Interaction between allelic variations in vitamin D receptor and retinoid X receptor genes on metabolic traits

BACKGROUND: Low vitamin D status has been shown to be a risk factor for several metabolic traits such as obesity, diabetes and cardiovascular disease. The biological actions of 1, 25-dihydroxyvitamin D, are mediated through the vitamin D receptor (VDR), which heterodimerizes with retinoid X receptor, gamma (RXRG). Hence, we examined the potential interactions between the tagging polymorphisms in the VDR (22 tag SNPs) and RXRG (23 tag SNPs) genes on metabolic outcomes such as body mass index, waist circumference, waist-hip ratio (WHR), high- and low-density lipoprotein (LDL) cholesterols, serum triglycerides, systolic and diastolic blood pressures and glycated haemoglobin in the 1958 British Birth Cohort (1958BC, up to n = 5,231). We used Multifactor- dimensionality reduction (MDR) program as a non-parametric test to examine for potential interactions between the VDR and RXRG gene polymorphisms in the 1958BC. We used the data from Northern Finland Birth Cohort 1966 (NFBC66, up to n = 5,316) and Twins UK (up to n = 3,943) to replicate our initial findings from 1958BC. RESULTS: After Bonferroni correction, the joint-likelihood ratio test suggested interactions on serum triglycerides (4 SNP - SNP pairs), LDL cholesterol (2 SNP - SNP pairs) and WHR (1 SNP - SNP pair) in the 1958BC. MDR permutation model testing analysis showed one two-way and one three-way interaction to be statistically significant on serum triglycerides in the 1958BC. In meta-analysis of results from two replication cohorts (NFBC66 and Twins UK, total n = 8,183), none of the interactions remained after correction for multiple testing (Pinteraction >0.17). CONCLUSIONS: Our results did not provide strong evidence for interactions between allelic variations in VDR and RXRG genes on metabolic outcomes; however, further replication studies on large samples are needed to confirm our findings.

Elevated fetal steroidogenic activity in autism

Autism affects males more than females, giving rise to the idea that the influence of steroid hormones on early fetal brain development may be one important early biological risk factor. Utilizing the Danish Historic Birth Cohort and Danish Psychiatric Central Register, we identified all amniotic fluid samples of males born between 1993 and 1999 who later received ICD-10 (International Classification of Diseases, 10th Revision) diagnoses of autism, Asperger syndrome or PDD-NOS (pervasive developmental disorder not otherwise specified) (n=128) compared with matched typically developing controls. Concentration levels of Δ4 sex steroids (progesterone, 17α-hydroxy-progesterone, androstenedione and testosterone) and cortisol were measured with liquid chromatography tandem mass spectrometry. All hormones were positively associated with each other and principal component analysis confirmed that one generalized latent steroidogenic factor was driving much of the variation in the data. The autism group showed elevations across all hormones on this latent generalized steroidogenic factor (Cohen's d=0.37, P=0.0009) and this elevation was uniform across ICD-10 diagnostic label. These results provide the first direct evidence of elevated fetal steroidogenic activity in autism. Such elevations may be important as epigenetic fetal programming mechanisms and may interact with other important pathophysiological factors in autism.

Interactions between uncoupling protein 2 gene polymorphisms, obesity and alcohol intake on liver function: a large meta-analysed population-based study

BACKGROUND AND OBJECTIVE: Given the role of uncoupling protein 2 (UCP2) in the accumulation of fat in the hepatocytes and in the enhancement of protective mechanisms in acute ethanol intake, we hypothesised that UCP2 polymorphisms are likely to cause liver disease through their interactions with obesity and alcohol intake. To test this hypothesis, we investigated the interaction between tagging polymorphisms in the UCP2 gene (rs2306819, rs599277 and rs659366), alcohol intake and obesity traits such as BMI and waist circumference (WC) on alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) in a large meta-analysis of data sets from three populations (n=20 242). DESIGN AND METHODS: The study populations included the Northern Finland Birth Cohort 1966 (n=4996), Netherlands Study of Depression and Anxiety (n=1883) and LifeLines Cohort Study (n=13 363). Interactions between the polymorphisms and obesity and alcohol intake on dichotomised ALT and GGT levels were assessed using logistic regression and the likelihood ratio test. RESULTS: In the meta-analysis of the three cohorts, none of the three UCP2 polymorphisms were associated with GGT or ALT levels. There was no evidence for interaction between the polymorphisms and alcohol intake on GGT and ALT levels. In contrast, the association of WC and BMI with GGT levels varied by rs659366 genotype (Pinteraction=0.03 and 0.007, respectively; adjusted for age, gender, high alcohol intake, diabetes, hypertension and serum lipid concentrations). CONCLUSION: In conclusion, our findings in 20 242 individuals suggest that UCP2 gene polymorphisms may cause liver dysfunction through the interaction with body fat rather than alcohol intake.

