Faculty Bibliography

The most distal portion of the ventricular conduction system (VCS) contains cardiac Purkinje cells (PCs), which are essential for synchronous activation of the ventricular myocardium. Contactin-2 (CNTN2), a member of the immunoglobulin superfamily of cell adhesion molecules (IgSF-CAMs), was previously identified as a marker of the VCS. Through differential transcriptional profiling, we discovered two additional highly enriched IgSF-CAMs in the VCS: NCAM-1 and ALCAM. Immunofluorescence staining showed dynamic expression patterns for each IgSF-CAM during embryonic and early postnatal stages, but ultimately all three proteins became highly enriched in mature PCs. Mice deficient in NCAM-1, but not CNTN2 or ALCAM, exhibited defects in PC gene expression and VCS patterning, as well as cardiac conduction disease. Moreover, using ST8sia2 and ST8sia4 knockout mice, we show that inhibition of post-translational modification of NCAM-1 by polysialic acid leads to disrupted trafficking of sarcolemmal intercalated disc proteins to junctional membranes and abnormal expansion of the extracellular space between apposing PCs. Taken together, our data provide insights into the complex developmental biology of the ventricular conduction system.

BACKGROUND:We previously reported The Alopecia Areata Consensus of Experts (ACE) Study: Results of an International Expert Opinion on Treatments for Alopecia Areata (AA). OBJECTIVE:To report the results of the ACE international expert opinion on diagnosis and laboratory evaluation for AA. METHODS:Fifty hair experts from 5 continents were invited to participate in a 3 round Delphi process. Consensus threshold was set at >66%. RESULTS:Of 148 questions, expert consensus was achieved in 82 (55%) questions. Following round 1 consensus was achieved in 10 of 148 (7%) questions. Round 2 achieved consensus in 47 of 77 questions (61%). The final face-to-face achieved consensus in 25 of 32 (78%) questions. Consensus was greatest for laboratory evaluation (12 of 14 (86%) questions), followed by diagnosis (11 of 14 (79%) questions) of AA. Overall, etiopathogenesis achieved the least category consensus (31 of 68 (46%) questions). LIMITATIONS/CONCLUSIONS:The study had low representation from Africa, South America and Asia. CONCLUSION/CONCLUSIONS:There is expert consensus on aspects of epidemiology, etiopathogenesis, clinical features, diagnosis, laboratory evaluation and prognostic indicators of AA. The study also highlights areas where future clinical research could be directed to address unresolved hypotheses in AA patient care.

Staphylococcus aureus has evolved into diverse lineages, known as clonal complexes (CCs), which exhibit differences in the coding sequences of core virulence factors. Whether these alterations affect functionality is poorly understood. Here, we studied the highly polymorphic pore-forming toxin LukAB. We discovered that the LukAB toxin variants produced by S. aureus CC30 and CC45 kill human phagocytes regardless of whether CD11b, the previously established LukAB receptor, is present, and instead target the human hydrogen voltage-gated channel 1 (HVCN1). Biochemical studies identified the domain within human HVCN1 that drives LukAB species specificity, enabling the generation of humanized HVCN1 mice with enhanced susceptibility to CC30 LukAB and to bloodstream infection caused by CC30 S. aureus strains. Together, this work advances our understanding of an important S. aureus toxin and underscores the importance of considering genetic variation in characterizing virulence factors and understanding the tug of war between pathogens and the host.

