Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy - A focus on energy expenditure.

OBJECTIVE: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. METHODS: Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. RESULTS: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. CONCLUSIONS: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

Associations between maternal physical activity in early and late pregnancy and offspring birth size: remote federated individual level meta-analysis from eight cohort studies.

OBJECTIVE: Evidence on the impact of leisure time physical activity (LTPA) in pregnancy on birth size is inconsistent. We aimed to examine the association between LTPA during early and late pregnancy and newborn anthropometric outcomes. DESIGN: Individual level meta-analysis, which reduces heterogeneity across studies. SETTING: A consortium of eight population-based studies (seven European and one US) comprising 72 694 participants. METHODS: Generalised linear models with consistent inclusion of confounders (gestational age, sex, parity, maternal age, education, ethnicity, BMI, smoking, and alcohol intake) were used to test associations between self-reported LTPA at either early (8-18 weeks gestation) or late pregnancy (30+ weeks) and the outcomes. Results were pooled using random effects meta-analyses. MAIN OUTCOME MEASURES: Birth weight, large-for-gestational age (LGA), macrosomia, small-for-gestational age (SGA), % body fat, and ponderal index at birth. RESULTS: Late, but not early, gestation maternal moderate to vigorous physical activity (MVPA), vigorous activity, and LTPA energy expenditure were modestly inversely associated with BW, LGA, macrosomia, and ponderal index, without heterogeneity (all: I2  = 0%). For each extra hour/week of MVPA, RR for LGA and macrosomia were 0.97 (95% CI: 0.96, 0.98) and 0.96 (95% CI: 0.94, 0.98), respectively. Associations were only modestly reduced after additional adjustments for maternal BMI and gestational diabetes. No measure of LTPA was associated with risk for SGA. CONCLUSIONS: Physical activity in late, but not early, pregnancy is consistently associated with modestly lower risk of LGA and macrosomia, but not SGA. TWEETABLE ABSTRACT: In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.

Weight loss after laparoscopic adjustable gastric band and resolution of the metabolic syndrome and its components.

BACKGROUND: Substantial weight loss in the setting of obesity has considerable metabolic benefits. Yet some studies have shown improvements in obesity-related metabolic comorbidities with more modest weight loss. By closely monitoring patients undergoing bariatric surgery, we aimed to determine the effects of weight loss on the metabolic syndrome and its components and determine the weight loss required for their resolution. METHODS: We performed a prospective observational study of obese participants with metabolic syndrome (Adult Treatment Panel III criteria) who underwent laparoscopic adjustable gastric banding. Participants were assessed for all criteria of the metabolic syndrome monthly for the first 9 months, then 3-monthly until 24 months. RESULTS: There were 89 participants with adequate longitudinal data. Baseline body mass index was 42.4±6.2 kg m-2 with an average age was 48.2±10.7 years. There were 56 (63%) women. Resolution of the metabolic syndrome occurred in 60 of the 89 participants (67%) at 12 months and 60 of the 75 participants (80%) at 24 months. The mean weight loss when metabolic syndrome resolved was 10.9±7.7% total body weight loss (TBWL). The median weight loss at which prevalence of disease halved was 7.0% TBWL (17.5% excess weight loss (EWL)) for hypertriglyceridaemia; 11% TBWL (26.1-28% EWL) for high-density lipoprotein cholesterol and hyperglycaemia; 20% TBWL (59.5% EWL) for hypertension and 29% TBWL (73.3% EWL) for waist circumference. The odds ratio for resolution of the metabolic syndrome with 10-12.5% TBWL was 2.09 (P=0.025), with increasing probability of resolution with more substantial weight loss. CONCLUSIONS: In obese participants with metabolic syndrome, a weight loss target of 10-12.5% TBWL (25-30% EWL) is a reasonable initial goal associated with significant odds of having metabolic benefits. If minimal improvements are seen with this initial target, additional weight loss substantially increases the probability of resolution.

The mechanism of weight loss with laparoscopic adjustable gastric banding: induction of satiety not restriction.

