Being born small-for-gestational-age is associated with an unfavourable dietary intake in Danish adolescent girls: findings from the Danish National Birth Cohort.

Individuals born small have an increased risk for developing type 2 diabetes. Altered food preferences in these subjects seem to play a role; however, limited evidence is available on the association between being born small-for-gestational-age (SGA) at term and food intake in adolescence. Alterations in leptin, ghrelin and dopamine levels are suggested mechanisms linking SGA with later food intake. From a large prospective Danish National Birth Cohort, we compared dietary intake of adolescents being born SGA with normal-for-gestational-age (NGA) adolescents. Intake of foods and nutrients was assessed by a validated food frequency questionnaire in a subsample of 15,607 14-year-old individuals born at term. SGA was defined by birth weight (BW) <10th percentile (n = 1470) and NGA as BW between 10 and 90th percentile (n = 14,137) according to sex and gestational age-specific BW standard curves. Girls born SGA had a 7% (95% CI: 3-12%, P = 0.002) higher intake of added sugar and a 2-8% lower intake of dietary fibre, vegetables, polyunsaturated fatty acids, and total n-6, compared with NGA girls (P < 0.05). Adjusting for parental socio-occupational status, maternal smoking and diet in pregnancy did not substantially change the differences in dietary intake, except from dietary fibre, which were no longer statistically significant. No significant differences in dietary intake between SGA and NGA boys were found. In summary, girls born SGA had an unfavourable dietary intake compared with NGA girls. These differences persisted after controlling for potential confounders, thus supporting a fetal programming effect on dietary intake in girls born SGA at term. However, residual confounding by other factors operating early in childhood cannot be excluded.

Human endogenous retroviruses and their implication for immunotherapeutics of cancer.

Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called 'viral mimicry'. By mimicking viral infections, HERVs could function as an 'intrinsic adjuvant', possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of 'viral mimicry' and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.

Criterion validity of the Physical Activity Scale (PAS2) in Danish adults.

BACKGROUND: The Physical Activity Scale (PAS2) was developed to measure physical activity (PA) during work, transportation and leisure time, in the Danish adult population. The objective of this study was to assess the criterion validity of PAS2 against a combined accelerometer and heart rate monitor in Danish adults and to investigate if the criterion validity differed by socio-demographic factors and body mass index. METHOD: A total of 330 Danish adults (mean age = 46.7 years, 38.5% men) participating in the Health2008 study completed the PAS2 questionnaire and wore a combined accelerometer and heart rate sensor for seven days. Average daily estimates from PAS2 were categorised into time spent in sedentary behaviour, light PA, moderate PA and vigorous PA and were compared to the objective measures. RESULTS: PAS2 accounted for 19.5 hours/day on average. Time spent in sedentary behaviour, light and moderate-intensity PA was weakly correlated with objective data (polychoric correlation coefficients (PCC): 0.18-0.20), whereas vigorous intensity PA was moderately correlated (PCC: 0.54, p = 0.04). Mean bias was -2.3 hours/day (95% limits of agreement (LoA): -9.04 to 4.34) for sedentary behaviour, 1.68 hours/day (LoA: 8.02 to -4.62) for light activity, 0.55 hours/day (LoA: 3.37 to -2.26) for moderate activity and 0.12 hours/day (LoA: 0.57 to 0.33) for vigorous activity. Criterion validity was lower in women, in participants who were above 40 years, overweight, had short education and were unemployed. CONCLUSIONS: PAS2 overestimated time spent on light, moderate and vigorous intensity PA and underestimated time spent on sedentary behaviour. Validity differed by key socio-demographic characteristics.

Overweight in childhood and adolescence: Does it lead to airway hyperresponsiveness in adulthood?

BACKGROUND: Obesity is increasing worldwide among children and adolescents, and has been associated with an increased incidence of asthma. However, the mechanisms underlying this association are incompletely understood. OBJECTIVE: In this cohort study we aimed to investigate whether being overweight in childhood and adolescence is associated with an increased risk of airway hyperresponsiveness (AHR), a hallmark of asthma, in early adulthood. METHODS: Of 527 subjects from a random population sample of children and adolescents (7-17 years) examined at baseline, a total of 184 subjects completed the follow-up visit 20 years later and were included in the present analysis. Both visits included assessment of height and weight, case history and spirometry. At both visits, bronchial provocation tests were performed using either histamine (baseline) or methacholine (follow-up). In addition, fractional exhaled nitric oxide (FeNO) was measured at follow-up. RESULTS: No significant difference in the prevalence of AHR at follow-up was found between subjects who were overweight or obese at baseline visit (n = 26) (pediatric definition, body mass index ≥ 85%percentile) and normal weight subjects (n = 158) (positive bronchial provocation tests: 15.4% vs. 22.2%, respectively, p = 0.35). Likewise, follow-up FeNO levels did not differ significantly between subjects who were lean and those who were overweight or obese at baseline (geometric mean (95% confidence interval [CI]) 15.1 (13.7, 16.6) parts per billion (ppb) versus 13.0 (10.6, 15.9) ppb, p = 0.23). CONCLUSION: In children and adolescents, being obese or overweight seems not to be associated with an increased risk of AHR or increased FeNO levels in early adulthood.

High fractional exhaled nitric oxide and sputum eosinophils are associated with an increased risk of future virus-induced exacerbations: A prospective cohort study.