Economic Impact of a Rotavirus Vaccine in Brazil

The study was done to evaluate the cost-effectiveness of a national rotavirus vaccination programme in Brazilian children from the healthcare system perspective. A hypothetical annual birth-cohort was followed for a five-year period. Published and national administrative data were incorporated into a model to quantify the consequences of vaccination versus no vaccination. Main outcome measures included the reduction in disease burden, lives saved, and disability-adjusted life-years (DALYs) averted. A rotavirus vaccination programme in Brazil would prevent an estimated 1,804 deaths associated with gastroenteritis due to rotavirus, 91,127 hospitalizations, and 550,198 outpatient visits. Vaccination is likely to reduce 76% of the overall healthcare burden of rotavirus-associated gastroenteritis in Brazil. At a vaccine price of US$ 7-8 per dose, the cost-effectiveness ratio would be US$ 643 per DALY averted. Rotavirus vaccination can reduce the burden of gastroenteritis due to rotavirus at a reasonable cost-effectiveness ratio.

Avaliação das alterações orais em candidatos ao transplante de células-tronco hematopoéticas: identificação de fatores de risco para complicações clínicas

Pós-graduação em Bases Gerais da Cirurgia - FMB

Correlates of change in self-perceived oral health among older adults in Brazil Findings from the Health, Well-Being and Aging Study

Background. Identifying changes in the oral health status of older populations, and their predictors and explanations, is necessary for public health planning. The authors assessed patterns of change in oral health-related quality of life in a large cohort of older adults in Brazil during a five-year period and evaluated associations between baseline characteristics and those changes. Methods. The sample consisted of 747 older people enrolled in a Brazilian cohort study called the Health, Well-Being and Aging (Saude, Bem-estar e Envelhecimento [SABE]) Study. Trained examiners measured participants' self-perceived oral health by using the General Oral Health Assessment Index (GOHAI). The authors calculated changes in the overall GOHAI score and in the scores for each of the GOHAI's three dimensions individually by subtracting the baseline score from the score at follow-up. A positive difference indicated improvement in oral health, a negative difference indicated a decline and a difference of zero indicated no change. Results. The authors found that 48.56 percent of the participants experienced a decline in oral health and 33.48 percent experienced an improvement. Participants with 16 or more missing teeth and eight or more years of education were more likely to have an improvement in total GOHAI score. Deterioration was more likely to occur among those with two or more diseases. Improvement and decline in GOHAI functional scores were related to the number of missing teeth. The authors found no significant model for the change in the psychosocial score, and Self-rated general health was the only variable related to both improvement and decline in pain or discomfort scores. Conclusions. The authors observed a bidirectional change in self-perceived oral health, with deterioration predominating. The strongest predictor of improvement in the total GOHAI score was the number of missing teeth, whereas the number of diseases was the strongest predictor of deterioration. Clinical Implications. Dental professionals and policymakers need to know the directions of change in older adults' oral health to establish treatment priorities and evaluate the impact of services directed at this population.

Preditores da realização de consultas odontológicas de rotina e por problema em pré-escolares

