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Rationale Sleep duration is critical to growth, learning, and immune function development in infancy. Strategies to ensure that national recommendations for sleep duration in infants are met require knowledge of perinatal factors that affect infant sleep. Objectives To investigate the mechanistic pathways linking maternal education and infant sleep. Methods An observational study was conducted on 619 infants whose mothers were enrolled at the Edmonton site of the CHILD birth cohort. Infant sleep duration at three months was assessed using the Brief Infant Sleep Questionnaire. Maternal education was collected via maternal report. Prenatal and postnatal depression scores were obtained from the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). Birth records and maternal report were the source of covariate measures. Mediation analysis (PROCESS v3.0) was used to examine the indirect effects of maternal education on infant sleep duration mediated through prenatal depression and birth mode. Measurements and main results At three months of age, infants slept on average 14.1 h. Lower maternal education and prenatal depression were associated with significantly shorter infant sleep duration. Emergency cesarean section birth was associated with 1-hour shorter sleep duration at three months compared to vaginal birth [without intrapartum antibiotic prophylaxis] (β: −0.99 h; 95% CI: −1.51, −0.48). Thirty percent of the effect of lower maternal education on infant total sleep duration was mediated sequentially through prenatal depression and birth mode (Total Indirect Effects: −0.12, 95% CI: −0.22, −0.03, p Conclusions Prenatal depression and birth mode sequentially mediate the effect of maternal education on infant sleep duration.

Background: Asthma is a multifactorial disease with numerous associated genetic and environmental risk factors, however, gene-environment interactions are poorly understood in modulating disease risk. This study determines the polygenic effects of multiple genetic loci and interactions with environmental exposures during early infancy on risk of recurrent wheeze and asthma in pre-school aged children. Methods: We conducted genome-wide association studies (GWAS) and applied a thresholding method to calculate genetic risk scores (GRS) of recurrent wheeze and asthma in 2835 children of the CHILD Cohort Study. Recurrent wheeze was defined as two or more episodes in one year between ages 2-5 years and asthma was diagnosed at age 5 years. In addition, we tested for interaction effects between the GRS and environmental exposures on these respiratory outcomes. Results: GWAS identified associations with known asthma loci on chromosome 17q12 - 17q21 (p < 5e-8). GRS analysis determined that the weighted addition of alleles at four childhood-asthma loci correlated with more than 2-fold higher prevalence of recurrent wheeze (p =1.5e-08) and asthma (p = 9.4e-08) between high vs. low GRS groups. In addition, the GRS interacts with breastfeeding (p = 0.02) and traffic air pollution (NO2; p < 0.01) during the first year of life to modulate risk of recurrent wheeze and childhood-onset asthma. Conclusions: This study reports polygenic effects of multiple genetic loci, which interact with early-life exposures, to determine risk of respiratory outcomes during early childhood. Thus, asthma risk may be determined early in infancy when exposures may modulate genetic risk.

Background Maternal overweight or obesity (OWOB) is linked to gestational diabetes, fetal macrosomia and higher rates of caesarean delivery. Objectives The study aims to assess whether maternal pre-pregnancy OWOB is associated with infant overweight in a sex-dependent manner, independent of microbiota-altering variables. Methods Weight and length measurements of 955 mother-infant pairs were obtained from the Canadian Healthy Infant Longitudinal Development cohort. Maternal pre-pregnancy weight was defined as follows: normal, overweight (25 ≤ body mass index 97th percentile were classified as infant overweight at age 1 year. Associations between pre-pregnancy and infant overweight were determined by linear and logistic regression, adjusting for covariates. Results Maternal pre-pregnancy OWOB were associated with infant weight-for-length and overweight risk at 1 year. Except for pre-pregnancy obesity, these associations were not attenuated appreciably after adjustment for birth mode, exclusivity of breastfeeding, exposure to antibiotics and infant sex. Yet only boys born to mothers with obesity were three times more likely to become overweight at age 1 independent of microbiota-altering variables. Pre-pregnancy obesity was associated with weight-for-length in male and female infants. Conclusions Maternal pre-pregnancy OWOB increases the risk of infant overweight, and this association is more evident in male infants.

Overweight and obesity affect over 20% of children worldwide. Emerging evidence shows that nonnutritive sweeteners (NNS) could adversely influence weight gain and metabolic health, particularly during critical periods of development. Thus, we aimed to investigate the impact of prenatal NNS exposure on postnatal growth and adiposity. Among 2298 families participating in the CHILD cohort study, children born to mothers who regularly consumed NNS during pregnancy had elevated body mass index and adiposity at 3 years of age. In a complementary study designed to eliminate confounding by human lifestyle factors and investigate causal mechanisms, we exposed pregnant mice and cultured adipocytes to NNS (aspartame or sucralose) at doses relevant to human consumption. In mice, maternal NNS exposure caused elevated body weight, adiposity and insulin resistance in offspring, especially in males. Further, in 3T3-L1 pre-adipocyte cells, sucralose exposure during early stages of differentiation caused increased lipid accumulation and expression of adipocyte differentiation genes (e.g. C/EBP-α, FABP4, FAS). The same genes were upregulated in the adipose tissue of male mouse offspring born to sucralose-fed dams. Together, these clinical and experimental findings provide evidence suggesting that maternal NNS consumption induces obesity risk in the offspring through effects on adiposity and adipocyte differentiation.One Sentence SummaryMaternal consumption of non-nutritive sweeteners during pregnancy stimulates adipocyte differentiation, insulin resistance, weight gain, and adiposity in mouse and human offspring.