BACKGROUND: The major trigger of asthma exacerbations is infection with a respiratory virus, most commonly rhinovirus. Type 2 inflammation is known to be associated with an increased risk of exacerbations in general. Whether type 2 inflammation at baseline increases the risk of future virus-induced exacerbations is unknown. OBJECTIVE: To assess whether type 2 inflammation is associated with an increased risk of virus-induced exacerbations of asthma. METHODS: Stable asthmatics had spirometry, skin prick test, measurement of FeNO and sputum induced for differential cell counts. Patients were followed up for 18 months, during which they were assessed at the research unit when they had symptoms of an exacerbation. Nasal swabs collected at these assessments underwent viral detection by PCR. RESULTS: A total of 81 asthma patients were recruited, of which 22 (27%) experienced an exacerbation during the follow-up period. Of these, 15 (68%) had a respiratory virus detected at exacerbation. Sputum eosinophils >1% at baseline increased the risk of having a subsequent virus-induced exacerbation (HR 7.6 95% CI: 1.6-35.2, P=.010) as did having FeNO >25 ppb (HR 3.4 95% CI: 1.1-10.4, P=.033). CONCLUSION AND CLINICAL RELEVANCE: Established type 2 inflammation during stable disease is a risk factor for virus-induced exacerbations in a real-life setting. Measures of type 2 inflammation, such as sputum eosinophils and FeNO, could be included in the risk assessment of patients with asthma in future studies.

Healthful dietary patterns and long-term weight change among women with a history of gestational diabetes mellitus.

BACKGROUND/OBJECTIVE: Diet represents a key strategy for the prevention of obesity and type 2 diabetes among women with a history of gestational diabetes mellitus (GDM), although effective dietary patterns to prevent weight gain in the long term are largely unknown. We sought to evaluate whether improvement in overall diet quality is associated with less long-term weight gain among high-risk women with prior GDM. SUBJECTS/METHODS: Women with a history of GDM (N=3397) were followed from 1991 to 2011, or until diagnosis of type 2 diabetes or other chronic disease. Usual diet was assessed via food frequency questionnaire every 4 years from which we calculated the Alternative Healthy Eating Index (aHEI-2010), Alternate Mediterranean Diet (AMED) and Dietary Approaches to Stop Hypertension (DASH) dietary pattern scores. Weight, lifestyle and health-related outcomes were self-reported every 2 years. We estimated the change in dietary score with change in body weight using linear regression models adjusting for age, baseline body mass index (BMI), baseline and simultaneous change in physical activity and smoking status and other risk factors. RESULTS: Women were followed up to 20 years, gaining an average 1.9 kg (s.d.=7.0) per 4-year period. Women in the highest quintile (Q5) of diet change (most improvement in quality) gained significantly less weight per 4-year period than the lowest quintile (Q1; decrease in quality), independent of other risk factors (4-year weight change, aHEI-2010: Q5=1.30 kg vs Q1=3.27 kg; AMED: Q5=0.94 kg vs Q1=2.56 kg, DASH: Q5=0.64 kg vs Q1=2.75 kg). Significant effect modification by BMI (p-interactions <0.001) indicated a greater magnitude of weight change among women with a higher baseline BMI for all three patterns. CONCLUSIONS: Increased diet quality was associated with less weight gain, independent of other lifestyle factors. Post-partum recommendations on diet quality may provide one strategy to prevent long-term weight gain in this high-risk group.

Weaver mutant mouse cerebellar granule cells respond normally to chronic depolarization.

We studied the effects of chronic K(+)-induced membrane depolarization and treatment with N-methyl-D-aspartate (NMDA) on cerebellar granule cells (CGCs) from weaver mutant mice and non-weaver litter-mates. The weaver mutation is a Gly-to-Ser substitution in a conserved region of the Girk2 G protein-coupled inward rectifying potassium channel [Patil N., Cox D. R., Bhat D., Faham M., Myers R. M. and Peterson A. S. (1995) Nature Genet. 11, 126-129] which induces early death of CGCs. The biochemical differentiation of CGCs was estimated as the rate of 2-deoxy-D-glucose accumulation and the expression of neural cell adhesion molecule (NCAM). High (25 mM) K+ ion concentration or treatment with NMDA greatly promoted the biochemical differentiation of both weaver mutant and non-weaver litter-mate mouse CGCs. In contrast to the marked effect on biochemical differentiation in both weaver and non-weaver mice CGSs, chronic high K+ treatment only had limited effect on survival. The survival of weaver mutant mouse CGCs in medium containing 5 mM K+ ions was very low, only 20% of the plated cells surviving at 7 days after plating, as opposed to the 50% for non-weaver CGCs. Chronic high K+ treatment improved the relative survival of weaver mutant mouse CGCs 1.6 2.2-fold and that of non-weaver CGCs 1.2-1.4-fold; the same number of CGCs (about 20% of the plated cells) were rescued by high K+ in both types of culture. The findings indicate that, in culture weaver mutant mouse, CGCs have a normal response to membrane depolarization and that the normal function of the Girk2 potassium channel is not critical for the survival of differentiated CGCs.

Ontogeny of the cell adhesion molecule L1 in the cerebellum of weaver and reeler mutant mice.

The ontogeny of cell adhesion molecule L1 in cerebellum was quantitatively assessed in weaver and reeler mutant mice and in heterozygous litter-mate controls. In the latter the concentration and the amount of L1 both increased from the first postnatal week to become maximum at the second. In contrast, in the weaver and reeler neurologic mutant mice, L1 decreased steadily. The L1 concentration and the amount of L1 was lower in the cerebellum of homozygous mutant mice than in litter-mate controls. The findings are consistent with L1 being a component of axonal plasma membranes. However, no evidence was found of any direct effect of the wv and rl phenotypes on L1 expression.