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author:("uaug, Ricardo")
1.  Health economic modeling to assess short-term costs of maternal overweight, gestational diabetes, and related macrosomia – a pilot evaluation 
Background: Despite the interest in the impact of overweight and obesity on public health, little is known about the social and economic impact of being born large for gestational age or macrosomic. Both conditions are related to maternal obesity and/or gestational diabetes mellitus (GDM) and associated with increased morbidity for mother and child in the perinatal period. Poorly controlled diabetes during pregnancy, pre- pregnancy maternal obesity and/or excessive maternal weight gain during pregnancy are associated with intermittent periods of fetal exposure to hyperglycemia and subsequent hyperinsulinemia, leading to increased birth weight (e.g., macrosomia), body adiposity, and glycogen storage in the liver. Macrosomia is associated with an increased risk of developing obesity and type 2 diabetes mellitus later in life.
Objective: Provide insight in the short-term health-economic impact of maternal overweight, GDM, and related macrosomia. To this end, a health economic framework was designed. This pilot study also aims to encourage further health technology assessments, based on country- and population-specific data.
Results: The estimation of the direct health-economic burden of maternal overweight, GDM and related macrosomia indicates that associated healthcare expenditures are substantial. The calculation of a budget impact of GDM, based on a conservative approach of our model, using USA costing data, indicates an annual cost of more than $1,8 billion without taking into account long-term consequences.
Conclusion: Although overweight and obesity are a recognized concern worldwide, less attention has been given to the health economic consequences of these conditions in women of child-bearing age and their offspring. The presented outcomes underline the need for preventive management strategies and public health interventions on life style, diet and physical activity. Also, the predisposition in people of Asian ethnicity to develop diabetes emphasizes the urgent need to collect more country-specific data on the incidence of macrosomic births and health outcomes. In addition, it would be of interest to further explore the long-term health economic consequences of macrosomia and related risk factors.
PMCID: PMC4438224  PMID: 26042038
maternal overweight; gestational diabetes mellitus; macrosomia; health economics; public health; burden
2.  Do routinely measured risk factors for obesity explain the sex gap in its prevalence? Observations from Saudi Arabia 
BMC Public Health  2015;15:254.
The prevalence of adult obesity is higher in women than men in most countries. However, the pathways that link female sex with excess obesity are still not fully understood. We examine whether socioeconomic and behavioural factors may mediate the association between sex and obesity in the Saudi Arabian setting where there is female excess in obesity.
We performed a mediation analysis using a cross-sectional, national household survey from Saudi Arabia with 4758 participants (51% female). A series of multivariable regression models were fitted to test if socioeconomic position, physical activity, sedentary behaviour, diet, and smoking mediate the association between sex and obesity (BMI >=30). The findings were confirmed using causal mediation analysis.
Women in this sample were roughly twice as likely as men to be obese (crude OR 1.9; 95% CI 1.6-2.3). The odds ratio remained significantly higher for women compared to men in models testing for mediation (OR range 1.95–2.06). Our data suggest that indicators of socio-economic position, physical activity, sedentary behaviour, diet, and smoking do not mediate the sex differences in obesity.
Our analysis shows that most commonly measured risk factors for obesity do not explain the sex differences in its prevalence in the Saudi context. Further research is needed to understand what might explain the female excess in obesity prevalence. We discuss how data related to the lived experience of Saudi men and women may tap into underlying mechanisms by which the sex difference in obesity prevalence are produced.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1608-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4371623  PMID: 25848853
Obesity; Sex differences; Gender differences; Mediation analysis; Health inequalities; Social epidemiology; Social determinants of health; Saudi Arabia; GCC
3.  Trends in Early Growth Indices in the First 24 Months of Life in Uruguay over the Past Decade 
Early growth is an important indicator of health and wellbeing of children and a good predictor of adult health. The objective of this study was to examine trends and determinants of overweight and stunting among infants aged 0 to 23 month(s) over the past decade (1999-2011) in Uruguay. Data were used from four large representative samples of 11,056 infants aged 0-23 month(s), who attended public and private health services in 1999, 2003, 2007, and 2011, using a similar methodology. Linear regression analysis was used for assessing trends in early growth indices and binary logistic regression to estimate the probability of being stunted and overweight. Although prevalence of overweight fell from 12.5% (1999) to 9.5% (2011) and stunting from 13.6% to 10.9% respectively, both rates remained higher than expected. Low birthweight (LBW) was the main predictor of stunting [OR 6.5 (5.6-7.6)] and macrosomia of overweight [6.7 (5.3-8.3)]. We did not observe changes in LBW (7.8-8.8%) or macrosomia (5.9-6.7%) over the last decade. Boys showed increased chance of being overweight [OR 1.2 (1.04-1.3)]. Being stunted doubles the chances of being overweight [OR 2.5 (2.2-3.0)]. Overweight [OR 7.1 (6.1-8.3)], LBW [OR 13.2 (11.0-15.9)], and non-breastfed infants [OR 1.9 (1.7-2.1)] showed rapid weight gain. Uruguay has taken positive steps to decline the prevalence of stunting and overweight but both remain excessively high.
PMCID: PMC4438690  PMID: 25895193
Breastfeeding; Low birthweight; Overweight; Rapid weight gain; Stunting; Uruguay
4.  Breast bud detection: a validation study in the Chilean Growth Obesity Cohort Study 
BMC Women's Health  2014;14:96.