Background Allergic disease is the most frequent chronic health issue in children and has been linked to early-life gut microbiome dysbiosis. Many lines of evidence suggest that microbially derived short-chain fatty acids, and particularly butyrate, can promote immune tolerance. Objective We sought to determine whether bacterial butyrate production in the gut during early infancy is protective against the development of atopic disease in children. Methods We used shotgun metagenomic analysis to determine whether dysbiosis in butyrate fermentation could be identified in human infants, before their developing allergic disease. Results We found that the microbiome of infants who went on to develop allergic sensitization later in childhood lacked genes encoding key enzymes for carbohydrate breakdown and butyrate production. Conclusions Our findings support the importance of microbial carbohydrate metabolism during early infancy in protecting against the development of allergies.

The optimal screening measures for obesity in children remain controversial. Our study aimed to determine the anthropometric measurement at age 10 years that most strongly predicts the incidence of cardio-metabolic risk factors at age 13 years.This was a prospective cohort study of a population-based cohort of 438 children followed between age 7 and 13 years of age. The main exposure variables were adiposity at age 10 years determined from body mass index (BMI) Z-score, waist circumference (WC) Z-score, waist-to-hip ratio and waist-to-height ratio. Outcome measures included systolic (SBP) and diastolic blood pressure (DBP), fasting high-density (HDL-c) and low-density lipoprotein cholesterol (LDL-c), triglycerides, insulin and glucose (homeostasis model of assessment, HOMA), and the presence of metabolic syndrome (MetS).WC Z-score at age 10 years was a stronger predictor of SBP (β 0.21, R(2) 0.38, P0.001 vs β 0.30, R(2) 0.20, P0.001) and HOMA (β 0.51, R(2) 0.25, P0.001 vs 0.40, R(2) 0.19, P0.001) at age 13 years compared with BMI Z-score. WC relative to height and hip was stronger predictors of cardio- metabolic risk than BMI Z-score or WC Z-score. The relative risk (RR) of incident MetS was greater for an elevated BMI Z-score than for an elevated WC (girls: RR 2.52, 95% confidence interval (CI): 1.46-4.34 vs RR 1.56, 95% CI 1.18-2.07) and (boys: RR 2.86, 95% CI 1.79-4.62 vs RR 2.09, 95% CI 1.59-2.77).WC was a better predictor of SBP and HOMA compared with BMI or WC expressed relative to height or hip circumference. BMI was associated with higher odds of MetS compared with WC. Thus, BMI and WC may each be clinically relevant markers of different cardio-metabolic risk factors, and important in informing obesity-related prevention and treatment strategies.

Breastfeeding may protect against excessive weight gain during infancy. However, the breast milk components responsible for this effect are unknown. We examined the variation of three breast milk hormones (adiponectin, leptin and insulin) according to maternal characteristics and determined their association with infant body composition. We studied a representative subset of 430 breastfed infants in the CHILD birth cohort. Breast milk was collected at 4 months postpartum and hormone concentrations were measured using the MesoScale Discovery System. Weight-for-length (WFL) and body mass index (BMI) z-scores were calculated according to the World Health Organization reference standard from infant anthropometrics measured at 4 months and 1 year. Maternal BMI and demographics were self-reported. Breast milk hormone concentrations varied widely between mothers. The geometric mean (range) was 19.4 (3.7–74.4) ngml−1 for adiponectin; 361 (31–3968) pgml−1 for leptin; and 589 (53–5557) pgml−1 for insulin. Maternal BMI was positively correlated with breast milk insulin (r=+0.40, P

Background The atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant allergic sensitization enhances subsequent development of these allergic diseases at age 3 years. Methods Children completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available. Results Atopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk [RR], 0.46; 95% CI, 0.11-1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36). Conclusions Atopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years.

Background It is hypothesised that complex interactions between genetic and environmental factors give rise to allergy and asthma in childhood. The Canadian Healthy Infant Longitudinal Development (CHILD) study was designed to explore these factors. Methods CHILD is a longitudinal, general population birth cohort study following infants from mid-pregnancy to age 5 years. Over this time period, biological samples, questionnaires, clinical measures and environmental data are collected. Results A total of 3624 families have been recruited, and many thousands of samples and questionnaires have been collected, annotated, and archived. This report outlines the rationale and methodology for collecting and storing diverse biological samples from parents and children in this study, and the mechanisms for their release for analyses. Conclusions The CHILD sample and data repository is a tremendous current and future resource and will provide a wealth of information not only informing studies of asthma and allergy, but also potentially in many other aspects of health relevant for Canadian infants and children.