Although distal radius fractures are quite common, bilateral distal radius fractures seldomly occur. Due to this, treatment is primarily based on surgeon experience with unilateral fractures, however bi- lateral fractures add a level of complexity : loss of functional independence. The purpose of this study was to examine a cohort of patients with bilateral distal radius fractures to identify differences in demographics, mechanism of injury, and outcomes to further our understanding of these rare injuries. 23 patients were identified retrospectively over a 5-year period that met inclusion criteria. The medical records were reviewed with multiple demographic and clinical parameters recorded and analyzed. Males were more likely to sustain high-energy mechanisms (80% vs. 53%). Patients <50 years old were more likely to sustain high-energy mechanisms (90% vs. 46%) and were more likely to be treated operatively (80% vs. 62%). The most commonly associated injury was a head injury (30%). All patients treated non-operatively reported minimal/no pain upon final follow-up where 57% of patients treated operatively noted regular pain. 75% of patients with medical comorbidities had minimal/no pain upon final follow- up. Conclusions : Patients with bilateral fractures were more likely to be younger males who suffered from higher energy mechanisms. Age was a critical factor in determining treatment strategy. Rates of associated head injuries were elevated, which is an important factor for the clinician to keep in mind when treating this population. As we further our understanding of this unique population, we can improve our treatment approaches and subsequently attain better outcomes.

The management of large segmental bone defects caused by trauma or disease remains clinically challenging within orthopaedics. The major impediment to bone healing with current treatment options is insufficient vascularization and incorporation of graft material. Lack of rapid adequate vascularization leads to cellular necrosis within the inner regions of the implanted material and a failure of bone regeneration. Current treatment options for critical size bone defects include the continued "gold standard" autograft, allograft, synthetic bone graft substitutes, vascularized fibular graft, induced membrane technique, and distraction osteogenesis. Bone tissue engineering (BTE) remains an exciting prospect for the treatment of large segmental bone defects; however, current clinical integration of engineered scaffolds remains low. We believe that the barrier to clinical application of bone tissue engineering constructs lies in the lack of concomitant vascularization of these scaffolds. This mini-review outlines the progress made and the significant limitations remaining in successful clinical incorporation or engineered synthetic bone substitutes for segmental defects.

Interest and research in biologic approaches for tissue healing are exponentially growing for a variety of musculoskeletal conditions. The recent hype concerning musculoskeletal biological therapies (including viscosupplementation, platelet-rich plasma, and cellular therapies, or "stem cells") is driven by several factors, including demand by patients promising regenerative evidence supported by substantial basic and translational work, as well as commercial endeavors that complicate the scientific and lay understanding of biological therapy outcomes. While significant improvements have been made in the field, further basic and preclinical research and well-designed randomized clinical trials are needed to better elucidate the optimal indications, processing techniques, delivery, and outcome assessment. Furthermore, biologic treatments may have potential devastating complications when proper methods or techniques are ignored. For these reasons, an association comprising several scientific societies, named the Biologic Association (BA), was created to foster coordinated efforts and speak with a unified voice, advocating for the responsible use of biologics in the musculoskeletal environment in clinical practice, spearheading the development of standards for treatment and outcomes assessment, and reporting on the safety and efficacy of biologic interventions. This article will introduce the BA and its purpose, provide a summary of the 2020 first annual Biologic Association Summit, and outline the future strategic plan for the BA.

Embryonic mammary gland development involves the formation of mammary placodes, invagination of flask-shaped mammary buds and development of miniature bi-layered ductal trees. Currently there is a good understanding of the factors that contribute to ectodermal cell movements to create these appendages and of pathways that lead to mammary specification and commitment. Gene expression profiles of early bipotent mammary stem cells populations as well as cell surface proteins and transcription factors that promote the emergence of unipotent progenitors have been identified. Analyses of these populations has illuminated not only embryonic mammary development, but highlighted parallel processes in breast cancer. Here we provide an overview of the highly conserved pathways that shape the embryonic mammary gland. Understanding the dynamic signaling events that occur during normal mammary development holds considerable promise to advance attempts to eliminate cancer by restoring differentiative signals.

