Mutations in the gene Centrosomal Protein 290 kDa ( CEP290 ) result in multiple ciliopathies ranging from the neonatal lethal disorder Meckel-Gruber Syndrome to multi-systemic disorders such as Joubert Syndrome and Bardet-Biedl Syndrome to nonsyndromic diseases like Leber Congenital Amaurosis (LCA) and retinitis pigmentosa. Results from model organisms and human genetics studies, have suggest that mutations in genes encoding protein components of the transition zone (TZ) and other cilia-associated proteins can function as genetic modifiers and be a source for CEP290 pleiotropy. We investigated the zebrafish cep290 fh297/fh297 mutant, which encodes a nonsense mutation (p.Q1217*). This mutant is viable as adults, exhibits scoliosis, and undergoes a slow, progressive cone degeneration. The cep290 fh297/fh297 mutants showed partial mislocalization of the transmembrane protein rhodopsin but not of the prenylated proteins rhodopsin kinase (GRK1) or the rod transducin subunit GNB1. Surprisingly, photoreceptor degeneration did not trigger proliferation of Müller glia, but proliferation of rod progenitors in the outer nuclear layer was significantly increased. To determine if heterozygous mutations in other cilia genes could exacerbate retinal degeneration, we bred cep290 fh297/fh297 mutants to arl13b , ahi1 , and cc2d2a mutant zebrafish lines. While cep290 fh297/fh297 mutants lacking a single allele of these genes did not exhibit accelerated photoreceptor degeneration, loss of one alleles of arl13b or ahi1 reduced visual performance in optokinetic response assays at 5 days post fertilization. Our results indicate that the cep290 fh297/fh297 mutant is a useful model to study the role of genetic modifiers on photoreceptor degeneration in zebrafish and to explore how progressive photoreceptor degeneration influences regeneration in adult zebrafish.
Mutations in the gene Centrosomal Protein 290 kDa (CEP290) result in multiple ciliopathies ranging from the neonatal lethal disorder Meckel-Gruber Syndrome to multi-systemic disorders such as Joubert Syndrome and Bardet-Biedl Syndrome to nonsyndromic diseases like Leber Congenital Amaurosis (LCA) and retinitis pigmentosa. Results from model organisms and human genetics studies, have suggest that mutations in genes encoding protein components of the transition zone (TZ) and other cilia-associated proteins can function as genetic modifiers and be a source for CEP290 pleiotropy. We investigated the zebrafish cep290fh297/fh297 mutant, which encodes a nonsense mutation (p.Q1217*). This mutant is viable as adults, exhibits scoliosis, and undergoes a slow, progressive cone degeneration. The cep290fh297/fh297 mutants showed partial mislocalization of the transmembrane protein rhodopsin but not of the prenylated proteins rhodopsin kinase (GRK1) or the rod transducin subunit GNB1. Surprisingly, photoreceptor degeneration did not trigger proliferation of Müller glia, but proliferation of rod progenitors in the outer nuclear layer was significantly increased. To determine if heterozygous mutations in other cilia genes could exacerbate retinal degeneration, we bred cep290fh297/fh297 mutants to arl13b, ahi1, and cc2d2a mutant zebrafish lines. While cep290fh297/fh297 mutants lacking a single allele of these genes did not exhibit accelerated photoreceptor degeneration, loss of one alleles of arl13b or ahi1 reduced visual performance in optokinetic response assays at 5 days post fertilization. Our results indicate that the cep290fh297/fh297 mutant is a useful model to study the role of genetic modifiers on photoreceptor degeneration in zebrafish and to explore how progressive photoreceptor degeneration influences regeneration in adult zebrafish.Nonstandard abbreviationsBBSBardet-Biedl SyndromeCOScone outer segmentsDpfDays post fertilizationGNB1rod transducin β subunitGRK1rhodopsin kinaseJTBSJoubert SyndromeLCALeber Congenital AmaurosisMKSMeckel SyndromeNPHPnephronophthisisOKRoptokinetic responsePNApeanut agglutinin lectinROSrod outer segmentsRP2Retinitis Pigmentosa 2
Objective: Comparing outcomes after cricopharyngeal myotomy (CM) performed by otolaryngologists (OTO) and non-otolaryngologists (NO).Methods: A retrospective analysis of the 2014-19 ACS-NSQIP database (American College of Surgeons National Surgical Quality Improvement Program) of patients who underwent open CM (CPT code 43030) as their primary procedure. Analyzed variables include medical comorbidities, operative time, the total length of stay, readmission, reoperation, concurrent procedures, postoperative complications, and postoperative diagnoses. 183 patients were included, 97 (53%) females and 86 (47%) males. 120 had surgery by OTO and 63 by NO.Results: There were no differences in preoperative morbidity. OTO had more outpatient surgeries compared to NO (p<.001). OTO had a longer mean operating time (p=.008). OTO had a higher proportion of concurrent laryngeal procedures and other unspecified procedures compared to NO, while NO had a higher proportion of concurrent esophageal procedures (p=.028). The total length of stay was not significantly different between the two groups. 5.8% OTO and 7.9% NO patients were readmitted for a related reason (p=.586). Complications were similar between the two groups (p>.05). NO had more postop diagnoses of acquired diverticula and achalasia of the stomach cardia, while OTO had more diagnoses of dysphagia and muscular dystrophy (p<.001).Conclusion: There were differences in the surgical setting, length of procedure, concurrent procedures, and postop diagnoses between NO and OTO surgeons but similar complication rates.
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