Our gut microbiota provide a number of important functions, one of which is the metabolism of dietary fiber and other macronutrients that are undigested by the host. The main products of this fermentation process are short-chain fatty acids (SCFAs) and other intermediate metabolites including lactate and succinate. Production of these metabolites is dependent on diet and gut microbiota composition. There is increasing evidence for the role of SCFAs in host physiology and metabolic processes as well as chronic inflammatory conditions such as allergic disease and obesity. We aimed to investigate differences in fecal SCFAs and intermediate metabolites in 163 infants at 3–5 months of age according to breastfeeding status. Compared to no exposure to human milk at time of fecal sample collection, exclusive breastfeeding was associated with lower absolute concentrations of total SCFAs, acetate, butyrate, propionate, valerate, isobutyrate, and isovalerate, yet higher concentrations of lactate. Further, the relative proportion of acetate was higher with exclusive breastfeeding. Compared to non-breastfed infants, those exclusively breastfed were four times more likely (aOR 4.50, 95% CI 1.58–12.82) to have a higher proportion of acetate relative to other SCFAs in their gut. This association was independent of birth mode, intrapartum antibiotics, infant sex, age, recruitment site, and maternal BMI or socioeconomic status. Our study confirms that breastfeeding strongly influences the composition of fecal microbial metabolites in infancy.

We report on life course stress determinants of overweight in children, using data from the longitudinal follow-up of the nested case-control arm of the SAGE (study of asthma genes and the environment) birth cohort in Manitoba, Canada. Waist and hip measurements were obtained during a clinic visit at age 9-11 years. Multiple linear regression was conducted to determine the relationship between the waist-to-hip ratio and maternal smoking during pregnancy, postpartum maternal distress and stress reactivity in children (cortisol, cortisol-DHEA [dihydroepiandrostrenone] ratio quartiles) following a clinic stressor at age 8-10 years. We found waist-to-hip risk at age 9-11 years to be elevated among boys and girls whose mothers had experienced distress in the postnatal period. This association varied by gender and asthma status. In healthy girls, postpartum distress increased waist-to-hip ratio by a factor of 0.034 (P < 0.01), independent of the child's stage of puberty and adrenarche, cortisol-DHEA ratio and duration of exclusive breastfeeding. Among girls with asthma, maternal smoking during pregnancy was associated with an increased waist-to-hip ratio, if the mother also experienced distress in the postpartum period (0.072, P = 0.038). Among asthmatic boys, an association between maternal distress and waist-to-hip ratio was evident at the highest cortisol-DHEA ratios. Stress-induced changes to leptin and infant over-eating pathways were proposed to explain the postnatal maternal distress effects. Drawing on the theories of evolutionary biology, our findings underscore the significance of postnatal stress in disrupting hypothalamic-pituitary-adrenal axis function in infants and increasing risk for child overweight.

Background: Monoclonal antibodies or soluble receptors have been used to block over-produced endogenous cytokines. However, they have disadvantages of short half-lives, high costs, and possible adverse effects. Using interleukin (IL)-4 as a model target, we sought to develop a novel therapeutic strategy by constructing an IL-4 peptide-based vaccine for blocking IL-4 on a persistent basis, and to evaluate its efficacy in a mouse model of asthma. Methods: A peptide was selected by antigenic prediction and structure analysis of IL-4/receptor complex. The vaccine was constructed by employing truncated hepatitis B core antigen as carrier with the peptide inserted using gene engineering methods. It was then expressed, purified and identified. Prior to intraperitoneal sensitization and intranasal challenge with ovalbumin, mice were subcutaneously immunized three times with the vaccine, or the carrier or saline as controls. Serum antibodies, inflammatory cells in bronchoalveolar lavage fluids (BALF), lung histology, and responsiveness to inhaled methacholine were analyzed. Results: The vaccine presented as virus-like particles and reacted to polyclonal anti-IL-4 in Western blotting. Vaccinated mice produced high titers of IgG to IL-4. Serum ovalbumin-specific IgE, eosinophil accumulation in BALF, goblet cell hyperplasia, tissue inflammation and methacoline-induced respiratory responses were markedly suppressed in vaccinated mice with statistical significance, as compared with those in the control groups. Conclusions: Administration of this novel IL-4 vaccine led to an overall decrease in the development of airway allergic inflammatory responses. The results indicate that cytokine peptide-based vaccines hold potential for treatment of asthma and, by extension, other diseases where over-expressed cytokines play a pivotal role in pathogenesis.

Obesity has been associated with disruption of the gut microbiota, which is established during infancy and vulnerable to disruption by antibiotics.To investigate the association between early-life antibiotic exposure and subsequent development of overweight and central adiposity.Provincial health-care records were linked to clinical and survey data from a Canadian longitudinal birth cohort study. Antibiotic exposure during the first year of life was documented from prescription records. Overweight and central adiposity were determined from anthropometric measurements at ages 9 (n=616) and 12 (n=431). Associations were determined by multiple logistic regression.Infants receiving antibiotics in the first year of life were more likely to be overweight later in childhood compared with those who were unexposed (32.4 versus 18.2% at age 12, P=0.002). Following adjustment for birth weight, breastfeeding, maternal overweight and other potential confounders, this association persisted in boys (aOR 5.35, 95% confidence interval (CI) 1.94-14.72) but not in girls (aOR 1.13, CI 0.46-2.81). Similar gender-specific associations were found for overweight at age 9 (aOR 2.19, CI 1.06-4.54 for boys; aOR 1.20, CI 0.53-2.70 for girls) and for high central adiposity at age 12 (aOR 2.85, CI 1.24-6.51 for boys; aOR 1.59, CI 0.68-3.68 for girls).Among boys, antibiotic exposure during the first year of life was associated with an increased risk of overweight and central adiposity in preadolescence, indicating that antibiotic stewardship is particularly important during infancy. Given the current epidemic of childhood obesity and the high prevalence of infant antibiotic exposure, further studies are necessary to determine the mechanisms underlying this association, to identify the long-term health consequences, and to develop strategies for mitigating these effects when antibiotic exposure cannot be avoided.

