Scaling up noncommunicable disease care in a resource-limited context: lessons learned and implications for policy.

BACKGROUND: Although primary care models for the care of common non-communicable diseases (NCD) have been developed in sub-Saharan Africa, few have described an integrated, decentralized approach at the community level. We report the results of a four-year, Ethiopian project to expand this model of NCD care to 15 primary hospitals and 45 health centres encompassing a wide geographical spread and serving a population of approximately 7.5 million people. METHODS: Following baseline assessment of the 60 sites, 30 master trainers were used to cascade train a total of 621 health workers in the diagnosis, management and health education of the major common NCDs identified in a scoping review (hypertension, diabetes, chronic respiratory disease and epilepsy). Pre- and post-training assessments and regular mentoring visits were carried out to assess progress and remedy supply or equipment and medicines shortages and establish reporting systems. The project was accompanied by a series of community engagement activities to raise awareness and improve health seeking behaviour. RESULTS: A total of 643,296 people were screened for hypertension and diabetes leading to a new diagnosis in 24,313 who were started on treatment. Significant numbers of new cases of respiratory disease (3,986) and epilepsy (1,925) were also started on treatment. Mortality rates were low except among patients with hypertension in the rural health centres where 311 (10.2%) died during the project. Loss to follow up (LTFU), defined as failure to attend clinic for > 6 months despite reminders, was low in the hospitals but represented a significant problem in the urban and rural health centres with up to 20 to 30% of patients with hypertension or diabetes absenting from treatment by the end of the project. Estimates of the population disease burden enrolled within the project, however, were disappointing; asthma (0.49%), hypertension (1.7%), epilepsy (3.3%) and diabetes (3.4%). CONCLUSION: This project demonstrates the feasibility of scaling up integrated NCD services in a variety of locations, with fairly modest costs and a methodology that is replicable and sustainable. However, the relatively small gain in the detection and treatment of common NCDs highlights the huge challenge in making NCD services available to all.

Type 1 diabetes in Africa: an immunogenetic study in the Amhara of North-West Ethiopia.

AIMS/HYPOTHESIS: We aimed to characterise the immunogenic background of insulin-dependent diabetes in a resource-poor rural African community. The study was initiated because reports of low autoantibody prevalence and phenotypic differences from European-origin cases with type 1 diabetes have raised doubts as to the role of autoimmunity in this and similar populations. METHODS: A study of consecutive, unselected cases of recently diagnosed, insulin-dependent diabetes (n = 236, ≤35 years) and control participants (n = 200) was carried out in the ethnic Amhara of rural North-West Ethiopia. We assessed their demographic and socioeconomic characteristics, and measured non-fasting C-peptide, diabetes-associated autoantibodies and HLA-DRB1 alleles. Leveraging genome-wide genotyping, we performed both a principal component analysis and, given the relatively modest sample size, a provisional genome-wide association study. Type 1 diabetes genetic risk scores were calculated to compare their genetic background with known European type 1 diabetes determinants. RESULTS: Patients presented with stunted growth and low BMI, and were insulin sensitive; only 15.3% had diabetes onset at ≤15 years. C-peptide levels were low but not absent. With clinical diabetes onset at ≤15, 16-25 and 26-35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had autoantibodies to GAD (GADA) as a single antibody; the prevalence of positivity for autoantibodies to IA-2 (IA-2A) and ZnT8 (ZnT8A) was low in all age groups. Principal component analysis showed that the Amhara genomes were distinct from modern European and other African genomes. HLA-DRB1*03:01 (p = 0.0014) and HLA-DRB1*04 (p = 0.0001) were positively associated with this form of diabetes, while HLA-DRB1*15 was protective (p < 0.0001). The mean type 1 diabetes genetic risk score (derived from European data) was higher in patients than control participants (p = 1.60 × 10-7). Interestingly, despite the modest sample size, autoantibody-positive patients revealed evidence of association with SNPs in the well-characterised MHC region, already known to explain half of type 1 diabetes heritability in Europeans. CONCLUSIONS/INTERPRETATION: The majority of patients with insulin-dependent diabetes in rural North-West Ethiopia have the immunogenetic characteristics of autoimmune type 1 diabetes. Phenotypic differences between type 1 diabetes in rural North-West Ethiopia and the industrialised world remain unexplained.

