A Longitudinal Investigation of Nasolabial Changes With and Without Revision Surgery in Patients with Non-Syndromic Unilateral Cleft Lip and Palate.

OBJECTIVE: To determine a baseline of anticipated change in nasolabial appearance following primary repair of unilateral cleft lip/palate and evaluate the degree to which revision surgery improves nasolabial appearance. DESIGN: Retrospective chart review. SETTING: Patients treated at the Lancaster Cleft Palate Clinic interdisciplinary clinic. PATIENTS: Twenty-three patients with complete unilateral cleft lip and palate who underwent primary surgical repair and 19 additional patients who underwent subsequent revision surgery were included. INTERVENTIONS: Patients in the non-revision group underwent a Tennison-Randall triangular flap lip repair at 3mo. Patients in the revision group underwent a modification of the Nakajima straight-line repair after primary Tennison-Randall triangular flap lip repair at an average age of 141mo. MAIN OUTCOME MEASURES: A modification of the Asher-McDade Aesthetic Index was utilized to evaluate Nasolabial Frontal (NLF), Nasolabial Profile (NLP), Vermillion Border (VB), and total change in appearance. Scores for patients in the revision group were evaluated before and after revision while appearance for patients without revision was evaluated at 3 distinct ages. Scores were averaged across time-points and inter-rater reliability was assessed. RESULTS: Nasolabial appearance in the non-revision sample did not change significantly over time, except for nasal profile. Scores improved after revision surgery - NLP: 3.48 to 2.97, (p = 0.001); NLF: 3.50 to 2.95 (p = 0.001); and Total Nasolabial Score: 3.29 to 3.01 (p = 0.004), with no significant change in VB. CONCLUSION: Decisions regarding need for nasolabial revision surgery may be made as early as 5yo with successful outcomes following secondary surgery improving appearance except for vermillion border appearance.

LRRC8A is dispensable for a variety of microglial functions and response to acute stroke.

Microglia, resident brain immune cells, are critical in orchestrating responses to central nervous system (CNS) injury. Many microglial functions, such as phagocytosis, motility and chemotaxis, are suggested to rely on chloride channels, including the volume-regulated anion channel (VRAC), but studies to date have relied on the use of pharmacological tools with limited specificity. VRAC has also been proposed as a drug target for acute CNS injury, and its role in microglial function is of considerable interest for developing CNS therapeutics. This study aimed to definitively confirm the contribution of VRAC in microglia function by using conditional LRRC8A-knockout mice, which lacked the essential VRAC subunit LRRC8A in microglia. We demonstrated that while VRAC contributed to cell volume regulation, it had no effect on phagocytic activity, cell migration or P2YR12-dependent chemotaxis. Moreover, loss of microglial VRAC did not affect microglial morphology or the extent of ischemic damage following stroke. We conclude that VRAC does not critically regulate microglial responses to brain injury and could be targetable in other CNS cell types (e.g., astrocytes) without impeding microglial function. Our results also demonstrate a role for VRAC in cell volume regulation but show that VRAC is not involved in several major cellular functions that it was previously thought to regulate, and point to other, alternative mechanisms of chloride transport in innate immunity.

Evaluation of pain related behaviors and disease related outcomes in an immunocompetent mouse model of prostate cancer induced bone pain.

Cancer-induced bone pain (CIBP) is the most common and devastating symptom of bone metastatic cancer that substantially disrupts patients' quality of life. Currently, there are few effective analgesic treatments for CIBP other than opioids which come with severe side effects. In order to better understand the factors and mechanisms responsible for CIBP it is essential to have clinically relevant animal models that mirror pain-related symptoms and disease progression observed in patients with bone metastatic cancer. In the current study, we characterize a syngeneic mouse model of prostate cancer induced bone pain. We transfected a prostate cancer cell line (RM1) with green fluorescent protein (GFP) and luciferase reporters in order to visualize tumor growth longitudinally in vivo and to assess the relationship between sensory neurons and tumor cells within the bone microenvironment. Following intra-femoral injection of the RM1 prostate cancer cell line into male C57BL/6 mice, we observed a progressive increase in spontaneous guarding of the inoculated limb between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. Daily running wheel performance was evaluated as a measure of functional impairment and potentially movement evoked pain. We observed a progressive reduction in the distance traveled and percentage of time at optimal velocity between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. We utilized histological, radiographic and µCT analysis to examine tumor induced bone remodeling and observed osteolytic lesions as well as extra-periosteal aberrant bone formation in the tumor bearing femur, similar to clinical findings in patients with bone metastatic prostate cancer. Within the tumor bearing femur, we observed reorganization of blood vessels, macrophage and nerve fibers within the intramedullary space and periosteum adjacent to tumor cells. Tumor bearing mice displayed significant increases in the injury marker ATF3 and upregulation of the neuropeptides SP and CGRP in the ipsilateral DRG as well as increased measures of central sensitization and glial activation in the ipsilateral spinal cord. This immunocompetent mouse model will be useful when combined with cell type selective transgenic mice to examine tumor, immune cell and sensory neuron interactions in the bone microenvironment and their role in pain and disease progression associated with bone metastatic prostate cancer.