Frataxin deficiency causes the complex neurological and cardiac phenotype of Friedreich ataxia (FRDA). The most common cause of death is cardiomyopathy. The results presented here are based on a systematic study of fixed and frozen archival heart specimens and include measurement of cardiomyocyte hypertrophy, frataxin assay, X-ray fluorescence (XRF) of iron (Fe) and zinc (Zn), inductively-coupled plasma optical emission spectrometry of these metals in digests of left ventricular wall (LVW), right ventricular wall (RVW), and ventricular septum (VS), Fe histochemistry, and immunohistochemistry and double-label immunofluorescence microscopy of cytosolic and mitochondrial ferritins, and of the inflammatory markers CD68 and hepcidin. Frataxin levels in LVW were extremely low at less than 15 ng/g wet weight (normal: 214.1±81.2). On cross-sections, cardiomyocytes were significantly larger than normal with case means ranging from 635-1856 μm2 for LVW and 483-1150 μm2 for VS (normal LVW, 140-460; normal VS, 237-613). Fe accumulations varied from minute granules to coarse aggregates in fibers undergoing phagocytosis. Measured by XRF, regional Fe concentration in LVW and VS were significantly increased while Zn remained normal. Total heart Fe and Zn did not differ from normal levels. Cytosolic and mitochondrial ferritins exhibited extensive co-localization, representing translational and transcriptional responses to Fe, respectively. All cases met the criteria of myocarditis. Inflammatory cells contained CD68 and ferritin, and most expressed the Fe-regulatory hormone hepcidin. In conclusion, inflammation plays a major role in the pathogenesis of FA cardiomyopathy, and hepcidin-induced retention of Fe in macrophages contributes to cardiac damage in FRDA.

We report the cross-reactivities and comparative molecular masses of the IgE epsilon chains in humans, rats, mice, and dogs. Monoclonal human, rat, and mouse IgE, and our purified polyclonal dog IgE were used in the study. IgE of the 4 species, separated by SDS-PAGE, were analyzed by immunoblotting with polyclonal and monoclonal antihuman IgE, polyclonal and monoclonal antimouse IgE, monoclonal antirat IgE, and polyclonal antidog IgE antibodies. The polyclonal antihuman and polyclonal antimouse IgE cross-reacted with the IgE of the other 3 species, while their monoclonal forms cross-reacted with dog IgE only. Polyclonal antidog IgE cross-reacted with human and mouse IgE, while the monoclonal antirat IgE did not cross-react with any other species. "Reverse' passive cutaneous anaphylaxis in ragweed-sensitized dogs revealed that polyclonal antihuman and polyclonal antimouse IgE were able to elicit positive skin responses, and monoclonal antihuman, antirat, and antimouse IgE antibodies were not. The molecular masses of the epsilon chains were 77 kDa for mice, 75 kDa for rats and dogs, and 70 kDa for humans.

Summary The homes of 120 patients with asthma, 57 in Vancouver and 63 in Winnipeg, were studied. The characteristics of the homes were assessed by a questionnaire. Dust samples were collected and the indoor relative humidity was measured four times during the year covering all four seasons in both cities. Mite allergen levels were determined using monoclonal antibodies against Der p I and Der f I by the ELISA method. The mean levels of both mite allergens in mattress and floor samples in the homes in Vancouver and in Winnipeg were relatively low for all seasons. Mite allergen levels were found to be associated with city, season and individual home differences. They were significantly higher in Vancouver than in Winnipeg. Der p I and Der f I in mattress samples in both cities and Der f I in floor samples in Vancouver, varied by season. The indoor relative humidity level in the homes in Vancouver were also significantly higher than those in Winnipeg. There was, however, no significant association between the levels of indoor relative humidity and the levels of mite allergens after adjusting for variations in city, season and individual home. Although individual home differences were highly associated with mite allergen levels, only a few home characteristics were found to be related to mite allergen levels such as the type and the age of the home, the type of heating, the use of feather pillows and the number of occupants in the homes. Whether low levels of mite allergens are partially responsible for the relatively low prevalence of childhood asthma in Canada remains to be investigated.