Type 1 Diabetes in a Resource-Poor Setting: Malnutrition Related, Malnutrition Modified, or Just Diabetes?

PURPOSE OF REVIEW: Very little is known about the occurrence of type 1 diabetes (T1DM) in resource-poor countries and particularly in their rural hinterlands. RECENT FINDINGS: Studies of the epidemiology of T1DM in Ethiopia and similar countries in sub-Saharan Africa show that the pattern of presenting disease differs substantially from that in the West. Typically, the peak age of onset of the disease is more than a decade later with a male excess and a low prevalence of indicators of islet-cell autoimmunity. It is also associated with markers of undernutrition. These findings raise the question as to whether the principal form of T1DM seen in these resource-poor communities has a different pathogenesis. Whether the disease is a direct result of malnutrition or whether malnutrition may modify the expression of islet-cell autoimmunity is unclear. However, the poor prognosis in these settings underlines the urgent need for detailed clinical and epidemiological studies.

The developmental origins of chronic rheumatic heart disease.

OBJECTIVES: Programming is the phenomenon whereby the body's structures and functions are permanently set by nutrition and other influences during early development. There is increasing evidence that programming in utero initiates cardiovascular disease. We hypothesized that susceptibility to developing chronic rheumatic heart disease on exposure to Streptococcus pyogenes is programmed. METHODS: We studied hospital admissions and deaths from chronic rheumatic heart disease in 20,431 people born in Helsinki, Finland, during 1924-1944. One hundred and one people, 56 men, and 45 women, had chronic rheumatic heart disease. RESULTS: The disease was not associated with body or placental size at birth. It was, however, associated with a long umbilical cord so that the hazard ratio for the disease was 1.23 (95% CI 1.04-1.45, P = 0.02) for every 10 cm increase in cord length. This association was present in people with mitral valve disease, hazard ratio 1.5 (1.20-1.89, P < 0.0001), but not in people with aortic valve disease, hazard ratio 1.0 (0.76-1.33, P = 0.97). Growing up in large households increased the risk of rheumatic heart disease. CONCLUSION: Longer umbilical cords have more spirals and a greater density of spirals per unit of length. Increased spiraling will increase the resistance to flow and the pressure load on the fetal heart. This could affect the development of the heart's valves and make them more vulnerable to the autoimmune process initiated by Streptococcus pyogenes. The mitral valve may be more vulnerable than the aortic valve because the valve leaflets are larger and therefore have greater wall stress.

The "Cairo Accord"- Towards the Eradication of RHD: An Update.

Rheumatic heart disease (RHD) is the most common cause of acquired heart disease in children and young adults. It continues to be prevalent in many low- and middle-income countries where it causes significant morbidity and mortality. Following the 2017 Cairo conference "Rheumatic Heart Disease: from Molecules to the Global Community," experts from 21 countries formulated an approach for addressing the problem of RHD: "The Cairo Accord on Rheumatic Heart Disease." The Accord attempts to set policy priorities for the eradication of acute rheumatic fever (ARF) and RHD and builds on a recent series of policy initiatives and calls to action. We present an update on the recommendations of the Cairo Accord and discuss recent progress toward the eradication of RHD, including contributions from our own Aswan Rheumatic Heart Disease Registry (ARGI).

Community-based prevalence of rheumatic heart disease in rural Ethiopia: Five-year follow-up.