Early puberty onset has been related to future chronic disease; however breast bud assessment in large scale population studies is difficult because it requires trained personnel. Thus our aim is to assess the validity of self and maternal breast bud detection, considering girl’s body mass index (BMI) and maternal education.
In 2010, 481 girls (mean age = 7.8) from the Growth and Obesity Chilean Cohort Study were evaluated by a nutritionist trained in breast bud detection. In addition, the girl(n = 481) and her mother(n = 341) classified the girl’s breast development after viewing photographs of Tanner stages. Concordance between diagnostics was estimated (kappa, Spearman correlation) considering girls’ BMI and mother’s educational level.
14% of the girls presented breast buds and 43% had excess weight (BMI z-score > 1, World Health Organization 2007). Self-assessment showed low concordance with the evaluator (K < 0.1) and girls with excess weight over-diagnosed more than girls of normal weight (44% vs. 24%, p-value < 0.05). Instead, mothers showed good concordance with the evaluator (K = 0.7, 95% confidence interval (CI) = 0.6-0.9), even in overweight girls and/or in mothers with low education (K = 0.7, 95% CI = 0.6-0.8).
Mothers were able to adequately evaluate the appearance of breast bud despite low educational level and girls’ excess weight. Mother could be a useful resource for defining puberty onset in epidemiological studies, particularly developing countries.
PMCID: PMC4137044  PMID: 25115568
Puberty onset; Sexual development; Puberty cohorts
5.  Endothelial heterogeneity in the umbilico-placental unit: DNA methylation as an innuendo of epigenetic diversity 
The endothelium is a multifunctional heterogeneous tissue playing a key role in the physiology of every organ. To accomplish this role the endothelium presents a phenotypic diversity that is early prompted during vascular development, allowing it to cope with specific requirements in a time- and site-specific manner. During the last decade several reports show that endothelial diversity is also present in the umbilico-placental vasculature, with differences between macro- and microvascular vessels as well as arterial and venous endothelium. This diversity is evidenced in vitro as a higher angiogenic capacity in the microcirculation; or disparity in the levels of several molecules that control endothelial function (i.e., receptor for growth factors, vasoactive mediators, and adhesion molecules) which frequently are differentially expressed between arterial and venous endothelium. Emerging evidence suggests that endothelial diversity would be prominently driven by epigenetic mechanisms which also control the basal expression of endothelial-specific genes. This review outlines evidence for endothelial diversity since early stages of vascular development and how this heterogeneity is expressed in the umbilico-placental vasculature. Furthermore a brief picture of epigenetic mechanisms and their role on endothelial physiology emphasizing new data on umbilical and placental endothelial cells is presented. Unraveling the role of epigenetic mechanisms on long term endothelial physiology and its functional diversity would contribute to develop more accurate therapeutic interventions. Altogether these data show that micro- versus macro-vascular, or artery versus vein comparisons are an oversimplification of the complexity occurring in the endothelium at different levels, and the necessity for the future research to establish the precise source of cells which are under study.
PMCID: PMC3973902  PMID: 24723887
endothelial; epigenetics; artery; vein; placenta; umbilical
6.  How can the Developmental Origins of Health and Disease (DOHaD) hypothesis contribute to improving health in developing countries?23 
The American journal of clinical nutrition  2011;94(6 0):10.3945/ajcn.110.000562.
The relevance of nutrition during pregnancy and early infancy in defining short-term health and survival has been well established. However, the Developmental Origins of Health and Disease (DOHaD) paradigm provides a framework to assess the effect of early nutrition and growth on long-term health. This body of literature shows that early nutrition has significant consequences on later health and well-being. In this article, we briefly present the main consequences of malnutrition that affect human growth and development and consider how the DOHaD paradigm, with its evolutionary implications, might contribute to better addressing the challenge of improving nutrition. We examine how this paradigm is particularly appropriate in understanding the health and nutrition transition in countries that face the double burden of nutrition-related diseases (acute malnutrition coexisting with obesity and other chronic diseases). We focus on stunting (low height-for-age) to examine the short- as well as long-term consequences of early malnutrition with a life-course, transgenerational, and multidisciplinary perspective. We present current global and regional prevalence of stunting and discuss the need to reposition maternal and infant nutrition not only in health and nutrition intervention programs but also in consideration of the emerging research questions that should be resolved to better orient program and policy decisions.
PMCID: PMC3808270  PMID: 21543534
7.  Effectiveness of the National Program of Complementary Feeding for older adults in Chile on vitamin B12 status in older adults; secondary outcome analysis from the CENEX Study (ISRCTN48153354) 
Nutrition Journal  2013;12:124.
Older people are at increased risk of vitamin B12 deficiency and the provision of fortified foods may be an effective way to ensure good vitamin B12 status in later life.
To evaluate the effectiveness of a vitamin B12 fortified food provided by a national program of complementary food for older people on plasma vitamin B12 levels.
Subjects and methods
A random sub-sample of 351 subjects aged 65-67y from a large cluster randomised controlled trial provided blood samples at baseline and after 24 months of intervention. The intervention arm (10 clusters 186 participants) received a vitamin B12 fortified food designed to deliver 1.4 μg/day, while the control arm did not receive complementary food (10 clusters, 165 participants). Serum vitamin B12 and folate levels determined by radioimmunoassay were used to estimate the effect of intervention on vitamin B12 levels, adjusting for baseline levels and sex.