The effect of treatment of allergic rhinitis with intranasal corticosteroids on lower airway responsiveness was assessed in a randomized, double-blind, placebo-controlled, crossover study. Twenty-one young patients with perennial allergic rhinitis and asthma, with documented lower airway hyperresponsiveness (PC20 methacholine8 mg/ml), were treated with intranasal aqueous beclomethasone dipropionate and placebo, each given for 4 weeks. Patients recorded rhinitis and asthma symptom scores and monitored peak expiratory flow rates every morning and evening. Patients recorded global assessment of rhinitis and global asthma symptom scores at the beginning and end of each treatment. PC20 methacholine was performed at baseline and at the end of each treatment period. Intranasal beclomethasone dipropionate significantly reduced global rhinitis symptom scores (p = 0.05) after 4 weeks of treatment. Global asthma scores did not change significantly (p = 0.2). Geometric mean PC20 methacholine improved significantly after 4 weeks of intranasal beclomethasone, but not after placebo (p = 0.04). Daily morning and evening rhinitis symptom scores were lower in patients treated with intranasal corticosteroids over the first 4 weeks of treatment, but carryover effect of steroids precluded comparative analysis of the second 4-week block (morning p = 0.06, evening p = 0.03). Morning asthma scores tended to decrease (p = 0.07). Evening asthma scores were significantly decreased at weeks 2 and 3 (p = 0.001, p = 0.02, respectively). No change in peak expiratory flow rate was seen. This study confirms that treatment of inflammation in the upper airways indirectly improves asthma symptoms and decreases bronchial hyperreactivity. Ignoring inflammation in the upper airway may lead to suboptimal results in asthma treatment.

This was an analysis of the SAGE nested case-control, comprised of children with asthma (40%), no asthma and no allergy (40%), and rhinitis no asthma (20%). 486 children were seen at 8-10 years and again at 12-13 years. All children were assessed by a pediatric allergist and had skin testing to common aeroallergens. At 8-10 years, the families of children with a positive sensitization to HDM received an information brochure on environmental control for HDM. Parent modification of their home environment was defined as encasement of the child’s mattress or pillow and/or removal of carpet for the child’ sb edroom. Results 113 of the 486 children were sensitized to HDM (D. pteronyssinus or D.farinae). Of the 113 families, 49 undertook a home environment change. 30/49 (61%) of parents had children with asthma and 19/49 (39%) did not. Interestingly, the percent of parents who modified their environment did not significantly differ between those with asthmatic children (44%) and those with healthy children (42%). Conclusion Almost two-thirds of the families in the SAGE study made changes to their home environment because of HDM sensitization in their asthmatic child. However, these families were no more likely to change their environment than families with a child without asthma. We need to better understand the factors involved with parents’ willingness to modify their home environment for a child with asthma.

Background: In adults with asthma, the selective β 2 -adrenergic agonist salmeterol has a prolonged bronchodilator and bronchoprotective effect. To date, there are few published studies of salmeterol in children. Methods: We compared the bronchodilator and bronchoprotective effects of salmeterol, 25 and 50 μg, with salbutamol, 200 μg, and with placebo, administered via metered-dose inhaler, in a randomized, double-blind, within-patient, four-way crossover, single-dose study in 20 children. Results: Mean baseline forced expiratory volume in 1 second (FEV 1 ) and PC 20 methacholine were not significantly different ( p >0.05) on the 4 study days, and did not change significantly after placebo. FEV, increased significantly from 5 to 30 minutes after salbutamol, and from 5 minutes to 12 hours after 25 μg or 50 μg salmeterol, compared with placebo. After 25 μg or 50 μg salmeterol, FEV 1 was significantly lower than after salbutamol at 5 and 10 minutes, did not differ from salbutamol at 30 minutes, and was significantly greater than after salbutamol from 3 to 12 hours. No significant difference occurred between the effect of 25 μg salmeterol and the effect of 50 μg salmeterol on FEV 1 . After salbutamol, there was a significant increase in PC 20 only at 30 minutes. After 25 μg or 50 μg salmeterol, PC 20 increased significantly from 30 minutes to 12 hours. Salmeterol, 25 μg and 50 μg provided significantly greater bronchoprotection than salbutamol from 3 to 12 hours and from 30 minutes to 12 hours, respectively. Salmeterol, 50 μg, provided significantly better bronchoprotection than 25 μg salmeterol from 30 minutes to 12 hours. The amount of change in PC 20 accounted for by change in FEV 1 varied from 14% to 28%, indicating that protection against bronchoconstriction was not entirely dependent on bronchodilation. Conclusions: Salmeterol is a potent, long-acting bronchodilator, with a slower onset of bronchodilation than salbutamol. It provides significantly greater and longer-lasting protection against bronchoconstriction than salbutamol.

Summary Background Fast food consumption and childhood asthma have rapidly increased in recent decades. During the same period there has been an increased rate of prolonged breastfeeding. Objective To evaluate if fast food consumption was associated with asthma in children, and if the proposed protective effect of breastfeeding on asthma was altered by fast food consumption. Methods This case–control study included 246 children with allergist-diagnosed asthma and 477 non-asthmatic controls at age 8–10 years. Information on fast food consumption and exclusive breastfeeding was obtained from questionnaire data. The association between asthma and fast food consumption was evaluated. Asthma in relation to exclusive breastfeeding was also evaluated, taking into account fast food consumption as a modifying factor. Results Children with asthma were more likely to consume fast food than children without asthma [crude odds ratio (OR) 1.70, 95% confidence interval (CI) 1.23–2.34]. In comparison to prolonged exclusive breastfeeding (12 weeks), asthma was positively associated with short-term exclusive breastfeeding (