BACKGROUND: As little is known about the prevalence and clinical progression of subclinical (latent) rheumatic heart disease (RHD) in sub-Saharan Africa, we report the results of a 5 year follow-up of a community based, echocardiographic study of the disease, originally carried out in a rural area around Jimma, Ethiopia. METHODS: Individuals with evidence of RHD detected during the baseline study as well as controls and their family members were screened with a short questionnaire together with transthoracic echocardiography. RESULTS: Of 56 individuals with RHD (37 definite and 19 borderline) in the original study, 36 (26 definite and 10 borderline) were successfully located 57.3 (range 44.9-70.7) months later. At follow-up two thirds of the definite cases still had definite disease; while a third had regressed. Approximately equal numbers of the borderline cases had progressed and regressed. Features of RHD had appeared in 5 of the 60 controls. There was an increased risk of RHD in the family relatives of borderline and definite cases (3.8 and 4.0 times respectively), notably among siblings. Compliance with penicillin prophylaxis was very poor. CONCLUSIONS: We show the persistence of echocardiographically demonstrable RHD in a rural sub-Saharan population. Both progression and regression of the disease were found; however, the majority of the individuals who had definite features of RHD had evidence of continuing RHD lesions five years later. There was an increased risk of RHD in the family relatives of borderline and definite cases, notably among siblings. The findings highlight the problems faced in addressing the problem of RHD in the rural areas of sub-Saharan Africa. They add to the evidence that community-based interventions for RHD will be required, together with appropriate ways of identifying active disease, achieving adequate penicillin prophylaxis and developing vaccines for primary prevention.

Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients Attending the Diabetic Clinic of the University of Gondar Hospital, Northwest Ethiopia.

OBJECTIVE: To investigate the level of diabetic retinopathy in type 2 diabetes (T2DM) patients attending the University of Gondar Hospital (UGH) Diabetic Clinic, Northwest Ethiopia. METHODS: An audit was carried out involving a total of 739 T2DM patients attending at the diabetic clinic of UGH. They represented approximately 90% and 50% of all T2DM patients under regular review at the urban and rural diabetic clinics of UGH, respectively. All were supervised by the same clinical team for a long period. Eye examinations were performed for visual acuity, cataract, and retinal changes (retinal photography and slit-lamp biomicroscopy). Body mass index (BMI) and HbA1c levels were measured. The presence or absence of hypertension was recorded. RESULTS: Men constituted 41.5% of the group, the mean age at diagnosis of T2DM was 50.4 years, and 50.2% were hypertensive. The BMI was 25.0 ± 4.1 kg/m2, and HbA1c was 7.75 ± 1.63% (61.2 ± 17.8 mmol/mol) (mean ± SD, for BMI and HbA1c)). Severe visual impairment/blindness was reported in 10.6%, 15.2% had cataract, 16.0% had retinopathy, and 11.1% had maculopathy. The prevalence of retinopathy increased with time from diagnosis of T2DM (chi-square for trend, p < 0.001) and with increasing HbA1c level (chi-square for trend, p=0.03). CONCLUSION: These results compare well with the most recent results in well-equipped, wealthier regions of the world and show the importance of stable healthcare infrastructure for chronic-disease management.

The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria.

BACKGROUND: Polycystic ovary syndrome (PCOS) is considered to be the most common endocrine disorder in women of reproductive age, yet debate over appropriate diagnostic criteria and design limitations with sampling methodology have left some doubt as to the actual prevalence in the community. The objective of this study was to create a representative prevalence estimate of PCOS in the community under the National Institutes of Health (NIH) criteria and the more recent Rotterdam consensus criteria and Androgen Excess Society (AES) criteria. METHODS: A retrospective birth cohort study was carried out in which 728 women born during 1973-1975 in a single maternity hospital were traced and interviewed in adulthood (age = 27-34 year; n = 728). Symptoms of PCOS (hyperandrogenism, menstrual dysfunction and polycystic ovaries) were identified by examination and the presence of polycystic ovaries in those that did not consent to the ultrasound were imputed. RESULTS: The estimated prevalence of PCOS in this birth cohort using the NIH criteria was 8.7 +/- 2.0% (with no need for imputation). Under the Rotterdam criteria, the prevalence was 11.9 +/- 2.4% which increased to 17.8 +/- 2.8% when imputed data were included. Under the AES recommendations, PCOS prevalence was 10.2 +/- 2.2%, and 12.0 +/- 2.4% with the imputed data. Of the women with PCOS, 68-69% did not have a pre-existing diagnosis. CONCLUSIONS: The Rotterdam and AES prevalence estimates were up to twice that obtained with the NIH criteria in this, as well other prevalence studies. In addition, this study also draws attention to the issue of many women with PCOS in the community remaining undiagnosed.

Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring.

BACKGROUND: Maternal nutrition during pregnancy has been linked with fetal brain development and psychopathology in the offspring. We examined for associations of maternal folate status and dietary intake during pregnancy with brain growth and childhood behavioural difficulties in the offspring. METHODS: In a prospective cohort study, maternal red blood cell folate (RCF) was measured at 14 weeks of pregnancy and total folate intake (TFI) from food and supplements was assessed in early and late pregnancy. The offspring's head circumference and body weight were measured at birth and in infancy, and 100 mothers reported on children's behavioural difficulties at a mean age of 8.75 years using the Strengths and Difficulties Questionnaire. RESULTS: Lower maternal RCF and TFI in early pregnancy were associated with higher childhood hyperactivity (RCF: beta = -.24; p = .013; TFI: beta = -.24; p = .022) and peer problems scores (RCF: beta = -.28; p = .004; TFI: beta = -.28; p = .009) in the offspring. Maternal gestational RCF was positively associated with head circumference at birth (adjusted for gestational age), and mediation analyses showed significant inverse indirect associations of RCF with hyperactivity/inattention and peer problems via fetal brain growth. Adjustment for mother's smoking and drinking alcohol during pregnancy did not change the results. CONCLUSIONS: Although the associations are small and residual confounding is possible, our data provide preliminary support for the hypothesis that lower folate status in early pregnancy might impair fetal brain development and affect hyperactivity/inattention and peer problems in childhood.

Fetal origins of mental health: evidence and mechanisms.

The concept of fetal programming states that changes in the fetal environment during sensitive periods of organ development may cause long-lasting changes in the structure and functioning of these organs later in life and influence the risk for chronic diseases such as coronary heart disease and type 2 diabetes. Fetal growth is a summary marker of the fetal environment and is reflected by relatively easy-to-obtain measures of size at birth such as birth weight. In the last two decades, a body of evidence emerged linking fetal growth with behavioural and mental health outcomes later in life. Cognitive functioning and behavioural problems in childhood, in particular inattention/hyperactivity, have been shown to be inversely related to fetal growth. Although results are mixed, risk for personality disorders and schizophrenia seems to be linked with fetal growth and adversity, while the evidence for mood disorders is weak. Vulnerability for psychopathology may also be influenced by prenatal adversity. There is evidence for associations of fetal growth with temperament in childhood as well as stress reactivity and distress. The associations of fetal growth with mental health later in life are potentially caused by specific prenatal factors such as maternal smoking, alcohol, toxins/drugs, nutrition, psychosocial stress and infection during pregnancy. The mechanisms likely involve changes in neurodevelopment and in the set point of neuroendocrine systems, and there is evidence that prenatal adversity interacts with genetic and postnatal environmental factors. Future studies should examine the effects of specific prenatal factors and attempt to disentangle genetic and prenatal environmental effects.

Sex-specific programming of cardiovascular physiology in children.

