The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin.

OBJECTIVE: SCN8A encephalopathy (early infantile epileptic encephalopathy; EIEE13) is caused by gain-of-function mutations resulting in hyperactivity of the voltage-gated sodium channel Nav 1.6. The channel is concentrated at the axon initial segment (AIS) and is involved in establishing neuronal excitability. Clinical features of SCN8A encephalopathy include seizure onset between 0 and 18 months of age, intellectual disability, and developmental delay. Seizures are often refractory to treatment with standard antiepileptic drugs, and sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of patients. In a recent study, high doses of phenytoin were effective in four patients with SCN8A encephalopathy. In view of this observation, we have investigated the relationship between the functional effect of the SCN8A mutation p.Ile1327Val and its response to phenytoin. METHODS: The mutation was introduced into the Scn8a cDNA by site-directed mutagenesis. Channel activity was characterized in transfected ND7/23 cells. The effects of phenytoin (100 µm) on mutant and wild-type (WT) channels were compared. RESULTS: Channel activation parameters were shifted in a hyperpolarizing direction in the mutant channel, whereas inactivation parameters were shifted in a depolarizing direction, increasing Na channel window current. Macroscopic current decay was slowed in I1327V channels, indicating an impairment in the transition from open state to inactivated state. Channel deactivation was also delayed, allowing more channels to remain in the open state. Phenytoin (100 µm) resulted in hyperpolarized activation and inactivation curves as well as greater tonic block and use-dependent block of I1327V mutant channels relative to WT. SIGNIFICANCE: SCN8A - I1327V is a gain-of-function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain-of-function mutations of SCN8A.

Aortic valve insufficiency due to myxomatous degeneration: a case report and literature review.

Myxomatous degeneration is a non-inflammatory degenerative process leading to disruption of the fibrosa layer of the valve with acid mucopolysaccharide accumulation. This type of degeneration commonly affects the mitral valve leading to mitral regurgitation; however, few cases have been reported regarding myxomatous degeneration of the aortic valve leading to acute decompensated heart failure. We report a case of myxomatous degeneration of the aortic valve as an etiology of acute decompensated heart failure to highlight the importance of considering myxomatous degeneration as an underlying etiology of symptomatic aortic insufficiency. A 64-year-old female presented with progressively worsening dyspnea, cough, and peripheral edema over a one-month duration. Clinical evaluation and imaging studies revealed aortic valve regurgitation (AVR). Subsequent aortic valve replacement was performed. The histopathology report was consistent with myxomatous degeneration of the aortic valve. Upon symptom improvement, the patient was discharged home. Subsequent transesophageal echocardiogram demonstrated a normal hemodynamic profile across the bioprosthetic valve without aortic regurgitation or paravalvular leak. We highlight a unique presentation of heart failure secondary to myxomatous degeneration of the aortic valve. Furthermore, a review of available literature on myxomatous degeneration of the aortic valve was conducted to illustrate the importance of early diagnosis and proper treatment to improve the patients' quality of life.

Azithromycin-Induced Bradycardia.

Azithromycin is a broad-spectrum antibiotic of the macrolide class and has multiple effects on the cardiovascular system, including prolonged corrected QT (QTc) interval. However, there is limited literature on the association between azithromycin and bradyarrhythmias. Monitoring the patient via telemetry can detect bradycardia. The diagnosis of azithromycin-induced bradycardia is usually made by the exclusion of other causes of bradycardia. We report a case of a 44-year-old female with past medical history of obstructive sleep apnea who presented to our hospital due to polysubstance drug overdose with possible aspiration pneumonia. The patient received azithromycin and subsequently developed symptomatic bradycardia two days post-onset of antibiotic treatment. This case raises awareness amongst physicians about the possibility of azithromycin-induced bradycardia and explains the different mechanisms that can cause it.

Resident and Faculty Perspectives on Prevention of Resident Burnout: A Focus Group Study.

CONTEXT: The high prevalence and negative implications of resident physicians' burnout is well documented, yet few effective interventions have been identified. OBJECTIVE: To document resident and faculty perspectives on resident burnout, including perceived contributing factors and their recommended strategies for attention and prevention. DESIGN: We conducted 14 focus groups with core faculty and residents in 5 specialties at a large integrated health care system in Southern California. Training programs sampled included family medicine, internal medicine, obstetrics and gynecology, pediatrics, and psychiatry. Discussions were recorded, transcribed, and analyzed using a matrix-based approach to identify common themes. MAIN OUTCOME MEASURES: Resident and faculty perspectives regarding causes of burnout, preventive factors, and potential intervention strategies. RESULTS: Five themes captured the range of factors participants identified as contributing or protective factors for resident burnout: 1) having or lacking a sense of meaning at work; 2) fatigue and exhaustion; 3) cultural norms in medicine; 4) the steep learning curve from medical school to residency; and 5) social relationships at and outside work. Recommended intervention strategies targeted individuals, residents' social networks, and the learning and work environment. CONCLUSION: We engaged residents and core faculty across specialties in the identification of factors contributing to burnout and possible targets for interventions. Our results highlight potential focus areas for future burnout interventions and point to the importance of interventions targeted at the social environments in which residents' work and learn.