Summary EOR holds significant potential for producing additional oil from known reservoirs in the U.S. However. the economical application of the tertiary processes required to produce this oil relies on the use of produce this oil relies on the use of existing wells as points of reservoir access. Abandonment of these wells could substantially reduce the future recovery potential of the huge known remaining oil resource. This paper summarizes the effect of well abandonments on recovery potential by various EOR methods for more than 1,400 major fields that account for 67% of total known original oil in place (OOlP) in the U.S. The study place (OOlP) in the U.S. The study concludes that replacing existing wells (after their abandonment) would significantly increase costs and reduce U.S. EOR reserves. Introduction At the end of 1987, known U.S. reservoirs were estimated to contain 513 billion bbl of OOIP. of this resource, 145 billion bbl has already been produced. Another 27 billion bbl remains as proved reserves, oil that can be economically recovered at current oil prices with current technology (Fig. 1). The prices with current technology (Fig. 1). The remaining two-thirds of the known resource, more than 340 billion bbl, cannot be economically produced with currently available technology. This oil is trapped or bypassed by conventional recovery techniques owing to reservoir heterogeneities and unfavorable rock and fluid properties within the reservoir. The remaining resource falls into two categories:unrecovered mobile oil that could, if contacted, be recovered through natural reservoir forces or displaced by water and recovered through the use of improved primary and secondary recovery techniques, such as advanced waterflooding and infill drilling, andimmobile oil that is residual to secondary recovery processes and can be recovered only by use of tertiary EOR processes, such as thermal recovery, miscible gas injection, or chemical flooding. Even with the technological and eco nomic limitations of current advanced secondary and tertiary methods, their widescale implementation could significantly increase U.S. proved oil reserves. A 1984 Natl. Petroleum Council (NPC)study estimated that up to 14.5 billion bbl of oil could be produced though tertiary recovery processes at a $30/bbl oil price. This estimate processes at a $30/bbl oil price. This estimate includes nearly 4.0 billion bbl of incremental reserves from ongoing thermal flooding activities in California. Future EOR projects clearly could boost U.S. production, or slow its rate of decline, for decades. The viability of these projects, however, is treated by recent trends in well abandonments. Low oil prices have accelerated the abandonment of stripper wells, and increasingly stringent environmental regulations have increased the costs of regulatory compliance while imposing potential future liabilities. potential future liabilities. The NPC estimates of incremental EOR reserves were based on the assumption that all existing wells penetrating candidate reservoirs could be fully utilized in future projects; only a small number of new wells projects; only a small number of new wells would be required to adjust the injection-pattern geometry in EOR floods. On the basis of these assumptions, most of the EOR project investment costs modeled by the project investment costs modeled by the NPC were for the purchase and installation of required injection/processing facilities and the upgrading and conversion of existing injection and production wells. This study assesses the effect of well abandonments on EOR reserve estimates on the basis of the additional costs of replacing existing wells. other additional costs for reactivating project areas, such as legal fees and bonus payments necessary to reacquire leases or to re-form production units alter their abandonment, are not considered. Therefore, this analysis can be interpreted as an optimistic assessment of the full effect of resource abandonment on U.S. EOR potential. potential. Historical and Current Trends The profitability of new EOR projects strongly depends on maintaining access to the immobile oil resource through existing wells. To the extent that existing wells are abandoned and are not available for use in new tertiary recovery projects, future EOR reserves in the U.S. could be reduced. No previous works, however, have addressed previous works, however, have addressed the effect of these abandonments on the future of domestic oil recovery. Throughout the U.S., declining production rates combined with low oil prices production rates combined with low oil prices threaten the economic viability of large numbers of wells and leases. After more than 125 years of the most extensive exploration and production in the world, the U.S. resource has matured. This maturation, shown in Fig.2, has been reflected in steady declines in production and reserves in the Lower 48. Year-end Lower 48 crude oil production in 1970 was reported as 3.4 production in 1970 was reported as 3.4 billion bbl and declined 39% to 2.1 billion bbl in 1989. Similarly, Lower 48 crude oil reserves decreased 31% to 19.8 billion bbl in 1989. As the resource has declined, the proportion of stripper wells (wells that proportion of stripper wells (wells that produce less than 10 barrels per day) produce less than 10 barrels per day) has grown to 73% of all producing wells. Stripper wells contribute about 19% of Lower 48 total crude oil production.

Background: Inadequate milk consumption and being overweight are each associated with asthma symptoms in children. Milk consumption has been inversely related to childhood overweight. Thus, being overweight may be a pathway or a confounder in milk–asthma relationship. A combination of both factors may be associated with greater risk of asthma than one factor alone. Methods: This study included 246 children with allergist-diagnosed asthma and 477 nonasthmatic controls at the age of 8–10 years. Information on milk consumption during the last 12 months was obtained from questionnaires. Being overweight was defined as body mass index ≥85th percentile. Being overweight as a possible pathway or confounder was formally tested. The odds ratio (OR) for combined infrequent milk consumption and being overweight in asthmatic vs nonasthmatic children was determined in multivariate logistic regression analyses. Results: There was a significant interaction between milk consumption and sex of the child in relation to asthma. Asthma was significantly associated with infrequent milk consumption in girls (crude OR 2.11, 95% CI 1.05–4.24) but not in boys. The asthma–milk relation in girls was neither mediated by being overweight (pmediation tests = 0.27) nor was the relationship confounded by being overweight (a 9% change in coefficient). Asthmatic girls had 3.6 times increased odds of having combination of infrequent milk consumption and being overweight than nonasthmatic girls (adjusted OR 3.64, 95% CI 1.18–11.24). Asthma was not associated with either factor or with absence of the other in girls. Conclusion: Infrequent milk consumption plus being overweight may have great risk for asthma in girls.

