Antisense oligonucleotide targeting of mRNAs encoding ENaC subunits α, β, and γ improves cystic fibrosis-like disease in mice

BackgroundThe epithelial sodium channel ENaC consists of three subunits encoded by Scnn1a, Scnn1b, and Scnn1g and increased sodium absorption through this channel is hypothesized to lead to mucus dehydration and accumulation in cystic fibrosis (CF) patients.MethodsWe identified potent and specific antisense oligonucleotides (ASOs) targeting mRNAs encoding the ENaC subunits and evaluated these ASOs in mouse models of CF-like lung disease.ResultsASOs designed to target mRNAs encoding each ENaC subunit or a control ASO were administered directly into the lungs of mice. The reductions in ENaC subunits correlated well with a reduction in amiloride sensitive channel conductance. In addition, levels of mucus markers Gob5, AGR2, Muc5ac, and Muc5b, periodic acid-Schiff's reagent (PAS) goblet cell staining, and neutrophil recruitment were reduced and lung function was improved when levels of any of the ENaC subunits were decreased.ConclusionsDelivery of ASOs targeting mRNAs encoding each of the three ENaC subunits directly into the lung improved disease phenotypes in a mouse model of CF-like lung disease. These findings suggest that targeting ENaC subunits could be an effective approach for the treatment of CF.     

Brachytherapy in the Palliation of Oesophageal Cancer: Effective but Impractical?

Dysphagia in people with advanced oesophageal cancer can be treated by oesophageal stents, external beam radiotherapy (EBRT) and intraluminal brachytherapy. Despite guidelines recommending brachytherapy for patients with a predicted life expectancy exceeding 3 months, its uptake in the UK has been limited. Here we examine the strength of the evidence supporting the use of brachytherapy compared with oesophageal stents and EBRT and possible reasons for its limited uptake. Trials and observational studies suggest brachytherapy alone confers a benefit to patients, but its impact is less immediate than oesophageal stents; the evidence on effectiveness and value-for-money is limited. Moreover, stronger evidence will probably be insufficient to increase uptake, due to the extra complexity of delivery compared with stents and EBRT and a lack of experience among specialists.     

Predictors of Initial Uptake of Human Papillomavirus Vaccine Uptake Among Rural Appalachian Young Women

Women in Appalachian Kentucky experience a high burden of cervical cancer and have low rates of human papillomavirus (HPV) vaccination. The purpose of this study was to identify normative influences predicting initial HPV vaccine uptake among a sample of young women in southeastern Kentucky. Women (N = 495), ages 18 through 26 years, were recruited from clinics and community colleges. After completing a questionnaire, women received a free voucher for HPV vaccination. Whether women redeemed the voucher for Dose 1 served as the primary outcome variable. Hierarchical logistic regression was used to estimate the influence of healthcare providers, friends, mothers, and fathers on vaccine uptake. One-quarter of the total sample (25.9 %) received Dose 1. Uptake was higher in the clinic sample (45.1 %) than in the college sample (6.9 %). On multivariate analysis, women indicating that their healthcare provider suggested the vaccine, that their friends would “definitely” want them to be vaccinated, and that their fathers would “definitely” want them to receive the vaccine all were 1.6 times more likely to receive Dose 1. Interaction effects occurred between recruitment site (clinic vs. community college) and all three of the normative influences retaining multivariate significance, indicating that the associations only applied to the clinic sample. HPV vaccine interventions may benefit from highlighting paternal endorsement, healthcare provider recommendation, and peer support.     

Obstetric and neonatal characteristics of pregnancy and delivery for infant birthweight ≥5.0 kg

Aim: Infant birthweight ≥5.0?kg represents a significant risk factor for mother and neonate. The objective of this study was to examine the obstetric and neonatal outcome measures in a large cohort of such deliveries.

Methods: The data used for this study were prospectively entered into an obstetric computerized database during the period 1989–2013. All pregnancies where the delivery resulted in an infant weighing?≥5.0?kg were identified. The results were retrospectively analyzed separately for parity, and a separate analysis was performed comparing the outcome measures observed in the earlier years of the study with those of the later years.

Results: There were 73,796 deliveries in the time period of which there were n?=?201 (0.3%) infants with birth weight ≥5.0?kg. The mean maternal body mass index (BMI) was in the obese category range (30.9?kg/m²) and the median gestation at delivery was 40.8 weeks. The cesarean delivery rate for nulliparous women was 56.3% and for parous women 30.8%. The overall rate of third degree perineal tears was 3.8%, the rate of shoulder dystocia was 4.6% and the rate of Erb’s Palsy was 1.5%. There was a significant increase in cesarean delivery in the latter of the study (26.7% versus 43.0%, p?=?0.02), due to an increase in the planned pre-labor cesarean deliveries (30.0 versus 12.9%, p?=?0.005). There was no difference in adverse outcomes in both groups.

Conclusion: These findings describe the features of pregnancy associated with infant birthweight ≥5.0?kg, and outline reliable maternal and neonatal morbidity data for these pregnancies. In this cohort, there was no apparent benefit from increased planned pre-labor cesarean delivery rates.     

Pearls

‘Pearls’ enables sports medicine professionals to share the practical tips they've developed through treating active patients. We invite you to send your contributions to Pearls Editor, THE PHYSICIAN AND SPORTSMEDICINE, 4530 W 77th St, Minneapolis, MN 55435. Selected pearls will be published, accompanied by the author's name.     

The Night Eating Questionnaire (NEQ): psychometric properties of a measure of severity of the Night Eating Syndrome

The purpose of this study was to evaluate the Night Eating Questionnaire (NEQ) as a measure of severity of the Night Eating Syndrome (NES). The 14-item NEQ assesses the behavioral and psychological symptoms of NES. The NEQ was evaluated in three samples: 1980 persons who completed the NEQ on the Internet; 81 persons diagnosed with NES; and 194 bariatric surgery candidates. Study 1, using principal components analysis, generated four factors (nocturnal ingestions, evening hyperphagia, morning anorexia, and mood/sleep) and an acceptable alpha (.70). Confirmatory factor analysis suggested that 99% of covariation among factors is accounted for by a higher-order construct. Study 2 found convergent validity of the NEQ with additional measures of night eating, disordered eating, sleep, mood, and stress. Study 3 compared scores from obese bariatric surgery candidates with and without NES and found appropriate discriminant validity of the NEQ. The NEQ appears to be an efficient, valid measure of severity for NES.