Attrition at 24 months was 16.7% and 23.6% in the intervention and control arms respectively (p = 0.07). Over 24 months of intervention, mean (95% CI) serum vitamin B12 decreased from 392 (359–425) pmol/dL to 357 (300–414) pmol/dL (p < 0.07) in the intervention arm and from 395 (350–440) pmol/dL to 351 (308–395) pmol/dL in the control arm. There was no significant effect of the intervention on folate status.
Our findings suggest that foods fortified with 1.4 μg/daily vitamin B12 as provided by Chile’s national programme for older people are insufficient to ensure adequate vitamin B12 levels in this population. Chile has a long and successful experience with nutrition intervention programs; however, the country’s changing demographic and nutritional profiles require a constant adjustment of the programs.
PMCID: PMC3848755  PMID: 24016218
Older people; Fortified foods; Nutrition programme; Vitamin B12
8.  School-Based Obesity Prevention Interventions for Chilean Children During the Past Decades: Lessons Learned12 
Advances in Nutrition  2012;3(4):616S-621S.
Obesity in Chilean children has increased markedly over the past decades. School-based obesity prevention interventions have been launched by the Ministry of Health and academic groups to tackle this condition. We summarize the main characteristics of the interventions that we have conducted and reflect on the lessons learned. Since 2002, we conducted 1 pilot study, a 2-y controlled intervention including 6- to 12–y-old children (Casablanca), another pilot study, and a 2-y controlled intervention including teachers and their 4- to 9–y-old students (Macul). Both interventions consisted of training teachers to deliver contents on healthy eating, increasing physical education classes, and, additionally in Macul, teachers participated in a wellness program. BMI Z-score and obesity prevalence were compared among children in intervention and control schools by year and among students of intervention and control teachers. In the Casablanca study, the impact was greatest on the younger children during the first school year when the study received the full funding that was required. In Macul, although intervention teachers exhibited improvements in anthropometry and blood measures, the impact on the children was not related to their results. The main lessons learned from these experiences are random allocation of schools, although methodologically desirable, is not always possible; participation of parents is very limited; obesity is not recognized as a problem; and increasing physical activity and implementing training programs for teachers is difficult due to an inflexible curriculum and lack of teachers’ time. Unless these barriers are overcome, obesity prevention programs will not produce positive and lasting outcomes.
PMCID: PMC3649735  PMID: 22798002
9.  Behaviour change for better health: nutrition, hygiene and sustainability 
BMC Public Health  2013;13(Suppl 1):S1.
As the global population grows there is a clear challenge to address the needs of consumers, without depleting natural resources and whilst helping to improve nutrition and hygiene to reduce the growth of noncommunicable diseases. For fast-moving consumer goods companies, like Unilever, this challenge provides a clear opportunity to reshape its business to a model that decouples growth from a negative impact on natural resources and health. However, this change in the business model also requires a change in consumer behaviour. In acknowledgement of this challenge Unilever organised a symposium entitled ‘Behaviour Change for Better Health: Nutrition, Hygiene and Sustainability’. The intention was to discuss how consumers can be motivated to live a more healthy and sustainable lifestlye in today’s environment. This article summarises the main conclusions of the presentations given at the symposium. Three main topics were discussed. In the first session, key experts discussed how demographic changes – particularly in developing and emerging countries – imply the need for consumer behaviour change. The second session focused on the use of behaviour change theory to design, implement and evaluate interventions, and the potential role of (new or reformulated) products as agents of change. In the final session, key issues were discussed regarding the use of collaborations to increase the impact and reach, and to decrease the costs, of interventions. The symposium highlighted a number of key scientific challenges for Unilever and other parties that have set nutrition, hygiene and sustainability as key priorities. The key challenges include: adapting behaviour change approaches to cultures in developing and emerging economies; designing evidence-based behaviour change interventions, in which products can play a key role as agents of change; and scaling up behaviour change activities in cost-effective ways, which requires a new mindset involving public–private partnerships.
PMCID: PMC3605264  PMID: 23530770
10.  Obesity is positively associated with dehydroepiandrosterone sulfate concentrations at 7 y in Chilean children of normal birth weight123 
Background: In low-birth-weight girls, obesity increases the risk of premature adrenarche and metabolic complications. However, the consistency of this association in normal-birth-weight children and its potential mediators remain unknown.
Objectives: The objectives were to assess the associations between obesity indicators and dehydroepiandrosterone sulfate (DHEAS) at 7 y of age and to evaluate the role of hormonal markers on these associations.
Design: We assessed in 969 participants (6.9 y; 48% girls; all Tanner I) in the Growth and Obesity Chilean Cohort Study the associations between DHEAS and weight, BMI, waist circumference (WC), waist-to-height ratio, skinfold thickness, and percentage total fat (bioimpedance) and determined whether these associations were related to insulin, insulin-like growth factor I (IGF-I), and leptin. We also compared BMI and height growth from 0 to 7 y of age in nonobese and obese children with normal and high DHEAS (≥75th percentile) at 7 y.