AIMS: Increasing evidence suggests that adverse prenatal environments, as indicated by low birth weight, cause long-term changes in cardiovascular physiology that predispose to circulatory disease. The mechanisms are poorly understood, most human studies have been carried out in adults and little is known about early pathophysiological changes. Therefore, we have assessed the relationship between birth weight and cardiovascular physiology in children. METHODS AND RESULTS: In 140 healthy boys and girls (aged 7-9 years), born at term and followed prospectively, we continuously recorded blood pressure, electrocardiograms and cardiac impedance before, during, and after 10 min of psychosocial stress (Trier Social Stress Test for Children). In boys, an association of lower birth weight with higher resting systemic arterial pressure (ß = -6.8 mmHg/kg, P= 0.03) and a trend towards higher vascular resistance (ß = -87 dyne s/cm(5)/kg, ns) were substantially strengthened following stress (ß = -9.5 mmHg/kg, P= 0.003 and ß = -139 dyne s/cm(5)/kg, P = 0.02, respectively). In girls, lower birth weight was associated with a shorter pre-ejection period (ß = 8.0 ms/kg, P = 0.005) and corrected QT interval (ß = 11.9 ms/kg, P = 0.003) at rest and little changed by stress. CONCLUSION: Smaller size at birth is associated with sex-specific alterations in cardiac physiology; boys had higher systemic vascular resistance and girls had increased cardiac sympathetic activation.

Effortful control mediates associations of fetal growth with hyperactivity and behavioural problems in 7- to 9-year-old children.

BACKGROUND: Inverse associations of fetal growth with behavioural problems in childhood have been repeatedly reported, suggesting long-term effects of the prenatal developmental environment on behaviour later in life. However, no study so far has examined effects on temperament and potential developmental pathways. Temperamental traits may be particularly susceptible to neurodevelopmental alterations, and they are linked to behavioural problems. Therefore, we tested for associations of fetal growth with behavioural problems in children and tested if temperament mediated such effects. METHODS: One hundred and thirty-nine mother-child pairs were recruited in early pregnancy.Weight, head circumference and gestational age were measured at birth, and the mother reported on their child's behavioural problems and temperament at age 7 to 9 years. RESULTS: Birth weight and head circumference at birth adjusted for gestational age (i.e., fetal growth) were inversely associated with hyperactivity and total behavioural problems, and positively associated with the temperamental trait Effortful Control. Path analyses showed that Effortful Control mediated the effects of fetal growth on hyperactivity and total behavioural problems. CONCLUSIONS: Our results suggest that an adverse fetal environment is associated with behavioural problems in childhood, in particular in those children that show a low capacity for attentional and behavioural regulation. An adverse fetal environment might induce vulnerability for behavioural problems, or it might induce changes in temperament and behavioural problems independently, representing a common cause. Pathways are likely to be based on long-lasting neurodevelopmental alterations due to prenatal adversity.

Evaluating the long-term consequences of air pollution in early life: geographical correlations between coal consumption in 1951/1952 and current mortality in England and Wales.

OBJECTIVE: To evaluate associations between early life air pollution and subsequent mortality. DESIGN: Geographical study. SETTING: Local government districts within England and Wales. EXPOSURE: Routinely collected geographical data on the use of coal and related solid fuels in 1951-1952 were used as an index of air pollution. MAIN OUTCOME MEASURES: We evaluated the relationship between these data and both all-cause and disease-specific mortality among men and women aged 35-74 years in local government districts between 1993 and 2012. RESULTS: Domestic (household) coal consumption had the most powerful associations with mortality. There were strong correlations between domestic coal use and all-cause mortality (relative risk per SD increase in fuel use 1.124, 95% CI 1.123 to 1.126), and respiratory (1.238, 95% CI 1.234 to 1.242), cardiovascular (1.138, 95% CI 1.136 to 1.140) and cancer mortality (1.073, 95% CI 1.071 to 1.075). These effects persisted after adjustment for socioeconomic indicators in 1951, current socioeconomic indicators and current pollution levels. CONCLUSION: Coal was the major cause of pollution in the UK until the Clean Air Act of 1956 led to a rapid decline in consumption. These data suggest that coal-based pollution, experienced over 60 years ago in early life, affects human health now by increasing mortality from a wide variety of diseases.

