Familial dysautonomia (FD) is characterized by severe and progressive sympathetic and sensory neuron loss caused by a highly conserved germline point mutation of the human ELP1/IKBKAP gene. Elp1 is a subunit of the hetero-hexameric transcriptional elongator complex, but how it functions in disease-vulnerable neurons is unknown. Conditional knockout mice were generated to characterize the role of Elp1 in migration, differentiation and survival of migratory neural crest (NC) progenitors that give rise to sympathetic and sensory neurons. Loss of Elp1 in NC progenitors did not impair their migration, proliferation or survival, but there was a significant impact on post-migratory sensory and sympathetic neuron survival and target tissue innervation. Ablation of Elp1 in post-migratory sympathetic neurons caused highly abnormal target tissue innervation that was correlated with abnormal neurite outgrowth/branching and abnormal cellular distribution of soluble tyrosinated α-tubulin in Elp1-deficient primary sympathetic and sensory neurons. These results indicate that neuron loss and physiologic impairment in FD is not a consequence of abnormal neuron progenitor migration, differentiation or survival. Rather, loss of Elp1 leads to neuron death as a consequence of failed target tissue innervation associated with impairments in cytoskeletal regulation.

2c Laryngoscope, 126:602-607, 2016.

BackgroundGlycemic control is a known modifiable risk factor for diabetic foot disease. Prior attempts to define its relationship with diabetic foot ulcer and Charcot arthropathy fail to account for variability in control and duration of diabetic disease. We developed a novel metric to reflect aggregate disease exposure in a diabetic, termed cumulative glycemic burden. We hypothesized that it would be positively associated with both diabetic foot ulcer and radiographically diagnosed Charcot arthropathy.MethodsPatients aged 18 to 90 years with ≥3 hemoglobin A1c (HbA1c) values were identified retrospectively at a single institution over a 15-year period. Primary outcomes were ICD-9 diagnosis of foot ulcer and radiographically diagnosed Charcot arthropathy. Cumulative glycemic burden was calculated by trapezoidal integration of the area under a curve defined by HbA1c values above 7 over time. Patients were stratified into quartiles based on cumulative glycemic burden (excellent, good, fair, and poor control). χ 2 tests compared the proportion of foot ulcer and Charcot across quartiles. Regression analysis identified associated demographic and comorbidity factors with diabetic foot disease. Statistical significance was set at P < .05.ResultsOut of 22,913 diabetics, 1643 (7.2%) had a foot ulcer; 54 out of 771 diabetics (7.0%) had radiographic Charcot arthropathy. There was a statistically significant stepwise increase in the incidence of foot ulcer with increasing cumulative glycemic burden by patient quartile (5.2 vs. 6.4 vs. 7.9 vs. 13.9%; P < .001). No significant trend was seen between incidence of Charcot arthropathy and greater cumulative glycemic burden (7.8 vs. 5.6 vs. 4.4 vs. 10.0%; P = .469). Peripheral vascular disease was most strongly associated with diabetic foot ulcer. Hypertension and diabetic neuropathy were independently associated with Charcot arthropathy.ConclusionsIncreasing cumulative glycemic burden is positively associated with diabetic foot ulcer. Greater attention should be paid towards the most poorly controlled diabetics with the longest duration of disease to reduce their risk. Cumulative glycemic burden is not associated with Charcot arthropathy.

Our studies suggest that outpatient TE confers similar safety profiles to inpatient TE with regards to 30-day postoperative overall complications, medical and surgical morbidity, and return to the operating room. A slightly increased risk for surgical site infection must be balanced against potential risk for known inpatient-related complications such as UTI and PE.

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