Results: DHEAS concentrations were similar between girls (30.3 ±1.86 μg/dL) and boys (29.4 ±1.73 μg/dL) (P > 0.05); 17.3% of children were obese (BMI-for-age z score ≥2 SD). Adiposity indicators were positively and similarly associated with DHEAS [ie, BMI, β standardized regression coefficient: 0.23 (95% CI: 0.17, 0.29); WC, β standardized regression coefficient: 0.23 (95% CI: 0.16, 0.30)]; these associations were only partially related to IGF-I and leptin. Obese children had twice the risk of high DHEAS (OR: 2.16; 95% CI: 1.51, 3.09); at 7 y, obese children with high DHEAS were fatter and more centrally obese than their counterparts (P < 0.05), although their previous growth was similar (P > 0.05). None of the results differed by sex (P > 0.05).
Conclusion: In children of normal birth weight, obesity is positively associated with DHEAS at 7 y of age.
PMCID: PMC3545681  PMID: 23283497
11.  Developmental Origins of Pediatric Obesity 
PMCID: PMC3426220  PMID: 22934119
12.  Comparison of two modes of vitamin B12 supplementation on neuroconduction and cognitive function among older people living in Santiago, Chile: a cluster randomized controlled trial. a study protocol [ISRCTN 02694183] 
Nutrition Journal  2011;10:100.
Older people have a high risk of vitamin B12 deficiency; this can lead to varying degrees of cognitive and neurological impairment. CBL deficiency may present as macrocytic anemia, subacute combined degeneration of the spinal cord, or as neuropathy, but is often asymptomatic in older people. Less is known about subclinical vitamin B12 deficiency and concurrent neuroconduction and cognitive impairment. A Programme of Complementary Feeding for the Older Population (PACAM) in Chile delivers 2 complementary fortified foods that provide approximately 1.4 μg/day of vitamin B12 (2.4 μg/day elderly RDA). The aim of the present study is to assess whether supplementation with vitamin B12 will improve neuroconduction and cognitive function in older people who have biochemical evidence of vitamin B12 insufficiency in the absence of clinical deficiency.
We designed a cluster double-blind placebo-controlled trial involving community dwelling people aged 70-79 living in Santiago, Chile. We randomized 15 clusters (health centers) involving 300 people (20 per cluster). Each cluster will be randomly assigned to one of three arms: a) a 1 mg vitamin B12 pill taken daily and a routine PACAM food; b) a placebo pill and the milk-PACAM food fortified to provide 1 mg of vitamin B12; c) the routine PACAM food and a placebo pill.
The study has been designed as an 18 month follow up period. The primary outcomes assessed at baseline, 4, 9 and 18 months will be: serum levels of vitamin B12, neuroconduction and cognitive function.
In view of the high prevalence of vitamin B12 deficiency in later life, the present study has potential public health interest because since it will measure the impact of the existing program of complementary feeding as compared to two options that provide higher vitamin B12 intakes that might potentially may contribute in preserving neurophysiologic and cognitive function and thus improve quality of life for older people in Chile.
Trial registration
PMCID: PMC3195703  PMID: 21952034
cobalamin; vitamin B12; cyanocobalamin; elderly; neurophysiology; cognitive disorders; nerve conduction; cluster randomized controlled trial; public health; Chile
13.  Effect of a Nutrition Supplement and Physical Activity Program on Pneumonia and Walking Capacity in Chilean Older People: A Factorial Cluster Randomized Trial 
PLoS Medicine  2011;8(4):e1001023.
Alan Dangour and colleagues report results from the CENEX (Cost-effectiveness Evaluation of a Nutritional supplement and EXercise program for older people) trial, which evaluates a nutritional and exercise program aiming to prevent pneumonia and physical decline in Chilean people.
Ageing is associated with increased risk of poor health and functional decline. Uncertainties about the health-related benefits of nutrition and physical activity for older people have precluded their widespread implementation. We investigated the effectiveness and cost-effectiveness of a national nutritional supplementation program and/or a physical activity intervention among older people in Chile.
Methods and Findings
We conducted a cluster randomized factorial trial among low to middle socioeconomic status adults aged 65–67.9 years living in Santiago, Chile. We randomized 28 clusters (health centers) into the study and recruited 2,799 individuals in 2005 (∼100 per cluster). The interventions were a daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions, or neither, for 24 months. The primary outcomes, assessed blind to allocation, were incidence of pneumonia over 24 months, and physical function assessed by walking capacity 24 months after enrolment. Adherence was good for the nutritional supplement (∼75%), and moderate for the physical activity intervention (∼43%). Over 24 months the incidence rate of pneumonia did not differ between intervention and control clusters (32.5 versus 32.6 per 1,000 person years respectively; risk ratio = 1.00; 95% confidence interval 0.61–1.63; p = 0.99). In intention-to-treat analysis, after 24 months there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters; 95% confidence interval 13.9–53.8; p = 0.001). The overall cost of the physical activity intervention over 24 months was US$164/participant; equivalent to US$4.84/extra meter walked. The number of falls and fractures was balanced across physical activity intervention arms and no serious adverse events were reported for either intervention.
Chile's nutritional supplementation program for older people is not effective in reducing the incidence of pneumonia. This trial suggests that the provision of locally accessible physical activity classes in a transition economy population can be a cost-effective means of enhancing physical function in later life.