Laparoscopic adjustable gastric banding (LAGB) has rapidly emerged as a popular bariatric procedure because of its safety, efficacy, durability and adjustability. Despite widespread use, there is limited understanding of how it induces weight loss. Previously, it has been classified as a restrictive procedure, physically limiting the patient to a small meal that subsequently slowly empties into the distal stomach. However, the tiny pouch of stomach created above the LAGB appears to be unable to accommodate even the smallest of meals. Therefore, the key mechanism has been hypothesized to be the induction of satiety via, as yet, undefined pathways. The critical question remains: what are the key physiological changes that lead to satiety and weight loss? In successful LAGB patients, a consistent intraluminal pressure at the level of the LAGB of 26.9 ± 19.8 mm Hg is observed. Studies using semi-solid swallows combined with intraluminal pressure recordings have demonstrated that semi-solid transit across the resistance of the LAGB is mediated by repeated esophageal peristaltic contractions (mean 4.5 ± 2.9) that produce episodic flow, interspersed by reflux events. Failed transit results in obstruction and regurgitation, whereas dilatation of the supraband stomach induces severe and intolerable reflux. Overall gastric emptying does not appear to be significantly altered following LAGB. Focused investigations have shown that the supraband stomach is empty of an ingested meal 1-2 min after intake ceases. Considerable progress has been made in understanding the mechanical physiological effects of the LAGB on esophageal and proximal gastric function. These have been correlated with patient outcomes and sensations. On the basis of recent data, it appears that the LAGB activates the peripheral satiety mechanism without physically restricting the meal size. Therefore, it should not be classified as a restrictive procedure. The precise mechanism of weight loss with the LAGB remains to be delineated.

Medium-term outcome of fundoplication after lung transplantation.

Gastroesophageal reflux disease (GERD) in lung transplant recipients has gained increasing attention as a factor in allograft failure. There are few data on the impact of fundoplication on survival or lung function, and less on its effect on symptoms or quality of life. Patients undergoing fundoplication following lung transplantation from 1999 to 2005 were included in the study. Patient satisfaction, changes in GERD symptoms, and the presence of known side effects were assessed. The effect on lung function, body mass index, and rate of progression to the bronchiolitis obliterans syndrome (BOS) were recorded. Twenty-one patients (13 males), in whom reflux was confirmed on objective criteria, were included, with a mean age of 43 years (range 20-68). Time between transplantation and fundoplication was 768 days (range 145-1524). The indication for fundoplication was suspected microaspiration in 13 and symptoms of GERD in 8. There was one perioperative death, at day 17. There were three other late deaths. Fundoplication did not appear to affect progression to BOS stage 1, although it may have slowed progression to stage 2 and 3. Forced expiratory volume-1% predicted was 72.9 (20.9), 6 months prior to fundoplication and 70.4 (26.8), six months post-fundoplication, P= 0.33. Body mass index decreased significantly in the 6 months following fundoplication (23 kg/m(2) vs. 21 kg/m(2), P= 0.05). Patients were satisfied with the outcome of the fundoplication (mean satisfaction score 8.8 out of 10). Prevalence of GERD symptoms decreased significantly following surgery (11 of 14 vs. 4 of 17, P= 0.002). Fundoplication does not reverse any decline in lung function when performed at a late stage post-lung transplantation in patients with objectively confirmed GERD. It may, however, slow progression to the more advanced stages of BOS. Reflux symptoms are well controlled and patients are highly satisfied. Whether performing fundoplication early post-lung transplant in selected patients can prevent BOS and improve long-term outcomes requires formal evaluation.

The role of cytokine gene polymorphisms in the pathogenesis of abdominal aortic aneurysms: a case-control study.

BACKGROUND: Cytokines are the primary mediators of inflammation and also influence matrix metalloproteinase expression, both of which are important in development of abdominal aortic aneurysm (AAA). A significant, but as yet unknown, familial factor contributes to the pathogenesis of AAA. Many cytokine genes contain polymorphic sites, some of which affect cytokine production in vitro. Cytokine gene polymorphisms may therefore influence the pathogenesis of AAA. The purpose of this study was to determine whether there is any association between cytokine gene polymorphisms and AAA. METHODS AND RESULTS: This case-control study comprised 100 patients with AAA and 100 age-matched and sex-matched control subjects. For each case and control subject in the study, genotypes at the following cytokine gene polymorphic loci were determined: interleukin (IL)-1beta +3953, IL-6 -174, IL-10 -1082, IL-10 -592, and tumor necrosis factors-alpha -308. Allele and genotype frequencies were compared between AAA and control groups, and odds ratios (OR) were calculated for the presence of AAA with each allele at each locus examined as risk factors. The IL-10 -1082 A allele was significantly more common in the AAA group than the control group (P =.03). The OR for the IL-10 -1082 A allele as a risk factor for AAA was 1.8 (95% confidence interval, 0.9-3.6). DISCUSSION: These associations suggest a significant role for IL-10 in the pathogenesis of AAA. This association of AAA with the IL-10 -1082 A allele is also biologically plausible; the IL-10 -1082 A allele is associated with low IL-10 secretion, and it may be that AAA develops in patients who are unable to mount the same anti-inflammatory response as those who do not have AAA.

