Copy Number Changes Identified Using Whole Exome Sequencing in Nonsyndromic Cleft Lip and Palate in a Honduran Population.

BACKGROUND: The majority of cleft lip with or without cleft palate cases appear as an isolated, nonsyndromic entity (NSCLP). With the advent of next generation sequencing, whole exome sequencing (WES) has been used to identify single nucleotide variants and insertion/deletions which cause or increase the risk of NSCLP. However, to our knowledge, there are no published studies using WES in NSCLP to investigate copy number changes (CNCs), which are a major component of human genetic variation. Our study aimed to identify CNCs associated with NSCLP in a Honduran population using WES. METHODS: WES was performed on two to four members of 27 multiplex Honduran families. CNCs were identified using two algorithms, CoNIFER and XHMM. Priority was given to CNCs that were identified in more than one patient and had variant frequencies of less than 5% in reference data sets. RESULTS: WES completion was defined as >90% of the WES target at >8 × coverage and >80% of the WES target at >20 × coverage. Twenty-four CNCs that met our inclusion criteria were identified by both CoNIFER and XHMM. These CNCs were confirmed using quantitative PCR. Pedigree analysis produced three CNCs corresponding to ADH7, AHR, and CRYZ segregating with NSCLP. Two of the three CNCs implicate genes, AHR and ADH7, whose known biological functions could plausibly play a role in NSCLP. CONCLUSION: WES can be used to detect candidate CNCs that may be involved in the pathophysiology of NSCLP. Birth Defects Research 109:1257-1267, 2017. © 2017 Wiley Periodicals, Inc.

Patterns in the evaluation of hoarseness: time to presentation, laryngeal visualization, and diagnostic accuracy.

OBJECTIVES/HYPOTHESIS: Controversial recommendations regarding the evaluation of dysphonia have been made in the absence of evidence related to clinical practice. This study aims to describe existing patterns of care for dysphonia to generate data for potential systemic improvement and provide a baseline for dysphonia recommendations. STUDY DESIGN: Retrospective review. METHODS: Information regarding the current complaint, including duration of hoarseness; inciting factors; number and type of previous physicians seen; Voice Handicap Index-10; and details of prior evaluation, diagnosis, and treatment was collected from patient records. RESULTS: A total of 259 patients complaining of hoarseness were evaluated. Of those, 35.1% presented directly to subspecialty care, whereas 61% were previously evaluated by another otolaryngologist. Median times (in months) from symptom onset to evaluation were as follows: initial evaluation, 3.0; laryngoscopy, 3.0; stroboscopic exam, 5.8; subspecialty evaluation, 6.6. A total of 64.5% of patients had at least one incoming diagnosis; 45% of all incoming diagnoses were revised on re-evaluation. Diagnoses most commonly revised included "no abnormality," edema or laryngopharyngeal reflux disease (LPR), infection or allergy, and muscle tension dysphonia (MTD) or behavioral disorders. Final diagnoses that most frequently differed from incoming diagnoses were paresis; MTD or behavioral disorders; malignancy; and sulcus, atrophy, or scar. CONCLUSIONS: Patients received prompt laryngeal visualization. However, we observed high rates of diagnostic error. Initial diagnoses of LPR, edema, infection, and allergy appear to be particularly likely to be revised on further evaluation; and scar, sulcus, atrophy, and paresis are likely to be overlooked.

Isoflurane preconditioning affords functional neuroprotection in a murine model of intracerebral hemorrhage.

INTRODUCTION: Exposure to isoflurane gas prior to neurological injury, known as anesthetic preconditioning, has been shown to provide neuroprotective benefits in animal models of ischemic stroke. Given the common mediators of cellular injury in ischemic and hemorrhagic stroke, we hypothesize that isoflurane preconditioning will provide neurological protection in intracerebral hemorrhage (ICH). METHODS: 24 h prior to intracerebral hemorrhage, C57BL/6J mice were preconditioned with a 4-h exposure to 1% isoflurane gas or room air. Intracerebral hemorrhage was performed using a double infusion of 30-µL autologous whole blood. Neurological function was evaluated at 24, 48 and 72 h using the 28-point test. Mice were sacrificed at 72 h, and brain edema was measured. RESULTS: Mice preconditioned with isoflurane performed better than control mice on 28-point testing at 24 h, but not at 48 or 72 h. There was no significant difference in ipsilateral hemispheric edema between mice preconditioned with isoflurane and control mice. CONCLUSION: These results demonstrate the early functional neuroprotective effects of anesthetic preconditioning in ICH and suggest that methods of preconditioning that afford protection in ischemia may also provide protection in ICH.