Trial registration
Current Controlled Trials ISRCTN 48153354
Please see later in the article for the Editors' Summary
Editors' Summary
By 2050, about a quarter of the world's population will be aged 60 years or over, with Asia and Latin America experiencing the most dramatic increases in the proportion of older people. For example, in Chile, which has recently undergone rapid demographic transition, the proportion of the population aged 60 years or over has increased from 8% to 12% over the past 25 years.
Current global policy initiatives that promote healthy ageing include an emphasis on adequate nutrient intakes, as longitudinal studies (conducted in high-income countries) suggest that achieving nutritional sufficiency and maintaining moderate levels of physical activity both decrease risk of mortality by preserving immune function and lean body mass and so reduce the numerous risk factors for disability and chronic disease in later life. Such interventions may also decrease the risk of infection, particularly pneumonia, a common cause of death in older people. However, older people in low- and middle-income countries frequently have diets with insufficient calories (energy) and/or micronutrients.
Why Was This Study Done?
Currently, there is no high-quality evidence to support the benefits of improved nutrition and increased physical activity levels from low-income or transition economies, where the ongoing demographic trends suggest that the needs are greatest. National policies aimed at preserving health and function in older people with interventions such as cash-transfers and provision of “food baskets” are often used in Latin American countries, such as Chile, but are rarely formally evaluated. Therefore, the purpose of this study (the Cost-effectiveness Evaluation of a Nutritional supplement and EXercise program for older people—CENEX) was to evaluate Chile's national nutritional supplementation program and/or physical exercise, to investigate whether this program prevented pneumonia and physical functional decline in older people in Santiago, and also to investigate whether these interventions were cost-effective.
What Did the Researchers Do and Find?
The researchers randomly allocated 28 participating health centers in Santiago, Chile, into one of four arms: (1) nutritional supplementation; (2) nutritional supplementation+physical activity; (3) physical activity alone; (4) control. From May to December 2005, 2,799 eligible adults aged 65–67.9 years and living in low to middle socioeconomic circumstances, who attended each health center, were recruited into the study and received the allocated intervention—daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions or neither—for 24 months. The researchers did not know the allocation arm of each patient and over the course of the study assessed the incidence of pneumonia (viral and bacterial as based on diagnosis at the health center or hospital) and physical function was measured by walking capacity (meters walked in 6 minutes). The researchers used administrative records and interviews with staff and patients to estimate the cost-effectiveness of the interventions.
Participant retention in the study was 84%, although only three-quarters of patients receiving the nutritional intervention and less than half (43%) of patients in the physical activity intervention arm adhered to their respective programs. Over 24 months, the incidence rate of pneumonia did not differ between intervention and control groups (32.5 versus 32.6 per 1,000 person years, respectively), but at the end of the study period, there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters). The number of falls and fractures in the study arms were similar. The overall costs over 24 months were US$91.00 and US$163.70 per participant for the nutritional supplement and physical activity interventions, respectively. The cost of the physical activity intervention per extra meter walked at 24 months was US$4.84.
What Do These Findings Mean?
The results of this trial suggest that there is little evidence to support the effectiveness of Chile's national nutritional supplementation program in reducing the incidence of pneumonia for 65.0–67.9 year olds. Therefore, given Chile's high burden of infectious and nutrition-related chronic diseases and the associated high health costs, this program should not be considered as a priority preventive public health intervention. However, the provision of locally available physical activity classes to older people could be of clinical benefit, especially in urban settings such as Santiago, although future challenges include increasing the uptake of, and retention to, such programs.
Additional Information
Please access these Web sites via the online version of this summary at
The World Health Organization provides information about the state of health in Chile
Wikipedia also provides information about health and health care in Chile (please note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC3079648  PMID: 21526229
14.  The Mechanism of Excessive Intestinal Inflammation in Necrotizing Enterocolitis: An Immature Innate Immune Response 
PLoS ONE  2011;6(3):e17776.
Necrotizing enterocolitis (NEC) is a devastating neonatal intestinal inflammatory disease, occurring primarily in premature infants, causing significant morbidity and mortality. The pathogenesis of NEC is associated with an excessive inflammatory IL-8 response. In this study, we hypothesized that this excessive inflammatory response is related to an immature expression of innate immune response genes. To address this hypothesis, intestinal RNA expression analysis of innate immune response genes was performed after laser capture microdissection of resected ileal epithelium from fetuses, NEC patients and children and confirmed in ex vivo human intestinal xenografts. Changes in mRNA levels of toll-like receptors (TLR)-2 and -4, their signaling molecules and transcription factors (MyD88, TRAF-6 and NFκB1) and negative regulators (SIGIRR, IRAK-M, A-20 and TOLLIP) and the effector IL-8 were characterized by qRT-PCR. The expression of TLR2, TLR4, MyD88, TRAF-6, NFκB1 and IL-8 mRNA was increased while SIGIRR, IRAK-M, A-20 and TOLLIP mRNA were decreased in fetal vs. mature human enterocytes and further altered in NEC enterocytes. Similar changes in mRNA expression were observed in immature, but not mature, human intestinal xenografts. Confirmation of gene expression was also validated with selective protein measurements and with suggested evidence that immature TRL4 enterocyte surface expression was internalized in mature enterocytes. Cortisone, an intestinal maturation factor, treatment corrected the mRNA differences only in the immature intestinal xenograft. Using specific siRNA to attenuate expression of primary fetal enterocyte cultures, both TOLLIP and A-20 were confirmed to be important when knocked down by exhibiting the same excessive inflammatory response seen in the NEC intestine. We conclude that the excessive inflammatory response of the immature intestine, a hallmark of NEC, is due to a developmental immaturity in innate immune response genes.