OBJETIVO: Estimar a prevalência do uso de serviços odontológicos por pré- escolares e fatores associados. MÉTODOS: Estudo transversal com 1.129 crianças de cinco anos de idade da Coorte de Nascimentos de Pelotas 2004, RS, de setembro de 2009 a janeiro de 2010. Registrou-se o uso de serviço odontológico pelo menos uma vez na vida e o motivo para a primeira consulta odontológica da criança. As categorias do desfecho foram: ter feito a primeira consulta por rotina, para resolver um problema ou nunca ter ido ao dentista. Os exames bucais e as entrevistas foram realizados nos domicílios. Aspectos socioeconômicos e variáveis independentes ligadas à mãe e à criança foram analisados por meio de regressão logística multinomial. RESULTADOS: A prevalência de uso por qualquer motivo foi 37,0%. Os principais preditores para consulta de rotina foram nível econômico mais elevado, mãe com maior escolaridade e ter recebido orientação sobre prevenção. Principais preditores para consulta por problema foram ter sentido dor nos últimos seis meses, mãe com maior escolaridade e ter recebido orientação sobre prevenção. Cerca de 45,0% das mães receberam orientação de como prevenir cárie, principalmente fornecida por dentistas. Filhos de mães com história de maior aderência a programas de saúde tiveram maior probabilidade de ter feito uma consulta odontológica de rotina. CONCLUSÕES: A taxa de utilização dos serviços odontológicos por pré- escolares foi inferior às de consultas médicas (puericultura). Além da renda e da escolaridade, comportamentos maternos têm papel importante no uso por rotina. Relato de dor nos últimos seis meses e número elevado de dentes afetados por cárie, independentemente dos demais fatores, estiveram associados ao uso para resolver problema. É necessária a integração de ações de saúde bucal nos programas materno-infantis.

Respiratory symptoms in preterm infants: burden of disease in the first year of life

Objective While respiratory symptoms in the first year of life are relatively well described for term infants, data for preterm infants are scarce. We aimed to describe the burden of respiratory disease in a group of preterm infants with and without bronchopulmonary dysplasia (BPD) and to assess the association of respiratory symptoms with perinatal, genetic and environmental risk factors. Methods Single centre birth cohort study: prospective recording of perinatal risk factors and retrospective assessment of respiratory symptoms during the first year of life by standardised questionnaires. Main outcome measures: Cough and wheeze (common symptoms), re-hospitalisation and need for inhalation therapy (severe outcomes). Patients: 126 preterms (median gestational age 28.7 weeks; 78 with, 48 without BPD) hospitalised at the University Children's Hospital of Bern, Switzerland 1999-2006. Results Cough occurred in 80%, wheeze in 44%, rehospitalisation in 25% and long term inhalation therapy in wheezers in 13% of the preterm infants. Using logistic regression, the main risk factor for common symptoms was frequent contact with other children. Severe outcomes were associated with maximal peak inspiratory pressure, arterial cord blood pH, APGAR and CRIB-Score. Conclusions Cough in preterm infants is as common as in term infants, whereas wheeze, inhalation therapy and re-hospitalisations occur more often. Severe outcomes are associated with perinatal risk factors. Preterm infants who did not qualify for BPD according to latest guidelines also showed a significant burden of respiratory disease in the first year of life.

Exposure to moderate air pollution during late pregnancy and cord blood cytokine secretion in healthy neonates

Background/Objectives Ambient air pollution can alter cytokine concentrations as shown in vitro and following short-term exposure to high air pollution levels in vivo. Exposure to pollution during late pregnancy has been shown to affect fetal lymphocytic immunophenotypes. However, effects of prenatal exposure to moderate levels of air pollutants on cytokine regulation in cord blood of healthy infants are unknown. Methods In a birth cohort of 265 healthy term-born neonates, we assessed maternal exposure to particles with an aerodynamic diameter of 10 µm or less (PM10), as well as to indoor air pollution during the last trimester, specifically the last 21, 14, 7, 3 and 1 days of pregnancy. As a proxy for traffic-related air pollution, we determined the distance of mothers' homes to major roads. We measured cytokine and chemokine levels (MCP-1, IL-6, IL-10, IL-1ß, TNF-α and GM-CSF) in cord blood serum using LUMINEX technology. Their association with pollution levels was assessed using regression analysis, adjusted for possible confounders. Results Mean (95%-CI) PM10 exposure for the last 7 days of pregnancy was 18.3 (10.3–38.4 µg/m3). PM10 exposure during the last 3 days of pregnancy was significantly associated with reduced IL-10 and during the last 3 months of pregnancy with increased IL-1ß levels in cord blood after adjustment for relevant confounders. Maternal smoking was associated with reduced IL-6 levels. For the other cytokines no association was found. Conclusions Our results suggest that even naturally occurring prenatal exposure to moderate amounts of indoor and outdoor air pollution may lead to changes in cord blood cytokine levels in a population based cohort.

