Randomised controlled trial of nebulised gentamicin in children with bronchiectasis.

AIM: Following trials of inhaled antibiotics in adults, this study investigates the efficacy of nebulised gentamicin to improve respiratory function in children with bronchiectasis. METHODS: This is a randomised, double-blind, placebo-controlled, crossover trial of 12-week nebulised placebo/gentamicin, 6-week washout, 12-week gentamicin/placebo. Participants were children (5-15 years) with bronchiectasis, chronic infection (any pathogen), and able to perform spirometry from a hospital bronchiectasis clinic. Primary outcomes were change in forced expiratory volume in 1 s (FEV1 ) and hospitalisation days. Secondary outcomes included sputum bacterial density, sputum inflammatory markers, additional antibiotics and symptom severity. Analyses were on an intention-to-treat basis. RESULTS: Fifteen children (mean 11.7-years-old) completed the study. There was no significant change in mean FEV1 (56%/55%, P = 0.38) or annual rate of hospital admissions (1.1/0, P = 0.12) between gentamicin and placebo, respectively. However, Haemophilus influenzae sputum growth (27% vs. 80%, P = 0.002) and bacterial density (2.4 log10 cfu/mL lower P < 0.001) improved with gentamicin. Sputum inflammatory markers interleukin-1ß (P < 0.001), interleukin-8 (P < 0.001) and tumour necrosis factor-α (P = 0.003) were lower with gentamicin. Poor recruitment limited study power and treatment adherence was challenging for this cohort. CONCLUSIONS: In this crossover study of nebulised gentamicin in children with bronchiectasis, there was a reduction in sputum bacterial density and inflammation. However, there were no major improvements in clinical outcomes and adherence was a challenge.

The relationship between diet and sleep in 2-y-old children: Results from Growing Up in New Zealand.

OBJECTIVES: This study aimed to examine the relationship between dietary practices and sleep in young children. METHODS: In this study, 2-y-old children (n = 6327) and their mothers were enrolled at birth and during pregnancy, respectively. The study obtained maternal demographic, health, and lifestyle data during late pregnancy. Parents reported the 2-y-old child's dietary practices on a food frequency questionnaire, as well as sleep duration and night-waking frequency. Measures of dietary intake quantified servings per day for each food group (grouped as low/moderate/high intake). Sleep measures were as inadequate sleep when <11 h sleep in a 24-h period and increased night waking when waking ≥2 times per night. Multivariable logistic regression analyses examined associations between toddler diet and sleep, which were described using adjusted odds ratios (ORs) and 95% confidence intervals. RESULTS: In this study, 2-y-old children (n = 6288) slept for a mean of 12.3 hours (standard deviation: ±1.5 hours) over a 24-h period, with 734 children (12%) getting <11 h of sleep in 24 h. Increased night waking occurred in 1063 children (17%). Compared with low intake, high soft drink/snack/fast food intake was associated with inadequate sleep (OR: 1.37) and increased night waking (OR: 1.34). High milk/cheese/yoghurt intake (OR: 1.55) was associated with increased odds of night waking, but moderate (OR: 0.81) or high (OR: 0.78) vegetable intake was associated with decreased odds of night waking. Exposure to screens (OR: 1.28) and heavy maternal cigarette smoking (OR: 2.20) were also associated with inadequate sleep and increased night waking, respectively. CONCLUSIONS: At age 2 y, higher consumption of soft drinks/snacks/fast foods is associated with shorter, more disrupted sleep. Conversely, higher vegetable consumption is associated with less disrupted sleep. Dietary modifications may improve toddlers' sleep.

Maternal and perinatal predictors of newborn iron status.

AIM: To describe iron status at birth in a population sample of children. METHOD: Cord blood samples were obtained at birth from 131 infants enrolled in the cohort study Growing Up in New Zealand. Cord blood serum ferritin (SF) and haemoglobin (Hb) concentrations were measured and associations of SF and Hb with maternal and birth characteristics were determined. RESULTS: Demographics were comparable to the larger cohort, except for having a higher pre-pregnancy body mass index (26.9 vs. 25.4 kg/m2, P=0.005), lower frequency of cigarette smoking during pregnancy (2% vs. 11%, P=0.0004), and smaller proportion with birth-weight <2500 g (0% vs. 5%, P=0.03). Median (interquartile range) SF was 135 (88-180) mcg/L and mean (plus or minus SD) Hb was 160 plus or minus 17 g/L. Eight newborns (7%) had cord SF levels indicative of iron deficiency (SF <35 mcg/L), two newborns were anaemic (Hb <130 g/L) and none had iron deficiency anaemia. Median SF was lower in newborns whose mothers consumed greater than or equal to 3 servings of milk/day during the pregnancy (131 vs. 151 mcg/L, P=0.04). No other associations with SF or Hb were observed. CONCLUSION: Iron deficiency is present in 7% of newborns in New Zealand. Newborns whose mothers consumed more milk during pregnancy had a lower median SF concentration.

Therapeutic reactivation of mutant p53 protein by quinazoline derivatives.

PURPOSE: The human tumour suppressor protein p53 is mutated in nearly half of human tumours and most mutant proteins have single amino acid changes. Several drugs including the quinazoline derivative 1 (CP-31398) have been reported to restore p53 activity in mutant cells. The side chain of 1 contains a styryl linkage that compromises its stability and we wished to explore the activity of analogues containing more stable side chains. METHODS: Reactivation of p53 function was measured by flow cytometry as the ability to potentiate radiation-induced G(1)-phase cell cycle arrest and by western blotting to determine expression of p21(WAF1). DNA binding was measured by competition with ethidium and preliminary pharmacological and xenograft studies were carried out. RESULTS: Screening of analogues for potentiation of radiation-induced G(1)-phase cell cycle arrest using NZOV11, an ovarian tumour cell line containing a p53(R248Q) mutation, demonstrated that the (2-benzofuranyl)-quinazoline derivative 5 was among the most active of the analogues. Compound 5 showed similar effects in several other p53 mutant human tumour cell lines but not in a p53 null cell line. 5 also potentiated p21(WAF1) expression induced by radiation. DNA binding affinity was measured and found to correlate with p53 reactivation activity. Plasma concentrations of 5 in mice were sufficient to suggest in vivo activity and a small induced tumour growth delay (7 days) of NZM4 melanoma xenografts was observed. CONCLUSION: Compound 5 restores p53-like function to a human tumour cells lines expressing a variety of mutant p53 proteins, thus providing a basis for the design of further new drugs.

The ubiquitin-proteasome system is inhibited by p53 protein expression in human ovarian cancer cells.

The ubiquitin-proteasome system (UPS) and autophagy provide major cellular pathways for protein degradation. Since the p53 pathway controls autophagy, we investigated whether p53 regulates UPS in ovarian tumour cell lines. A reporter cell line (SKOV3-EGFPu) was established to measure UPS function against a constant genetic background. Transient expression of either wild type or mutant p53 in SKOV3-EGFPu cells reduced UPS activity as compared to vector control. These results, together with those from endogenous p53 expression in seven ovarian cancer cell lines, suggest that expression of both wild-type and mutant p53 protein impairs UPS function. Thus, p53 expression may regulate protein homeostasis by down-regulating UPS function in response to cellular stress.