PMCID: PMC3061868  PMID: 21445298
15.  A randomised controlled trial investigating the effect of vitamin B12 supplementation on neurological function in healthy older people: the Older People and Enhanced Neurological function (OPEN) study protocol [ISRCTN54195799] 
Nutrition Journal  2011;10:22.
Vitamin B12 deficiency is common in older people and the prevalence increases with age. Vitamin B12 deficiency may present as macrocytic anaemia, subacute combined degeneration of the spinal cord, or as neuropathy, but is often asymptomatic in older people. The diagnosis and indications for treatment are clear for individuals with low plasma levels of vitamin B12 in the setting of megaloblastic anaemia and neuropathy, but the relevance of treatment of vitamin B12 deficiency in the absence of such clinical signs is uncertain.
The aim of the present study is to assess whether dietary supplementation with crystalline vitamin B12 will improve electrophysiological indices of neurological function in older people who have biochemical evidence of vitamin B12 insufficiency in the absence of anaemia. To test this hypothesis we designed a randomized double-blind placebo-controlled trial involving 200 older people aged 75 years or greater who were randomly allocated to receive either a daily oral tablet containing 1 mg vitamin B12 or a matching placebo tablet. The primary outcome assessed at 12 months is change in electrophysiological indices of peripheral and central neurosensory responses required for mobility and sensory function. We here report the detailed study protocol.
In view of the high prevalence of vitamin B12 deficiency in later life, the present trial could have considerable significance for public health.
PMCID: PMC3062585  PMID: 21396086
16.  Feeding the world healthily: the challenge of measuring the effects of agriculture on health 
Agricultural production, food systems and population health are intimately linked. While there is a strong evidence base to inform our knowledge of what constitutes a healthy human diet, we know little about actual food production or consumption in many populations and how developments in the food and agricultural system will affect dietary intake patterns and health. The paucity of information on food production and consumption is arguably most acute in low- and middle-income countries, where it is most urgently needed to monitor levels of under-nutrition, the health impacts of rapid dietary transition and the increasing ‘double burden’ of nutrition-related disease. Food availability statistics based on food commodity production data are currently widely used as a proxy measure of national-level food consumption, but using data from the UK and Mexico we highlight the potential pitfalls of this approach. Despite limited resources for data collection, better systems of measurement are possible. Important drivers to improve collection systems may include efforts to meet international development goals and partnership with the private sector. A clearer understanding of the links between the agriculture and food system and population health will ensure that health becomes a critical driver of agricultural change.
PMCID: PMC2935110  PMID: 20713404
health; nutrition; agriculture; food consumption; food policy
17.  Maternal anthropometry and feeding behavior toward preschool children: association with childhood body mass index in an observational study of Chilean families 
A better understanding of the link between eating behavior and maternal feeding practices with childhood and maternal weight status is of great interest.
To assess the association between childhood anthropometric measures with mothers' Body Mass Index (BMI) and their feeding practices toward preschool children in Chile.
1029 children (504 boys, 4.3 ± 0.3 years) and their mothers were selected from public nurseries located in low income neighborhoods in Santiago. Mothers' BMI, children's BMI and waist-to-height ratios were registered. Maternal feeding practices towards their children's nutritional habits were measured using an adapted version of the Child Feeding Questionnaire (CFQ).
We found a direct correlation (p < 0.001) between children's BMI z-score and their mothers' BMI, both in boys (Spearman rho = 0.26) and girls (rho = 0.30). A direct association was also found between children's BMI z-score with scores of the subscale "concern for child's weight" (Spearman rho = 0.26 in boys and rho = 0.37 in girls; p < 0.001) and "food restriction" (rho = 0.19 in boys and rho = 0.27 in girls; p < 0.001). A reverse significant association was found between children's BMI z-score with scores of "pressure to eat" (rho = -0.30 in boys and rho = -0.36 in girls; p < 0.001). Analyses of the combined categories of childhood obesity and/or maternal obesity showed an important influence of children's weight status on CFQ scores.
Mothers' BMI and children's BMI z-scores are highly correlated. We found significant associations between mothers' behaviour subscales and children's BMI z-score. It is not possible to establish a causal link between mother's CFQ scores and children's nutritional status, given the cross-sectional nature of this study and the bidirectional influences that exist between mothers and their children.
PMCID: PMC2809038  PMID: 20040107
18.  Maternal attitudes and child-feeding practices: relationship with the BMI of Chilean children 
Nutrition Journal  2009;8:37.
Chile has experienced the nutritional transition due to both social and economic progress. As a consequence, higher rates of overweight and obesity have been observed in children. In western countries, researchers have tried to determine pathways by which parents influence their children's eating behavior; up to now findings have been inconsistent. The objective of this study was to evaluate the cross-sectional and retrospective relationship between maternal attitudes and child-feeding practices and children's weight status in children who had been subject of an obesity prevention intervention for two years.