Results 16 adolescents (M = 11, F = 5); age 12-19; 15/16 peanut allergic, 10/16 other food allergens All had epinephrine auto-injectors (EpiPen = 11; Allerject = 5) Teens believe they are well informed; often from parents; however they did identify important topics to incorporate into an education program for teens. Teens need/want to learn more about: cross-contamination, advisory statements on food labels, allergens in nonfood products, recognizing a reaction, staying calm during a reaction, teaching friends – signs of a reaction and auto-injector use, communicating confidently with others – strategies for what to say in situations and hands on practice with the auto-injectors. Food allergy related topics teens would like to discuss: travelling, dating, partying, grocery shopping, cooking, symptoms of a reaction versus anxiety, new treatments and research. Concerning themes around anaphylaxis noted were: reactions are dealt with by “waiting it out” or “sleeping it off”; epinephrine is only used if you can’t breathe, can’t talk or think you’re dying); antihistamines can be used as first line treatment.

Summary Objective Epinephrine (Epi) is the treatment of choice for reversing cardiovascular collapse in anaphylactic shock (AS). In this condition, most treatment guidelines have been anecdotally derived and no randomized clinical trials have been conducted. In the present study, we examined the time course of haemodynamic recovery in a canine model of AS when Epi was administered at the initiation of allergen challenge before fully developed shock had occurred. Methods Randomized, controlled, crossover studies were performed approximately 3–5 weeks apart in ragweed-sensitized dogs while the animals were ventilated and anaesthetized. Epi was administered by bolus intravenous (i.v.), subcutaneous (s.c.), intramuscular (i.m.) routes and by continuous i.v. infusion (CI). The findings obtained in the Epi treatment (T) studies were compared with those found in a no treatment (NT) study. In the bolus studies, Epi was administered at 0.01 mg/kg, while in the CI study, the dose of Epi was titrated to maintain mean arterial pressure (MAP) at 70% of preshock levels. MAP, cardiac output (CO), stroke volume (SV), and pulmonary wedge pressure (Pwp) were determined over a 3 h period. Results In the CI study, haemodynamics (CO, MAP, and SV) were significantly higher than those measured in the NT study and the bolus studies over approximately the first hour of the study. In the CI study, the amount of Epi infused was significantly less than in the bolus studies. Conclusion When administered at the initiation of allergen challenge, bolus treatment of Epi by i.m., i.v., or s.c. routes caused limited haemodynamic improvement in AS. In contrast, constant infusion of Epi at a lower total dose produced significant haemodynamic improvement. Within the limits of this anaesthetized canine model, the results suggest that CI should be the preferred route in the treatment of AS when this treatment option is available.

Study objective To evaluate the effects of nebulized ipratropium bromide on intraocular pressures and pupillary responses in children with asthma. Design A double-blind, randomized, crossover study. Setting Children's Hospital of Winnipeg, University of Manitoba. Patients or participants Age 6 to 17 years with asthma. Intervention Nebulized ipratropium bromide added to albuterol sulfate, albuterol alone, or saline solution was given by face mask and nebulizer. Before and 0.5 h after nebulization, intraocular pressures (mm Hg), pupillary size (mm), and pupillary responses were measured. In a subsequent open study, patients who had been admitted to hospital with acute asthma who were treated with nebulized ipratropium bromide were recruited for measurement of intraocular pressures, pupillary size, and pupillary responses. Measurements and results Twenty patients completed the double-blind study, and 26 patients completed the open study. There were no changes in intraocular pressures, pupillary size, or pupillary response after any treatment on any study day in either the double-blind or the open studies. Conclusion In children with asthma, who have no preexisting ocular abnormalities, the risk of an adverse reaction to nebulized ipratropium bromide delivered by face mask inadvertently absorbed in the eye is extremely small.

The objective of the present document is to review the impact of new information on the recommendations made in the last (1999) Canadian Asthma Consensus Guidelines. It includes relevant published studies and observations or comments regarding what are considered to be the main issues in asthma management in children and adults in office, emergency department, hospital and clinical settings. Asthma is still insufficiently controlled in a large number of patients, and practice guidelines need to be integrated better with current care. This report re-emphasises the need for the following: objective measures of airflow obstruction to confirm the diagnosis of asthma suggested by the clinical evaluation; identification of contributing factors; and the establishment of a treatment plan to rapidly obtain and maintain optimal asthma control according to specific criteria. Recent publications support the essential role of asthma education and environmental control in asthma management. They further support the role of inhaled corticosteroids as the mainstay of anti-inflammatory therapy of asthma, and of both long acting beta2-agonists and leukotriene antagonists as effective means to improve asthma control when inhaled corticosteroids are insufficient. New developments, such as combination therapy, and recent major trials, such as the Children’s Asthma Management Project (CAMP) study, are discussed.