Familial aggregation and heritability of adult lung function: results from the Busselton Health Study.

Decreased spirometric indices are characteristic of asthma and other respiratory diseases. The aim of this study was to investigate the genetic and environmental components of variance of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured in adulthood in an Australian population-based sample of 468 Caucasian nuclear families. The inter-relationships of the genetic determinants of these traits with asthma and atopic rhinitis were also investigated. Serial cross-sectional studies were conducted in the town of Busselton in Western Australia between 1966 and 1981 and follow-up of previous attendees was undertaken in 1995. Data from each subject included in this study were from a single survey in adulthood (25-60 yrs of age) when the subject was as close to age 45 yrs as possible. Multivariate analysis suggested that FEV1 and FVC levels were associated with age, sex, height, tobacco smoke exposure, asthma and atopic rhinitis. After adjustment for relevant covariates, FEV1 levels had a narrow-sense heritability (h2N) of 38.9% (SE 9.1%). FVC levels had an h2N of 40.6% (SE 8.9%). Extended modelling demonstrated little overlap in the genetic determinants of asthma or atopic rhinitis and either FEV1 or FVC levels. The results of this study were consistent with the existence of important genetic determinants of adult lung function that are independent of asthma or other atopic disease, cigarette smoking, height, age or sex.

Gibbs sampling-based segregation analysis of asthma-associated quantitative traits in a population-based sample of nuclear families.

Asthma is a common, complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, and increased airway responsiveness are physiological traits that are characteristic of asthma. Few studies have investigated major gene effects for these traits in a population-based sample. Further, it is not known if any putative major genes may be common to two or more of these traits. We investigated the existence and nature of major genes modulating asthma-associated quantitative traits in an Australian population-based sample of 210 Caucasian nuclear families. The sharing of these major genes was also investigated. Segregation analysis was based upon a Markov Chain Monte Carlo (Gibbs sampling) approach as implemented in the program BUGS v0.6. All models included adjustment for age, height, tobacco smoke exposure, and gender. The segregation of total IgE levels, blood eosinophil counts, and dose-response slope (DRS) of methacholine challenge were all consistent with major loci at which a recessive allele acted to increase or decrease the phenotype. The respective estimated frequencies of the recessive alleles were 68% (total IgE), 10% (blood eosinophil count), and 27% (DRS). Extensive modelling suggested that the major loci controlling total serum IgE levels, blood eosinophil counts, and airway responsiveness represent different genes. These data provide evidence, for the first time, of the existence of at least 3 distinct genetic pathways involving major gene effects on physiological traits closely associated with asthma. These results have implications for gene discovery programs.

Hemizygous p16(INK4A) deletion in pediatric acute lymphoblastic leukemia predicts independent risk of relapse.

The genes at the INK4A/ARF locus at 9p21 are frequently involved in human cancer. Virtually all p16(INK4A) exon 2 (henceforth called p16) inactivation in pediatric acute lymphoblastic leukemia (ALL) occurs by gene deletion. The results of this study illustrate that real-time quantitative polymerase chain reaction is capable of detecting gene deletion in primary patient specimens with a precision not previously achieved by conventional methods. Importantly, this assay includes the detection of hemizygous deletions. The study revealed, strikingly, that the risk ratio for relapse for hemizygous deletion compared with no deletion was 6.558 (P =.00687) and for homozygous deletion was 11.558 (P =.000539). These results confirm and extend the authors' previous findings that homozygous deletion of p16 in pediatric ALL patients is an independent prognostic indicator of outcome from therapy.

Familial aggregation and heritability of asthma-associated quantitative traits in a population-based sample of nuclear families.