In 2006, for a cross-sectional study, a random sample of 232 children (125 girls, mean age 11.91 ± 1.56 y and 107 boys mean age 11.98 ± 1.51 y) was selected from three primary schools from a small city called Casablanca. Weight and height were determined to assess their nutritional status, using body mass index (BMI) z scores. Child-feeding practices and attitudes were determined cross-sectionally in 2006, using the Child Feeding Questionnaire (CFQ). To analyze the relationship between trends in weight change and child-feeding practices and attitudes, BMI z scores of all the 232 children in 2003 were used.
Cross-sectionally, mothers of overweight children were significantly more concerned (P < 0.01) about their child's weight. Mothers of normal weight sons used significantly more pressure to eat (P < 0.05). Only in boys, the BMI z score was positively correlated with concern for child's weight (r = 0.28, P < 0.05) and negatively with pressure to eat (r = -0.21, P < 0.05). Retrospectively, the change in BMI z score between age 9 and 12 was positively correlated with concern for child's weight, but only in boys (r = 0.21, P < 0.05). Perceived child weight and concern for child's weight, explained 37% in boys and 45% in girls of the variance in BMI z score at age 12.
Mothers of overweight children were more concerned with their children's weight; this indicated the Western negative attitude towards childhood overweight. None of the child-feeding practices were significantly correlated with a change in BMI z score.
PMCID: PMC2736172  PMID: 19678925
19.  Dietary fish and meat intake and dementia in Latin America, China, and India: a 10/66 Dementia Research Group population-based study123 
Background: Evidence of an association between fish and meat consumption and risk of dementia is inconsistent and nonexistent in populations in developing countries.
Objective: The objective was to investigate associations between fish and meat consumption with dementia in low- and middle-income countries.
Design: One-phase cross-sectional surveys were conducted in all residents aged ≥65 y in 11 catchment areas in China, India, Cuba, the Dominican Republic, Venezuela, Mexico, and Peru. A total of 14,960 residents were assessed by using the 10/66 standardized protocol, which includes face-to-face interviews for dietary habits and a cross-culturally validated dementia diagnosis.
Results: Dietary intakes and the prevalence of dementia varied between sites. We combined site-specific Poisson regression prevalence ratios (PRs) for the association between fish and meat consumption and dementia in 2 fixed-effect model meta-analyses adjusted for sociodemographic and health characteristics and fish and meat consumption as appropriate. We found a dose-dependent inverse association between fish consumption and dementia (PR: 0.81; 95% CI: 0.72, 0.91) that was consistent across all sites except India and a less-consistent, dose-dependent, direct association between meat consumption and prevalence of dementia (PR: 1.19; 95% CI: 1.07, 1.31).
Conclusions: Our results extend findings on the associations of fish and meat consumption with dementia risk to populations in low- and middle-income countries and are consistent with mechanistic data on the neuroprotective actions of omega-3 (n–3) long-chain polyunsaturated fatty acids commonly found in fish. The inverse association between fish and prevalent dementia is unlikely to result from poorer dietary habits among demented individuals (reverse causality) because meat consumption was higher in those with a diagnosis of dementia.
PMCID: PMC3008672  PMID: 19553298
20.  Methods for economic evaluation of a factorial-design cluster randomised controlled trial of a nutrition supplement and an exercise programme among healthy older people living in Santiago, Chile: the CENEX study 
In an effort to promote healthy ageing and preserve health and function, the government of Chile has formulated a package of actions into the Programme for Complementary Food in Older People (Programa de Alimentación Complementaria para el Adulto Mayor - PACAM). The CENEX study was designed to evaluate the impact, cost and cost-effectiveness of the PACAM and a specially designed exercise programme on pneumonia incidence, walking capacity and body mass index in healthy older people living in low- to medium-socio-economic status areas of Santiago. The purpose of this paper is to describe in detail the methods that will be used to estimate the incremental costs and cost-effectiveness of the interventions.
Methods and design
The base-case analysis will adopt a societal perspective, including the direct medical and non-medical costs borne by the government and patients. The cost of the interventions will be calculated by the ingredients approach, in which the total quantities of goods and services actually employed in applying the interventions will be estimated, and multiplied by their respective unit prices. Relevant information on costs of interventions will be obtained mainly from administrative records. The costs borne by patients will be collected via exit and telephone interviews. An annual discount rate of 8% will be used, consistent with the rate recommended by the Government of Chile. All costs will be converted from Chilean Peso to US dollars with the 2007 average period exchange rate of US$1 = 522.37 Chilean Peso. To test the robustness of model results, we will vary the assumptions over a plausible range in sensitivity analyses.
The protocol described here indicates our intent to conduct an economic evaluation alongside the CENEX study. It provides a detailed and transparent statement of planned data collection methods and analyses.
Trial registration
PMCID: PMC2702284  PMID: 19473513
21.  A factorial-design cluster randomised controlled trial investigating the cost-effectiveness of a nutrition supplement and an exercise programme on pneumonia incidence, walking capacity and body mass index in older people living in Santiago, Chile: the CENEX study protocol 
Nutrition Journal  2007;6:14.
Chile is currently undergoing a period of rapid demographic transition which has led to an increase in the proportion of older people in the population; the proportion aged 60 years and over, for example, increased from 8% of the population in 1980 to 12% in 2005. In an effort to promote healthy ageing and preserve function, the government of Chile has formulated a package of actions into the Programme of Complementary Feeding for the Older Population (PACAM) which has been providing a nutritional supplement to older people since 1998. PACAM distributes micronutrient fortified foods to individuals aged 70 years and over registered at Primary Health Centres and enrolled in the programme. The recommended serving size (50 g/day) of these supplements provides 50% of daily micronutrient requirements and 20% of daily energy requirements of older people. No information is currently available on the cost-effectiveness of the supplementation programme.