Understanding Faculty and Trainee Needs Related to Scholarly Activity in a Large, Nonuniversity Graduate Medical Education Program.

CONTEXT: Graduate medical education (GME) programs must develop curriculum to ensure scholarly activity among trainees and faculty to meet accreditation requirements and to support evidence-based medicine. OBJECTIVE: Test whether research-related needs and interests varied across four groups: primary care trainees, specialty trainees, primary care faculty, and specialty faculty. DESIGN: We surveyed a random sample of trainees and faculty in Kaiser Permanente Southern California's GME programs. We investigated group differences in outcomes using Fisher exact and Kruskal-Wallis tests. MAIN OUTCOME MEASURES: Research experiences, skills, barriers, motivators, and interests in specific research skills development. RESULTS: Participants included 47 trainees and 26 faculty (response rate = 30%). Among primary care faculty, 12 (71%) reported little or no research experience vs 1 (11%) for specialty faculty, 14 (41%) for primary care trainees, and 1 (8%) for specialty trainees (p < 0.001). Submission of research to the institutional review board, an abstract to a conference, or a manuscript for publication in the previous year varied across groups (p = 0.001, p = 0.003, and p < 0.001, respectively). Overall self-reported research skills also differed across groups (p < 0.001). Primary care faculty reported the lowest skill level. Research barriers that differed across groups included other work roles taking priority; desire for work-life balance; and lack of managerial support, research equipment, administrative support, and funding. CONCLUSION: Faculty and trainees in primary care and specialties have differing research-related needs that GME programs should consider when designing curricula to support scholarly activity. Developing research skills of primary care faculty is a priority to support trainees' scholarly activity.

Early kinetics of integration of collagen-glycosaminoglycan regenerative scaffolds in a diabetic mouse model.

BACKGROUND: Collagen-glycosaminoglycan scaffolds, originally designed to treat severe burns, are now commonly used in patients with complex wounds associated with diabetes mellitus. In this study, the authors investigated how the thickness of the scaffold would affect cellular integration with the diabetic host and whether this can be accelerated using subatmospheric pressure wound therapy devices. METHODS: Collagen-glycosaminoglycan scaffolds, 500 to 2000-µm thick, were applied to dorsal wounds in genetically diabetic mice. In addition, 1000-µm collagen-glycosaminoglycan scaffolds with and without silicone were treated with a subatmospheric pressure device (-125 mmHg). On days 5 and 10, cellular and vascular integration of tissues was studied by histology, immunohistochemistry, corrosion casting, and qRT-polymerase chain reaction. RESULTS: Cells and vessels from the wound surface populated the scaffold to form layers with varying cellular density. Areas of high cell density and proliferation were noted at the bottom of the scaffold. Increasing the thickness of the scaffold did not affect the extent of cellular ingrowth, so that thicker scaffolds had a thicker residual acellular layer on the surface. The thickness of cellular ingrowth was stable between days 5 and 10, whereas vessels seen in the scaffolds on day 10 were not yet present on day 5. Subatmospheric pressure devices applied to silicone-covered collagen-glycosaminoglycan scaffolds minimized the granulation tissue formation beneath the scaffold, which enhanced vessel ingrowth. CONCLUSIONS: The early kinetics of cellular integration into collagen-glycosaminoglycan scaffolds is independent of scaffold thickness in a diabetic wound model. Scaffold adherence to the wound and integration can be improved using a subatmospheric pressure device.

Do pre-irradiation dental extractions reduce the risk of osteoradionecrosis of the mandible?

BACKGROUND: This study was done to determine if pre-radiotherapy (pre-RT) dental extractions reduce the risk of osteoradionecrosis (ORN). METHODS: Between 1987 and 2004, 413 patients with oropharyngeal carcinomas were treated with definitive RT at the University of Florida. Dentate patients underwent pretreatment dental evaluation. Teeth in the RT field were usually extracted if thought to have poor long-term prognosis from dental disease. The endpoint was > or = grade 2 ORN using a modified staging system. Patients were excluded for local recurrence, additional RT above the clavicles, or head and neck surgery besides neck dissection. RESULTS: ORN rates were as follows: edentulous, <1%; teeth in-field with pre-RT extractions, 15%; and teeth in-field without pre-RT extractions, 9%. Patients with poor in-field teeth and pre-RT extractions had a higher 5-year incidence of ORN than those who did not have pre-RT extractions (16% vs 6%, p = .48). Likewise, for those with in-field teeth in good condition and pre-RT extractions, the 5-year ORN incidence was higher than for those who did not undergo extractions (15% vs 2%, p = .42). Multivariate analysis revealed increased ORN risk with doses of >70 Gy, once-daily fractionation, or brachytherapy. CONCLUSION: Pre-RT extractions do not appear to reduce the risk of ORN.