Asthma is a common, genetically complex human disease. Elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts, variably reduced spirometric measures and increased airway responsiveness (AR) are physiological traits which are characteristic of asthma. We investigated the genetic and environmental components of variance of serum total and specific IgE levels, blood eosinophil counts, the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), and AR in an Australian population-based sample of 232 Caucasian nuclear families. With the exception of FVC levels, all traits were closely associated with clinical asthma in this population. Loge total serum IgE levels had a narrow-sense heritability (h2N) of 47.3% (SE = 10. 0%). Specific serum IgE levels against house dust mite and Timothy grass, measured as a RAST Index, had a h2N of 33.8% (SE = 7.3%). FEV1 levels had a h2N of 6.1% (SE = 11.6%), whilst FVC levels had a h2N of 30.6% (SE = 26.8%). AR, quantified by the loge dose-response slope to methacholine (DRS), had a h2N of 30.3% (SE = 12.3%). These data are consistent with the existence of important genetic determinants of the pathophysiological traits associated with asthma. Our study suggests that total and specific serum IgE levels, blood eosinophil counts and airways responsiveness to inhaled agonist are appropriate phenotypes for molecular investigations of the genetic susceptibility to asthma.

A simplified method of harvesting and dilating the radial artery achieves acceptable clinical outcomes.

BACKGROUND: The recent successful revival of the radial artery as a coronary-bypass conduit has been attributed to a minimally traumatic harvesting technique without diathermy, combined with long-term oral calcium antagonist therapy. We describe a simplified technique of harvesting the radial artery, which reduces procurement time and maintains conduit relaxation. METHODS: Radial arteries were harvested using diathermy and topical glyceryl trinitrate-verapamil dilator solution. Postoperatively, intravenous glyceryl trinitrate, but no calcium antagonist was used. The clinical results in the first 100 consecutive patients receiving radial artery grafts (RA group), procured using this technique, were compared with a group of 100 patients receiving saphenous vein conduits (SV group) immediately prior to the introduction of the radial artery at our institution. RESULTS: There were no demographic differences between the two groups, other than the SV group being slightly older. There was one intraoperative death in each group. There was no difference in the rate of peri-operative myocardial infarction or length of stay in the intensive care unit. At a median follow-up time of 16 months for the RA group, and 25 months for the SV group, the survival rates were 97 and 94%, respectively. All survivors were in the New York Heart Association class I. In the SV group, two postoperative angioplasties were performed. CONCLUSIONS: These early results suggest that this method of procuring the radial artery using diathermy, glyceryl trinitrate and no postoperative calcium antagonists, is rapid, safe and effective. The continued use of this technique is justified, while awaiting the results of long-term angiographic studies.

Genome-wide linkage analysis using genetic variance components of alcohol dependency-associated censored and continuous traits.

We used variance-components analysis to investigate the additive genetic effects regulating some of the phenotypes included in the GAW11 data set. Variance-components models were fitted using Gibbs sampling methods in BUGS v 0.6. Linkage analyses for both multivariate normal (MvN) traits and right censored survival times (age-of-onset) were based upon standard Haseman-Elston identity-by-descent sib-pair methods applied directly to traits showing evidence of substantial additive genetic determination (residualized for any important covariates) and to the estimated sigma A2 residuals for those traits. Harm avoidance behavior (TPQ subscale) showed evidence of linkage to markers on chromosomes 1, 13, and 18. P300 levels at the Fp1 site showed evidence of linkage to markers on chromosomes 2, 3, 9, 12, 17, 19, and 20. Platelet monoamine oxidase B (MAOB) levels showed evidence of linkage to D4S1651. The age-of-onset for ALDX1 in those over 30 years old showed evidence of linkage to markers on chromosomes 1, 6, 14, and 15. The age-of-onset for the more strictly defined ALDX2 in those over 30 years old showed evidence of linkage to markers on chromosomes 7 and 14. These results are consistent with a complex, multifactorial susceptibility to alcohol dependency.

Association between breast feeding and asthma in 6 year old children: findings of a prospective birth cohort study.