A prospective study of the impact of air pollution on respiratory symptoms and infections in infants

Rationale: There is increasing evidence that short-term exposure to air pollution has a detrimental effect on respiratory health, but data from healthy populations, particularly infants, are scarce. Objectives: To assess the association of air pollution with frequency and severity of respiratory symptoms and infections measured weekly in healthy infants. Methods: In a prospective birth cohort of 366 infants of unselected mothers, respiratory health was assessed weekly by telephone interviews during the first year of life (19,106 total observations). Daily mean levels of particulate matter (PM10), nitrogen dioxide (NO2), and ozone (O3) were obtained from local monitoring stations. We determined the association of the preceding week's pollutant levels with symptom scores and respiratory tract infections using a generalized additive mixed model with an autoregressive component. In addition, we assessed whether neonatal lung function influences this association and whether duration of infectious episodes differed between weeks with normal PM10 and weeks with elevated levels. Measurements and Main Results: We found a significant association between air pollution and respiratory symptoms, particularly in the week after respiratory tract infections (risk ratio, 1.13 [1.02-1.24] per 10 μg/m(3) PM10 levels) and in infants with premorbid lung function. During times of elevated PM10 (>33.3 μg/m(3)), duration of respiratory tract infections increased by 20% (95% confidence interval, 2-42%). Conclusions: Exposure to even moderate levels of air pollution was associated with increased respiratory symptoms in healthy infants. Particularly in infants with premorbid lung function and inflammation, air pollution contributed to longer duration of infectious episodes with a potentially large socioeconomic impact.

Elevated exhaled nitric oxide in newborns of atopic mothers precedes respiratory symptoms

RATIONALE: Exhaled nitric oxide (NO) is a well-known marker of established airway inflammation in asthma. Its role in the disease process before the onset of respiratory symptoms remains unclear. Objectives: To examine whether elevated NO in newborns with clinically naive airways is associated with subsequent respiratory symptoms in infancy. METHODS: We measured exhaled NO concentration and output after birth and prospectively assessed respiratory symptoms during infancy in a birth cohort of 164 unselected healthy neonates. We examined a possible association between NO and respiratory symptoms using Poisson regression analysis. RESULTS: In infants of atopic mothers, elevated NO levels after birth were associated with increased risk of subsequent respiratory symptoms (risk ratio [RR], 7.5; 95% confidence interval [CI], 1.7-32.4 for each nl/s increase in NO output; p = 0.007). Similarly, a positive association between NO and symptoms was seen in infants of smoking mothers (RR, 6.6; 95% CI, 2.3-19.3; p = 0.001), with the strongest association in infants whose mothers had both risk factors (RR, 21.8; 95% CI, 5.8-81.3; p < 0.001). CONCLUSIONS: The interaction of NO with maternal atopy and smoking on subsequent respiratory symptoms is present early in life. Clinically, noninvasive NO measurements in newborns may prove useful as a new means to identify high-risk infants. Future confirmation of a role for NO metabolism in the evolution of respiratory disease may provide an avenue for preventative strategies.

Maternal tobacco smoking and decreased leukocytes, including dendritic cells, in neonates

Maternal smoking in pregnancy is associated with respiratory diseases in the offspring, possibly due to prenatal influences on the developing immune system. We investigated whether maternal smoking in pregnancy was associated with cord blood leukocyte numbers, including precursor dendritic cells, adjusting for concomitant factors. In a prospective healthy birth cohort study, total leukocyte counts were reduced in neonates of smoking mothers [10.7 (8.4-13.0), n=14] compared with nonexposed infants [14.7 (13.7-15.7), n=74, p=0.002] [geometric mean cells x 10(3)/microL (95% confidence interval)]. All leukocyte subsets were decreased, most prominently segmented neutrophils [4.3 (2.8-5.7) versus 6.2 (5.5-6.8), p=0.021], lymphocytes [3.8 (2.9-4.8) versus 5.0 (4.5-5.6), p=0.036], and myeloid precursor dendritic cells [12.7 cells/microL (9.1-17.8) versus 18.3 (15.8-21.2), p=0.055]. These differences persisted after adjustment for possible confounders. Predictors of myeloid precursor dendritic cell numbers in multivariable models were maternal smoking (-5.1 cells/microL, p=0.042), age (-0.5 cells/microL/y, p=0.035), and, marginally, asthma (+8.1 cells/microL, p=0.075). The decrease of all leukocytes in neonates of smoking mothers could be clinically significant and suggests a decreased cell production, increased peripheral recruitment, or retention in bone marrow. Given the importance of dendritic cells in early immune responses, their decrease might reflect an impact of maternal smoking on the developing fetal immune system.

