Endoscopic posterior cordotomy for treatment of dyspnea due to vocal fold immobility.

INTRODUCTION: Several surgical procedures have been described for the treatment of respiratory distress secondary to vocal fold immobility (VFI), but the contribution of posterior cordotomy (PC) to tracheostomy weaning or prevention has not been studied in depth, particularly in the acute setting. The objective of this study was to show the effectiveness of PC to relieve dyspnea, prevent the need for tracheostomy, and enable decannulation in patients with VFI. METHODS: We conducted a retrospective study and reviewed the medical records of all patients whose dyspnea warranted surgical intervention from January 2013 to January 2018. Data were retrieved on epidemiology, etiology, and duration of VFI, tracheostomy dependence, success in decannulation from tracheostomy or respiratory relief, number of procedures until decannulation, and complications. RESULTS: Twelve suitable patients were identified of whom eleven had bilateral VFI and one had unilateral VFI. Five were tracheostomy-dependent. Ten patients underwent unilateral PC, and two patients underwent bilateral PC. All the patients experienced respiratory relief, eleven after a single PC and one after two PCs. All tracheostomy-dependent patients were decannulated. The mean follow-up after PC was 24.55 months during which none of the patients required a re-tracheostomy and three patients required revision of the PC. There were no surgical complications. Postoperatively, eight patients (67%) experienced a breathy voice and three patients (25%) had dysphagia for fluids. No patient had aspiration pneumonia. CONCLUSIONS: We conclude that PC is an easy, safe, and effective procedure for tracheostomy weaning and respiratory relief in patients with VFI. A revision PC may be indicated in some patients. A breathy voice is to be expected, and a few patients will experience dysphagia to fluids that may be addressed by instructing the patient to use a fluid thickener and take small sips.

Connexin43 and Runx2 Interact to Affect Cortical Bone Geometry, Skeletal Development, and Osteoblast and Osteoclast Function.

The coupling of osteoblasts and osteocytes by connexin43 (Cx43) gap junctions permits the sharing of second messengers that coordinate bone cell function and cortical bone acquisition. However, details of how Cx43 converts shared second messengers into signals that converge onto essential osteogenic processes are incomplete. Here, we use in vitro and in vivo methods to show that Cx43 and Runx2 functionally interact to regulate osteoblast gene expression and proliferation, ultimately affecting cortical bone properties. Using compound hemizygous mice for the Gja1 (Cx43) and Runx2 genes, we observed a skeletal phenotype not visible in wild-type or singly hemizygous animals. Cortical bone analysis by micro-computed tomography (µCT) revealed that 8-week-old male, compound Gja1+/- Runx2+/- mice have a marked increase in cross-sectional area, endosteal and periosteal bone perimeter, and an increase in porosity compared to controls. These compound Gja1+/- Runx2+/- mice closely approximate the cortical bone phenotypes seen in osteoblast-specific Gja1-conditional knockout models. Furthermore, µCT analysis of skulls revealed an altered interparietal bone geometry in compound hemizygotes. Consistent with this finding, Alizarin red/Alcian blue staining of 2-day-old Gja1+/- Runx2+/- neonates showed a hypomorphic interparietal bone, an exacerbation of the open fontanelles, and a further reduction in the hypoplastic clavicles compared to Runx2+/- neonates. Expression of osteoblast genes, including osteocalcin, osterix, periostin, and Hsp47, was markedly reduced in tibial RNA extracts from compound hemizygous mice, and osteoblasts from compound hemizygous mice exhibited increased proliferative capacity. Further, the reduced osteocalcin expression and hyperproliferative nature of osteoblasts from Cx43 deficient mice was rescued by Runx2 expression. In summary, these findings provide evidence that Cx43 and Runx2 functionally intersect in vivo to regulate cortical bone properties and affect osteoblast differentiation and proliferation, and likely contributes to aspects of the skeletal phenotype of Cx43 conditional knockout mice. © 2017 American Society for Bone and Mineral Research.

Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation.

In skeletal tissue, loss or mutation of the gap junction protein connexin 43 (Cx43, also known as GJA1) in cells of the osteoblast lineage leads to a profound cortical bone phenotype and defective tissue remodeling. There is mounting evidence in bone cells that the C-terminus (CT) of Cx43 is a docking platform for signaling effectors and is required for efficient downstream signaling. Here, we examined this function, using a mouse model of Cx43 CT-truncation (Gja1 K258Stop). Relative to Gja1+/- controls, male Gja1-/K258Stop mice have a cortical bone phenotype that is remarkably similar to those reported for deletion of the entire Cx43 gene in osteoblasts. Furthermore, we show that the Cx43 CT binds several signaling proteins that are required for optimal osteoblast function, including PKCδ, ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1, respectively) and ß-catenin. Deletion of the Cx43 CT domain affects these signaling cascades, impacting osteoblast proliferation, differentiation, and collagen processing and organization. These data imply that, at least in bone, Cx43 gap junctions not only exchange signals, but also recruit the appropriate effector molecules to the Cx43 CT in order to efficiently activate signaling cascades that affect cell function and bone acquisition.