Despite massive improvements in productivity due to technology advances, the E&P industry has averaged a disappointing 7% return on net assets (less than its cost of capital). Its market capitalization relative to the S&P 500, even at recent high oil and gas prices, is about half what it was a decade ago. A small scale, very simple case study suggests that at least part of the reason for this disappointing performance lies in the conventional way that the industry allocates capital and selects portfolios of projects. Conventional ranking of projects by deterministic estimates of value significantly overstates value, understates risk, and misallocates capital by incurring unnecessary, uncompensated risks. Suggestions for improvements in the project selection/capital allocation prices are offered. Why Change? Petroleum exploration and production is enjoying a "golden age" in technology. Over the past two decades, finding costs have fallen more than three fold and lifting costs by half or better (EIA, 1998). Three-D seismic has improved exploration success rates by as much as 90% and development success rates by 30% (Bohi, 1997). Yet, at the same time, the return on net assets by the largest U.S. based companies in the E&P sector has averaged 7% for both integrated majors and large independents (Figure 1, Simpson et al., 1999). This return is the result of projects selected because they all exceeded the minimum estimated internal rate of return "hurdle rates", generally set at 15% or more, and were all financed with capital that generally cost in the range of 10 – 12%. This would appear to indicate long-term destruction of shareholder value. Investors have noted these discouraging results and have responded accordingly. Figure 2 illustrates the AMEX Oil Index (16 major and independent U.S.-traded companies) and the Standard and Poors (S&P) 500 Index (the largest 500 U.S.-traded, non-financial companies, of which many of the oil companies are a subset) since January of 1990. The two indices show a continuing and accelerating divergence. Almost any major equity index other than the S&P would show an even greater divergence with the oil index. Some would argue that this was a period of volatile and often low oil prices. To examine if price variation accounts for the divergence, the Oil Index was "normalized" relative to the larger market for equities by dividing both by their 1990 values and then dividing the normalized oil index by the normalized S&P 500. If the two indexes moved together, the ratio would remain constant at unity. This normalized value is plotted against inflation-adjusted "real" oil prices (West Texas Intermediate in 2000 dollars) in Figure 3. In January of 1990, oil prices in real terms were about where they were in June of 2000. The Gulf War caused a price "spike" to nearly $45/b (in 2000 dollars) in October, and, as a result, oil company stock prices rose about 10% more than the full market during the late summer and early autumn, followed by a steady decline in both relative share prices and oil prices. Over the period 1991 to 1997, oil prices ranged between $16 and $26/b, but share prices gradually drifted from about 80% of comparable index stocks to 70%. In 1998 began a collapse of oil prices to nearly $11/b in December 1998 before recovering to around $30 in the spring of 2000. During this latest oil price cycle, oil company shares have held constant at about 50% of their value in 1990 relative to the market value of the full S&P Index. An interpretation of these data is that, despite significant technological advances, the E&P industry's performance over a sustained period has been such as to erode shareholder value and the confidence. Stock prices today are about half what they were a decade ago when adjusted for oil prices and the general market trend. Such a loss in investor confidence could have devastating consequences in the future for this capital-intensive industry. A number of factors have contributed to this overall performance. The present paper questions whether part of the answer may lie in the way that projects are evaluated and selected. Specifically, a simple case study is used to examine whether conventional treatment of uncertainty contribute to over-estimation of returns, under-estimation of risk, and/or misallocation of capital.

Abstract At tile same time that natural gas is being promoted as an environmentally preferred fuel with expectations of rising use, future environmental requirements may constrain U.S. supplies. A desire to reconcile contradictory environmental objectives has led the U.S. natural gas exploration and production (E&P) industry to call for a better understanding (and better balancing) of the costs and benefits of environmental requirements that may confront it. The use of systematic "cost/benefit analyses" is one approach that many claim can assist in characterizing explicitly and quantitatively (and ultimately balancing) the environmental and economic impacts of environmental initiatives. This paper presents a methodology, currently under development by the U.S. Department of Energy (DOE), that could allow the costs and benefits associated with alternative environmental compliance requirements affecting natural gas E&P - operations to be more systematically and comprehensively analyzed within a total market context, while still accounting for the site-specific geological and engineering aspects affecting operator economic decision-matting. Through presentation of this developing analytical capability, the authors hope to begin a dialogue on potential methods for considering the costs and benefits of proposed future environmental requirements on the U.S. gas industry. Introduction Environmental protection activities in the United States are becoming increasing complex and costly, currently exceeding $100 billion annually. The domestic oil and gas E&P industry faces a wide range of federal, state, and local environmental regulations which continue to become more stringent. Over the last decade, environmental compliance costs for this industry increased at a rate of 3% to 5% per year, with current oil and gas E&P industry expenditures for environmental protection activities estimated at $1 to $2 billion annually. At tile same time, many interested parties. including many environmental groups, are promoting tile environmental benefits associated with natural gas, touting its "clean" characteristics relative to competing fuels such as oil and coal. This conflict between the need for low cost supplies of environmentally preferred natural gas with the increased environmental compliance requirements imposed on E&P operations will continually challenge tile U.S. natural gas industry. P. 129