Burn scars and scar contractures cause significant morbidity for patients. Recently, cell-based therapies have been proposed as an option for improving healing and reducing scarring after burn injury, through their known pro-angiogenic and immunomodulatory paracrine effects. Our lab has developed a pullulan-collagen hydrogel that, when seeded with mesenchymal stem cells (MSCs), improves cell viability and augments their pro-angiogenic capacity in vivo. Concurrently, recent research suggests that prospective isolation of cell subpopulations with desirable transcriptional profiles can be used to further improve cell-based therapies. In this study, we examined whether adipose-derived stem cell-seeded hydrogels could improve wound healing following thermal injury using a murine contact burn model. Partial thickness contact burns were created on the dorsum of mice. On days 5 and 10 following injury, burns were debrided and received either ASC-hydrogel, ASC injection alone, hydrogel alone, or no treatment. On days 10 and 25, burns were harvested for histologic and molecular analysis. This experiment was repeated using CD26+/CD55+ FACS-enriched ASCs to further evaluate the regenerative potential of ASCs in wound healing. ASC-hydrogel-treated burns demonstrated accelerated time to re-epithelialization, greater vascularity, and increased expression of the pro-angiogenic genes MCP-1, VEGF, and SDF-1 at both the mRNA and protein level. Expression of the pro-fibrotic gene Timp1 and pro-inflammatory gene Tnfa were down-regulated in ASC-hydrogel treated burns. ASC-hydrogel treated burns exhibited reduced scar area compared to hydrogel-treated and control wounds, with equivalent scar density. CD26+/CD55+ ASC-hydrogel treatment resulted in accelerated healing, increased dermal appendage count, and improved scar quality with a more reticular collagen pattern. Here we find that ASC-hydrogel therapy is effective for treating burns, with demonstrated pro-angiogenic, fibro-modulatory and immunomodulatory effects. Enrichment for CD26+/CD55+ ASCs has additive benefits for tissue architecture and collagen remodeling post-burn injury. Research is ongoing to further facilitate clinical translation of this promising therapeutic approach.

The rising prevalence of autism spectrum disorder (ASD) necessitates a greater understanding of the academic experience of diagnosed children. The present study investigates several predictors of teacher-reported academic competence among a sample of elementary school children. All children in the sample were referred for an ASD evaluation and approximately half received a diagnosis. Children with and without ASD did not differ on overall academic competence, social skills, or problem behaviors. Regression analyses indicated that cognitive ability, social skills, and problem behaviors accounted for significant variance in academic competence. Moderation analyses indicated that the relations between the predictors and academic competence were comparable for children with and without ASD. Implications and future directions are discussed.

BACKGROUND:The therapeutic effect of carotid endarterectomy (CEA) on visual disturbance caused by chronic ocular ischemia due to carotid artery stenosis has not been validated. This prospective observational study aims to investigate whether CEA is associated with an increase in ocular blood flow (OBF) and postoperative visual improvement. METHODS:In total, 41 patients with carotid artery stenosis treated by CEA between March 2015 and September 2018 were enrolled in this study. OBF was evaluated by laser speckle flowgraphy, which can measure the mean blur ratio (MBR) which is well correlated to the absolute retinal blood flow. Visual acuity was assessed before and after CEA by subjective improvement and objective visual assessment using CSV-1000, an instrument used to test contrast sensitivity. RESULTS:OBF increased after CEA on the operated side (mean MBR 33.5 vs 38.2, p < 0.001) but not on the non-operated side (mean MBR 37.8 vs 37.5, p = 0.50). After CEA, 23 patients (56.1%) reported subjective visual improvement on the operated side. The mean CSV-1000 score among the patients with increased OBF after CEA (5.44 vs 5.88, p = 0.04) but not among those without increased OBF (5.48 vs 5.95, p = 0.09). The mean CSV-1000 scores increased significantly after CEA in 18 patients with decreased vision and decreased OBF (4.51 vs 5.37, p < 0.001), but not in the 23 patients without those (6.19 vs 6.31, p = 0.6). CONCLUSION/CONCLUSIONS:CEA may successfully reverse visual dysfunction caused by chronic ocular ischemia due to carotid artery stenosis by increasing OBF.