OBJECTIVES: To investigate the association between the duration of exclusive breast feeding and the development of asthma related outcomes in children at age 6 years. DESIGN: Prospective cohort study. SETTING: Western Australia. SUBJECTS: 2187 children ascertained through antenatal clinics at the major tertiary obstetric hospital in Perth and followed to age 6 years. MAIN OUTCOME MEASURES: Unconditional logistic regression to model the association between duration of exclusive breast feeding and outcomes related to asthma or atopy at 6 years of age, allowing for several important confounders: sex, gestational age, smoking in the household, and early childcare. RESULTS: After adjustment for confounders, the introduction of milk other than breast milk before 4 months of age was a significant risk factor for all asthma and atopy related outcomes in children aged 6 years: asthma diagnosed by a doctor (odds ratio 1.25, 95% confidence interval 1.02 to 1.52); wheeze three or more times since 1 year of age (1.41, 1.14 to 1.76); wheeze in the past year (1.31, 1.05 to 1.64); sleep disturbance due to wheeze within the past year (1.42, 1.07 to 1.89); age when doctor diagnosed asthma (hazard ratio 1.22, 1.03 to 1.43); age at first wheeze (1.36, 1.17 to 1.59); and positive skin prick test reaction to at least one common aeroallergen (1.30, 1.04 to 1.61). CONCLUSION: A significant reduction in the risk of childhood asthma at age 6 years occurs if exclusive breast feeding is continued for at least the 4 months after birth. These findings are important for our understanding of the cause of childhood asthma and suggest that public health interventions to optimise breast feeding may help to reduce the community burden of childhood asthma and its associated traits.

The relationship between asthma and smoking during pregnancy.

Asthma is the most common and potentially serious medical problem encountered in pregnancy. The prevalence of asthma during pregnancy is generally quoted as being between 1% and 4% which is much lower than general population estimates. The aim of this analysis was to estimate the prevalence of asthma and smoking during pregnancy; and to describe the relationship between the two. A cross-sectional random sample survey of recently delivered Western Australian mothers was carried out in 1995 and 82% of mothers responded. In total 21.3% of women reported ever having asthma at some stage in their life and 12.4% currently had asthma. These results are consistent with general population estimates. Overall 22.7% of women smoked at some stage in pregnancy, which is consistent with the limited comparison data available. Current asthmatics were more likely to smoke during pregnancy than non-asthmatics, although this difference was not statistically significant. Continued vigorous efforts are required to discourage all women and girls from taking up smoking and to encourage those who smoke to quit. This is particularly pertinent for asthmatic women who are pregnant or planning a pregnancy.

A polymorphism of the CC16 gene is associated with an increased risk of asthma.

Several quantitative traits associated with the asthma phenotype have been linked to markers on chromosome 11q13, although the gene responsible has yet to be well established. The gene for Clara cell secretory protein (CC16) is an ideal candidate for involvement in an inherited predisposition to asthma because of its chromosomal location, the role of the CC16 protein in controlling airway inflammation, and differences in levels of the protein between asthmatics and healthy controls. All three CC16 exons were screened in an unselected population of 266 subjects from 76 families and a cohort of 52 severely asthmatic children. A combination of single strand conformational polymorphism (SSCP) analysis, heteroduplex analysis, DNA sequencing, and restriction digestion was used. Mutation detection methods identified an adenine to guanine substitution in the CC16 gene at position 38 (A38G) downstream from the transcription initiation site within the non-coding region of exon 1. In the unselected population, 43.6% were homozygous for the polymorphic sequence (38GG) and 46.2% were heterozygous (38AG). All the asthmatic and unaffected children from both populations were selected for an unmatched case control analysis consisting of 67 asthmatic and 46 unaffected subjects. Those homozygous for the published sequence (38AA) had a 6.9-fold increased risk of developing asthma (p=0.049) and heterozygotes (38AG) a 4.2-fold increased risk (p=0.028). Modelling of genotype as a continuous covariate indicated evidence of a significant linear trend across the three genotypes (odds ratio=2.84 per unit increase in genotype code, p=0.018). These associations were independent of age, gender, and tobacco smoke exposure. These data and the known anti-inflammatory role of CC16 in the respiratory tract suggest that alteration to the gene at position 38 may contribute to asthma.

Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a potent modulator of immune and inflammatory responses, and has been implicated in a variety of autoimmune diseases, including asthma. Increased levels of TNFalpha have been detected in both sputa and bronchoalveolar lavage fluid of asthmatic subjects during acute attacks. Interindividual variation in TNFalpha levels may be genetically determined and polymorphisms within the TNF genes and nearby HLA Class II region have been associated with differences in TNFalpha production. OBJECTIVE: To investigate the association of differences in asthma-related phenotypes with two biallelic polymorphisms: a G to A substitution at position - 308 of the TNFalpha gene promoter (TNF1 and TNF2 alleles) and an NcoI polymorphism in the first intron of the lymphotoxin alpha gene (LT-alpha*1 and LT-alpha*2 alleles). METHODS: The regions of interest were amplified from genomic DNA using specific primers and PCR. Dot blot analysis was used for genotyping individuals for the TNFalpha - 308 polymorphism, while restriction enzyme digestion was used for genotyping individuals for the LT-alpha gene NcoI polymorphism. A case-control analysis was then performed on 74 asthmatic and 50 non-asthmatic unrelated children for each polymorphism. RESULTS: The TNFalpha - 308 TNF1 allele was present at a significantly higher frequency in cases than controls (OR= 2.4, P=0.003), and homozygosity for the TNF1 allele was associated with a fivefold increased risk of physician diagnosed asthma relative to the other genotypes (OR = 5.23, P = 0.004). The LT-alpha*2 allele showed similar associations, including an approximately fivefold higher risk of physician diagnosed asthma for LT-alpha*2 homozygotes (OR = 4.89, P = 0.019). Evidence of a significant linear trend in asthma risk across the three genotypes was found for both polymorphisms. CONCLUSION: These results suggest an important role for the TNFalpha gene or a linked locus in an inherited asthma diathesis.

Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome.

The p16 gene (MTS1, CDKN2, p16INK4A, CDKI) encoding an inhibitor of cyclin-dependent kinase 4 (cdk4) has been found to be deleted in various types of tumors, including leukemia, and is thought to code for a tumor suppressor gene. Our preliminary findings on eight pediatric patients with acute lymphoblastic leukemia (ALL) suggested that the survival of patients carrying a homozygous p16 gene deletion was significantly inferior to that of those without a deletion. The present study on 48 patients tested the hypothesis that the clinical outcome for pediatric ALL patients is correlated with the presence or absence of the p16 gene. Overall, nine of 48 children (18.3%) carried a homozygous p16 deletion. Such deletions were significantly more common (P = .003) among T-ALL patients (five of eight, 62.5%) than among precursor-B-ALL patients (four of 40, 10.0%). Of nine patients exhibiting p16 deletions, eight (88.9%) were classified as high-risk patients by the recognized prognostic factors of age, white blood cell count, and T-cell phenotype. The 4-year event-free survival in the study population as a whole was 72.7%. Without adjustment for other risk factors (univariate model), the presence of a homozygous p16 deletion was associated with a markedly increased probability of both relapse (P = .0003) and death (P = .002). These findings raise the question of whether the p16 deletion itself confers an increased risk of relapse after adjusting for the known risk factors. In this analysis, the estimated risk multiplier factor for relapse in patients carrying the p16 deletion was 14.0 (P = .0004) and for the risk of death 15.6 (P = .0008). We therefore conclude that the presence of a homozygous p16 deletion may well be an important risk factor for both relapse and death in childhood ALL, and that its prognostic effect is not a consequence of confounding by other factors already known to influence outcome in this disease.

Effects of maternal smoking during pregnancy and a family history of asthma on respiratory function in newborn infants.

INTRODUCTION: Infants of mothers who smoke have reduced respiratory function and are more likely to develop wheezing. Little evidence is available on the effect of in-utero cigarette-smoke exposure as opposed to postnatal exposure to environmental tobacco smoke. We used a previously validated non-invasive method to measure the time to peak tidal expiratory flow (tPTEF) as a proportion of expiratory time (tE) in newborn infants soon after birth to examine the effects of a family history of asthma and in-utero cigarette-smoke exposure on the infants' respiratory function. METHODS: We collected respiratory-function data from 500 healthy infants of mothers taking part in the Western Australia Pregnancy Cohort Study. During behaviourally defined quiet sleep, measurements were obtained a median of 58 h (range 26-159) after the infants were born. We used uncalibrated inductance plethysmography. The uncalibrated volume signal was differentiated to flow and used to calculate respiratory rate, total inspiratory time, tE, and tPTEF. Mothers answered questionnaires on demographic, medical, and pregnancy characteristics, including smoking history. Serum cotinine measurements were available to validate self-reported smoking history in a subset of mothers (238). RESULTS: Data suitable for analysis were obtained from 461 infants. In multivariate regression analysis, lower values of tPTEF/tE were independently associated with respiratory rate (beta coefficient per 10 breaths/min 0.018 [SE 0.005], p < 0.01), age (beta coefficient per 10 h -0.008 [0.003], p < 0.01), maternal smoking during pregnancy (> 10 cigarettes daily; beta coefficient -0.049 [0.022], p < 0.05), maternal hypertension during pregnancy (-0.037 [0.015], p < 0.02), and a family history of asthma (-0.028[0.014], p < 0.05). CONCLUSIONS: In-utero smoke exposure, a family history of asthma, and maternal hypertension during pregnancy are associated with reduced respiratory function after birth. We speculate that these factors adversely affect lung development in utero.

