRAM (30.0 percent), or DIEP (40.8 percent) flap reconstruction. The frequency of surgically repaired abdominal hernia following breast reconstruction was highest among the pedicled TRAM flap group (pedicled TRAM, 7.0 percent; free TRAM, 5.7 percent; DIEP, 1.8 percent). A hospital encounter for hernia repair, whether inpatient or ambulatory, generated substantial health care charges (pedicled TRAM,

Predicting incisional hernia after bariatric surgery: a risk stratification model based upon 2161 operations

39,704; free TRAM,

Chemical component separation: a systematic review and meta-analysis of botulinum toxin for management of ventral hernia

48,378; DIEP,

Classification of synpolydactyly: experience in 10 children.

46,481). On multivariate analysis, patients who developed a surgical-site infection within 30 days of discharge (incidence rate ratio, 1.99; 95 percent CI, 1.44 to 2.75) had a higher incidence of surgically repaired abdominal hernia. Conclusions: Surgically repaired abdominal hernia is common following abdominally based autologous breast reconstruction and is associated with significant health care expenditures. The authors demonstrate that the amount of rectus muscle sacrificed correlates to the likelihood of developing a surgically repaired abdominal hernia, and identify surgical-site infection as a predictive perioperative factor. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Ulnar Thumb Pulp Reconstruction Using the Anterograde Homodigital Neurovascular Island Flap

BACKGROUND Incisional hernia (IH) is a persistent cause of morbidity and diminished quality of life and a substantial source of healthcare resource utilization. The literature suggests prophylactic mesh augmentation reduces IH risk in bariatric surgery, but no predictive models are available. OBJECTIVES Identify factors associated with IH after bariatric surgery to develop a clinically actionable preoperative risk stratification tool to optimize outcomes and mitigate healthcare costs after bariatric surgery. SETTING University hospital, United States. METHODS All patients undergoing open or laparoscopic bariatric surgery from January 2005 to June 2013 at one institution were identified. Co-morbidities and operative characteristics were assessed. The primary outcome was surgically treated IH after index procedures. Patients with prior hernia,<1-year follow-up, or body mass index<40 kg/m2 were excluded. Cox hazard regression modeling with bootstrapped validation, risk factor stratification, and assessment of model performance were conducted. RESULTS A total of 2161 bariatric patients were included, 2.4% of whom developed IH (follow-up 28.3±25.4 mo). Predictors for IH included open surgical approach (hazard ratio [HR] = 10.3), malnutrition (HR = 3.10), prior abdominal surgery (HR = 2.89), and body mass index>60 kg/m2 (HR = 2.60). Based on these risk factors, patients were stratified into low-, moderate-, and high-risk categories for IH development. Of the high-risk patients, 15.2% developed IH compared with .6% of low-risk patients (C-statistic = .85). Treatment of IH and associated complications exceeded

Pollicization of Biphalangeal Index Finger for Type IV Thumb Hypoplasia: A Case Report Describing Preoperative Planning, Intraoperative Decision-Making, and Technical Modifications

3.5 million in healthcare costs. CONCLUSION Bariatric surgery conferred an IH risk of 2.4%. IH was associated with additional readmissions and complications and substantially greater costs and resource utilization. This risk stratification tool identifies candidates for prophylactic mesh augmentation, which may optimize outcomes while mitigating costs.

Abstract P28. Soft Tissue Reconstruction after Complicated Knee Replacement: Principles and Predictors of Knee Salvage

Abstract Background: Ventral hernia represents a surgical challenge plagued by high morbidity and recurrence rates. Primary closure of challenging hernias is often prohibited by severe lateral retraction and tension of the abdominal wall musculature. Botulinum toxin injections have recently been identified as a potential pre-operative means to counteract abdominal wall tension, reduce hernia size, and facilitate fascial closure during hernia repair. This systematic review and meta-analysis reviews outcomes associated with botulinum toxin injections in the setting of ventral hernia, and demonstrates an opportunity to leverage this mainstream aesthetic product for use in abdominal wall reconstruction. Methods: A literature review was conducted according to PRISMA guidelines using MeSH terms ‘ventral hernia’, ‘herniorrhaphy’, ‘hernia repair’, and ‘botulinum toxins’. Relevant studies reporting pre- and postinjection data were included. Outcomes of interest included changes in hernia defect width and lateral abdominal muscle length, recurrence, complications, and patient follow-up. Qualitative findings were also considered to help demonstrate valuable themes across the literature. Results: Of 133 results, 12 were included for qualitative review and three for quantitative analysis. Meta-analysis revealed significant hernia width reduction (mean = 5.79 cm; n = 29; p < 0.001) and lateral abdominal wall muscular lengthening (mean = 3.33 cm; n = 44; p < 0.001) following botulinum injections. Mean length of follow-up was 24.7 months (range = 9–49). Conclusions: Botulinum toxin injections offer tremendous potential in ventral hernia management by reducing hernia width and lengthening abdominal wall muscles prior to repair. Although further studies are needed, there is a significant opportunity to bridge the knowledge gap in preoperative practice measures for ventral hernia risk reduction.