Isolation of human bocavirus from Swiss infants with respiratory infections

Human bocavirus (HBoV) is a novel agent associated with respiratory symptoms in adults and children. We studied prospectively the first acute respiratory infection in a birth cohort of healthy neonates in Switzerland. HBoV was identified in 5 (4.5%) of 112 infants as young as 3 months of age. In 4 of the 5 infants, HBoV was associated with other respiratory viruses. We conclude that HBoV circulates in the community and is acquired early in life.

Prospectively assessed incidence, severity, and determinants of respiratory symptoms in the first year of life

Respiratory symptoms are common in infancy. Nevertheless, few prospective birth cohort studies have studied the epidemiology of respiratory symptoms in normal infants. The aim of this study was to prospectively obtain reliable data on incidence, severity, and determinants of common respiratory symptoms (including cough and wheeze) in normal infants and to determine factors associated with these symptoms. In a prospective population-based birth cohort, we assessed respiratory symptoms during the first year of life by weekly phone calls to the mothers. Poisson regression was used to examine the association between symptoms and various risk factors. In the first year of life, respiratory symptoms occurred in 181/195 infants (93%), more severe symptoms in 89 (46%). The average infant had respiratory symptoms for 4 weeks and 90% had symptoms for less than 12 weeks (range 0 to 23). Male sex, higher birth weight, maternal asthma, having older siblings and nursery care were associated with more, maternal hay fever with fewer respiratory symptoms. The association with prenatal maternal smoking decreased with time since birth. This study provides reliable data on the frequency of cough and wheeze during the first year of life in healthy infants; this may help in the interpretation of published hospital and community-based studies. The apparently reduced risk in children of mothers with hayfever but no asthma, and the decreasing effect of prenatal smoke exposure over time illustrate the complexity of respiratory pathology in the first year of life.

Prospective population-based study of RSV-related intermediate care and intensive care unit admissions in Switzerland over a 4-year period (2001-2005)

OBJECTIVES: Respiratory syncytial virus (RSV) infections are a leading cause of hospital admissions in small children. A substantial proportion of these patients require medical and nursing care, which can only be provided in intermediate (IMC) or intensive care units (ICU). This article reports on all children aged < 3 years who required admission to IMC and/or ICU between October 1, 2001 and September 30, 2005 in Switzerland. PATIENTS AND METHODS: We prospectively collected data on all children aged < 3 years who were admitted to an IMC or ICU for an RSV-related illness. Using a detailed questionnaire, we collected information on risk factors, therapy requirements, length of stay in the IMC/ICU and hospital, and outcome. RESULTS: Of the 577 cases reported during the study period, 90 were excluded because the patients did not fulfill the inclusion criteria; data were incomplete in another 25 cases (5%). Therefore, a total of 462 verified cases were eligible for analysis. At the time of hospital admission, only 31 patients (11%) were older than 12 months. Since RSV infection was not the main reason for IMC/ICU admission in 52% of these patients, we chose to exclude this subgroup from further analyses. Among the 431 infants aged < 12 months, the majority (77%) were former near term or full term (NT/FT) infants with a gestational age > or = 35 weeks without additional risk factors who were hospitalized at a median age of 1.5 months. Gestational age (GA) < 32 weeks, moderate to severe bronchopulmonary dysplasia (BPD), and congenital heart disease (CHD) were all associated with a significant risk increase for IMC/ICU admission (relative risk 14, 56, and 10, for GA < or = 32 weeks, BPD, and CHD, respectively). Compared with NT/FT infants, high-risk infants were hospitalized at an older age (except for infants with CHD), required more invasive and longer respiratory support, and had longer stays in the IMC/ICU and hospital. CONCLUSIONS: In Switzerland, RSV infections lead to the IMC/ICU admission of approximately 1%-2% of each annual birth cohort. Although prematurity, BPD, and CHD are significant risk factors, non-pharmacological preventive strategies should not be restricted to these high-risk patients but also target young NT/FT infants since they constitute 77% of infants requiring IMC/ICU admission.