Sudden infant death syndrome in Australian aboriginal and non-aboriginal infants: an analytical comparison.

Our previous research has shown that the sudden infant death syndrome (SIDS) rate for Aboriginal infants in Western Australia (WA) is markedly higher than that for non-Aboriginal infants. The aim of this study was to identify factors that may be important in explaining this disparity. A case-control study was conducted based on routinely collected data for the population of WA singleton births from 1980 to 1990 inclusive. Cases were infants born and classified as dying from SIDS in WA (Aboriginal n = 88, non-Aboriginal n = 409). Controls were infants born in WA and not classified as dying from SIDS; 2% samples of both Aboriginal and non-Aboriginal infants were included. The risk of dying from SIDS in Aboriginal infants was 3.86 times [95% confidence interval (CI) = 2.98 to 5.02] that in non-Aboriginal infants. Statistically significant univariable risk factors for SIDS in Aboriginal infants were preterm birth, low birthweight and small-for-gestational-age; for non-Aboriginal infants they included these factors as well as single marital status, young maternal age, parity of one or greater and male sex. Comparing Aboriginal with non-Aboriginal controls, most of the risk factors were more common in the Aboriginal population. Multiple logistic regression analysis indicated that Aboriginal infants were 1.43 times [95% CI = 1.04 to 1.95] more likely to die from SIDS than non-Aboriginal infants. Differences in the risk factor profile for Aboriginal and non-Aboriginal infants were sought using interaction terms. The only important differences were that the risk of SIDS in Aboriginal infants, unlike that in non-Aboriginal infants, appeared not to be strongly related to male sex or to single marital status. Thus, the results show that the disparity between the incidence of SIDS in the Aboriginal and non-Aboriginal populations can be explained largely, although not totally, by the high prevalence of routinely recorded risk factors in the Aboriginal population. A limitation of this study is that data on the postnatal risk factors of prone sleeping, maternal smoking and non-breastfeeding were unavailable. The residual excess risk for Aboriginal infants may be a result of these recognised postnatal risk factors and/or other infant care practices that are not routinely recorded in our data base, or to underlying social and economic conditions. Further study of all these potential risk factors is warranted.

Night cough in a population-based sample of children: characteristics, relation to symptoms and associations with measures of asthma severity.

Nocturnal cough in asthma is a common but poorly understood phenomenon. The aims of this study were to determine the relationship between recorded night cough, reported night cough and current wheeze in a population-based sample of children previously identified as wheezy, and to examine the relationship of nocturnal cough to current symptoms, markers of asthma severity and environmental exposure. Children were reassessed in the early school years by measuring current symptoms, ventilatory function, bronchial reactivity, peak flow variability, respiratory symptom diaries and home monitoring of overnight cough, transcutaneous arterial oxygen saturation, room temperature and humidity. Night studies were performed on 59 asymptomatic children and 41 children with current wheeze. Cough occurred more frequently in current wheezers compared to asymptomatic children (16 out of 41 (39%) vs 11 out of 59 (19%)), and more cough episodes were recorded (median 3.5 vs 2.0). Night cough was not associated with bronchial reactivity, peak flow variability, degree of morning dip, mean overnight arterial oxygen saturation, ventilatory function, maternal smoking or treatment of asthma. However, it was associated with lower overnight air temperature. Although night cough is more common in current wheezers, there is poor agreement between recorded and reported night cough. Objective tests of asthma severity are of little use in predicting its presence in this age group. The sleeping environment deserves further study.