Neal Jain

A Novel Mutation in NFKBIA/IKBA Results in a Degradation- Resistant N-Truncated Protein and Is Associated With Ectodermal Dysplasia With Immunodeficiency

Alterations in nuclear factor kappa B (NF‐κB) essential modulator (NEMO; HUGO‐approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF‐κB inhibitor IκBα, one of two phosphorylation sites that are essential for targeting IκBα for proteasomal degradation and hence for activation of NF‐κB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO‐approved symbol, NFKBIA) gene of a 1‐year‐old male child with EDI that introduces a premature termination codon at position Glu14. An in‐frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N‐terminally truncated protein lacks both serine phosphorylation sites and inhibits NF‐κB signaling by functioning as a dominant negative on NF‐κB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF‐κB in the human immune response. Hum Mutat 29(6), 861–868, 2008. Published 2008, Wiley‐Liss, Inc.

Effect of montelukast on peripheral airflow obstruction in children with asthma

BACKGROUND Montelukast is a widely used controller agent in childhood asthma. It is modestly effective in reducing symptoms, decreasing the need for rescue albuterol, and improving forced expiratory volume in 1 second (FEV1). OBJECTIVE To determine whether montelukast therapy improves peripheral airway obstruction as measured by lung volumes, air trapping, airway resistance (Raw), and specific conductance (Sgaw). METHODS Twenty-one children aged 9 to 18 years with mild-to-moderate asthma were randomized into a double-blind, placebo-controlled study to receive montelukast (5 or 10 mg) or matching placebo daily for 8 weeks. Symptoms and albuterol use were recorded twice daily, and exhaled nitric oxide measurement, forced oscillometry, spirometry, and body box plethysmography (before and after beta-agonist use) were performed at randomization and at 2, 4, 6, and 8 weeks. Circulating eosinophil counts and serum eosinophil cationic protein (ECP) levels were obtained at randomization and at 8 weeks. RESULTS Montelukast-treated patients had lower residual volume (P = .05), residual volume-total lung capacity ratio (P = .04), Raw (P = .02), Sgaw (P = .03), and serum ECP levels (P = .02) at 8 weeks compared with those treated with placebo. There was a trend toward reduced daytime and nighttime albuterol use, although the difference did not reach statistical significance. There were no significant differences in FEV1, FEV1-forced vital capacity ratio, exhaled nitric oxide levels, or daytime and nighttime symptom scores between the 2 groups. CONCLUSIONS Montelukast therapy was associated with less air trapping, hyperinflation, and Raw and better Sgaw compared with placebo. Lower serum ECP levels, a surrogate measure of airway inflammation, were associated with improvements in lung function.

Bathing frequency recommendations for pediatric atopic dermatitis: are we adding to parental frustration?

Bathing is an activity of daily living frequently addressed by providers as part of a treatment plan for patients with atopic dermatitis (AD). However, studies evaluating bathing frequency in pediatric AD are limited.1e4 Consequently, the jury remains out on this topic. Hence, there is likely to be confusionwhen AD guidelines have not provided clear and consistent evidence-based advice in this area.5e8 Two recent practice guidelines from the United States5 and Europe6 fail to comment entirely on bathing frequency. Instead they focus on duration of bathing based on expert opinion: US guidelines recommend at least 10-minute soaking baths,5 and European guidelines recommend short, 5-minute baths.6 Our goal was to determine what parents of children with AD interpret from their providers concerning bathing frequency. Given the lack of clarity in AD guidelines, we hypothesized that advice received by parents concerning bathing frequency in AD would lack consistency and subsequently contribute to further confusion and frustration in this often difficult to manage disease. In testing this hypothesis, an online institutional review boardeapproved 7-question survey was posted to the National Eczema Association (NEA) website, quarterly electronic newsletter, and Facebook page. The NEA is a nonprofit organization dedicated to AD research, education, and advocacy. Membership includes parents of pediatric patients with AD. The survey was posted for a period of 6 weeks in the spring of 2012, and members of the NEA were invited to participate voluntarily and anonymously by clicking a SurveyMonkey link (www.surveymonkey.com). Participation implied consent. The survey questions can be found in Table 1. Confidence intervals (CIs) were calculated using an online statistical computation tool available through Vassar Stats (http://www. vassarstats.net/prop1.html). A total of 354 NEA members responded to the survey. Basic demographics were gathered on which health care providers parents see for their child’s AD. The focus was on frequency, not method of bathing; showers vs soaking baths were not distinguished, although this too remains an area of uncertainty.9 With regard to moisturizing, there is general agreement within AD guidelines that emollients should serve as first-line therapy. We chose to focus on the area of bathing frequency, where the guidelines were lacking. The results of the survey are found in Table 1. Most parents see a specialist for their child’s AD. Of those, 82.7% had been referred to a dermatologist, and 49.8% to an allergist/immunologist. Parents reported that their primary care provider (PCP) recommended “frequent/daily bathing” less than 50% of the time, whereas they reported their specialist recommended “frequent/daily bathing” more than 50% of the time (with nonoverlapping CIs). Of those who

Measurement of fractional exhaled nitric oxide in real-world clinical practice alters asthma treatment decisions

BACKGROUND Assessment of asthma using clinical measures alone often fails to detect underlying airway inflammation. Fractional exhaled nitric oxide (FeNO) is a recognized biomarker of type 2 airway inflammation in asthma. Measurement of FeNO is instrumental in the assessment and management of patients with corticosteroid-sensitive asthma. OBJECTIVE To determine the impact of measuring FeNO on asthma management in real-world clinical practices. METHODS Clinicians from 337 US practices performed a clinical assessment and recorded treatment plans before and after measuring FeNO in 7,901 patients with asthma. Airway inflammation was classified as low, intermediate, or high according to the clinicians usual procedures, including clinical examination, spirometry, and symptoms. Clinicians recorded asthma medication plans, indicating medications to be initiated, continued, or stopped. FeNO measurement was performed, followed by documentation of any change(s) in the treatment plans based on the FeNO value (eg, initiating new medications or changing the dose of or discontinuing existing medications). RESULTS Clinical assessment was concordant with FeNO measurement in only 56% of cases, matching FeNO more frequently in patients with low inflammation (64%) vs high inflammation (34%). After FeNO measurement, clinicians modified their treatment plan in 31% and altered prescriptions for inhaled corticosteroids in 90% of cases. Inhaled corticosteroids were initiated or their dose increased in 66% of patients with high inflammation but discontinued or their dose decreased in only 9% of patients with low inflammation. CONCLUSION Measurement of FeNO enabled clinicians to assess underlying airway inflammation, leading to a significant revision of their treatment plans compared with real-world clinical assessment of asthma alone.

Should exhaled nitric oxide be part of routine asthma management

although data for patients with asthma did not meet statistical significance and asthmawas not listed as a predictor of admission in our study population, we did see a difference in admission rates between the patients with asthma and the patients without asthma groups. As Mulla and Simon stated in their letter, “A comparison group of patients with anaphylaxis who were not hospitalized would be needed to allow the calculation of a confounder-adjustedmeasure of association (eg, anodds ratio for the relationshipbetweenasthmaand anaphylaxis hospitalization after controlling for age, race, sex, and comorbidities).” Given our differences in examining predictors of hospitalization in those patients with a diagnosis of anaphylaxis and theexclusionofasthma inourfinal recommendations, ourdatawould indicate that physicians maintain a low threshold for admission in patients presenting with our risk factors for admission: specifically, a patient presentingwith an anaphylactic episode involvingmultiple organ systems including gastrointestinal symptoms after exposure to an ingested allergen and a history of anaphylaxis.