The aim of the CENEX cluster randomised controlled trial is to evaluate the cost-effectiveness of an ongoing nutrition supplementation programme, and a specially designed physical exercise intervention for older people of low to medium socio-economic status living in Santiago, Chile.
The study has been conceptualised as a public health programme effectiveness study and has been designed as a 24-month factorial cluster-randomised controlled trial conducted among 2800 individuals aged 65.0–67.9 years at baseline attending 28 health centres in Santiago. The main outcomes are incidence of pneumonia, walking capacity and change in body mass index over 24 months of intervention. Costing data (user and provider), collected at all levels, will enable the determination of the cost-effectiveness of the two interventions individually and in combination. The study is supported by the Ministry of Health in Chile, which is keen to expand and improve its national programme of nutrition for older people based on sound science-base and evidence for cost-effectiveness.
Trial registration
PMCID: PMC1933543  PMID: 17615064
22.  A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636] 
Nutrition Journal  2006;5:20.
The number of individuals with age-related cognitive impairment is rising dramatically in the UK and globally. There is considerable interest in the general hypothesis that improving the diet of older people may slow the progression of cognitive decline. To date, there has been little attention given to the possible protective role of n-3 long-chain polyunsaturated fatty acids (n-3 LCPs) most commonly found in oily fish, in age-related loss of cognitive function. The main research hypothesis of this study is that an increased dietary intake of n-3 LCPs will have a positive effect on cognitive performance in older people in the UK.
To test this hypothesis, a double-blind randomised placebo-controlled trial will be carried out among adults aged 70–79 years in which the intervention arm will receive daily capsules containing n-3 LCP (0.5 g/day docosahexaenoic acid and 0.2 g/day eicosapentaenoic acid) while the placebo arm will receive daily capsules containing olive oil. The main outcome variable assessed at 24 months will be cognitive performance and a second major outcome variable will be retinal function. Retinal function tests are included as the retina is a specifically differentiated neural tissue and therefore represents an accessible window into the functioning of the brain.
The overall purpose of this public-health research is to help define a simple and effective dietary intervention aimed at maintaining cognitive and retinal function in later life. This will be the first trial of its kind aiming to slow the decline of cognitive and retinal function in older people by increasing daily dietary intake of n-3 LCPs. The link between cognitive ability, visual function and quality of life among older people suggests that this novel line of research may have considerable public health importance.
PMCID: PMC1564406  PMID: 16945130
23.  Community-Based Randomized Double-Blind Study of Gastrointestinal Effects and Copper Exposure in Drinking Water 
Environmental Health Perspectives  2004;112(10):1068-1073.
We assessed gastrointestinal effects in 1,365 adults exposed to either < 0.01 (controls), 2, 4, or 6 mg copper/L of drinking water for 2 months in a randomized, double-blind community-based study. The risk of symptoms increased with increasing Cu exposure and decreased with time. The best model by counting-process analysis included Cu concentration and sex. The risk of symptoms remained significantly higher in women than in men during weeks 1–4 for all concentrations tested; at week 1 comparison with the < 0.01-mg/L group showed that differences became significant in women at 4 mg/L [relative risk (RR) = 1.53; 95% confidence interval (CI), 1.02–2.05), and in men at 6 mg/L (RR = 1.9; 95% CI, 1.02–2.79). At week 2 for men and week 4 in women, the Cu concentration required to obtain significant differences on symptom report was > 6 mg Cu/L. We conclude that exposure to Cu in drinking water results in gastrointestinal symptoms, which are modulated by Cu concentration, time, and sex.
PMCID: PMC1247379  PMID: 15238279
adults; copper; drinking water; exposure; nausea
24.  Grandparenting and psychosocial health among older Chileans: A longitudinal analysis 
Aging & Mental Health  2012;16(8):1047-1057.
Objectives: To investigate factors associated with Chilean grandparents’ provision of help to grandchildren and associations between provision of such help and grandparents’ mental well-being two years later.
Methods: Data are drawn from a representative sample of 2000 people aged 66–68 resident in low- or middle-income areas of Santiago who were surveyed in 2005 and re-interviewed two years later. Multivariable analyses were used to investigate factors associated with provision of help to grandchildren at baseline and associations between providing such help and life satisfaction, SF36-Mental Component Summary scores, and depression two years later.
Results: 41% of grandparents lived with one or more grandchildren and over half provided four or more hours per week of help to grandchildren. Models controlling for baseline mental health, grandchild characteristics, marital and household characteristics, socio-economic status and functional health showed that grandfathers who provided four or more hours per week of help to grandchildren had better life satisfaction two years later and that those providing material help had higher SF36 MCS scores at follow-up. Grandmothers providing four or more hours of help a week had lower risks of depression.
Conclusion: Older Chileans make important contributions to their families through the provision of help to grandchildren and these appear to have some benefits for their own psychosocial health. Gender differences in the pattern of associations may reflect differences in overall family responsibilities and merit further investigation.
PMCID: PMC3431550  PMID: 22690765
depression; quality of life/wellbeing; mental health

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