Prevalence and functionality of paucimorphic and private MC4R mutations in a large, unselected European British population, scanned by meltMADGE.

Identification of unknown mutations has remained laborious, expensive, and only viable for studies of selected cases. Population-based "reference ranges" of rarer sequence diversity are not available. However, the research and diagnostic interpretation of sequence variants depends on such information. Additionally, this is the only way to determine prevalence of severe, moderate, and silent mutations and is also relevant to the development of screening programs. We previously described a system, meltMADGE, suitable for mutation scanning at the population level. Here we describe its application to a population-based study of MC4R (melanocortin 4 receptor) mutations, which are associated with obesity. We developed nine assays representing MC4R and examined a population sample of 1,100 subjects. Two "paucimorphisms" were identified (c.307G>A/p.Val103Ile in 27 subjects and c.-178A>C in 22 subjects). Neither exhibited any anthropometric effects, whereas there would have been >90% power to detect a body mass index (BMI) effect of 0.5 kg/m(2) at P=0.01. Two "private" variants were also identified. c.335C>T/p.Thr112Met has been previously described and appears to be silent. A novel variant, c.260C>A/p.Ala87Asp, was observed in a subject with a BMI of 31.5 kg/m(2) (i.e., clinically obese) but not on direct assay of a further 3,525 subjects. This mutation was predicted to be deleterious and analysis using a cyclic AMP (cAMP) responsive luciferase reporter assay showed substantial loss of function of the mutant receptor. This population-based mutation scan of MC4R suggests that there is no severe MC4R mutation with high prevalence in the United Kingdom, but that obesity-causing MC4R mutation at 1 in 1,100 might represent one of the commonest autosomal dominant disorders in man.

Stress responsiveness in adult life: influence of mother's diet in late pregnancy.

CONTEXT: Men and women whose mothers ate an unbalanced high-protein, low-carbohydrate diet in late pregnancy have raised blood pressure. We recently showed that they also have raised fasting plasma cortisol concentrations. Because raised fasting cortisol concentrations probably reflect a greater response to the stress of fasting and venesection, we suspected that this diet may have led to increased stress responsiveness in the adult offspring. OBJECTIVE: The aim was to determine whether an unbalanced high-protein diet during pregnancy is associated with increased cortisol secretion in response to psychological stress in the offspring. DESIGN AND PARTICIPANTS: Salivary cortisol concentrations were measured during a modified Trier Social Stress Test in 70 men and women aged 36.3 yr whose mothers had taken part in a dietary intervention in which they were advised to eat 1 pound (0.45 kg) of red meat daily during pregnancy and to avoid carbohydrate-rich foods. RESULTS: The offspring of women who reported greater consumption of meat and fish in the second half of pregnancy had higher cortisol concentrations during the Trier Test. Compared with the offspring of mothers who had reported eating no more than 13 meat/fish portions per week, the average cortisol concentrations were raised by 22% (95% confidence interval, 13 to 71%) and 46% (5 to 103%) in the offspring of those eating 14-16 and at least 17 portions per week, respectively. CONCLUSIONS: These findings provide the first human evidence that an unbalanced high protein maternal diet during late pregnancy leads to increased cortisol secretion in response to psychological stress in the offspring.

Body size at birth predicts hypothalamic-pituitary-adrenal axis response to psychosocial stress at age 60 to 70 years.

BACKGROUND: Studies in humans and animals have suggested intrauterine programming of hypothalamic-pituitary-adrenal axis (HPAA) function as an important mechanism in linking fetal life conditions with adult disease. OBJECTIVE: Our aim was to assess how body size at birth, a marker of intrauterine conditions, is associated with hypothalamic-pituitary-adrenal axis response to psychosocial stress in late adulthood. DESIGN AND SETTING: We conducted a clinical study in the Helsinki Birth Cohort. PARTICIPANTS: Two hundred eighty-seven men and women born between 1934 and 1944 whose birth measurements and gestational age came from hospital records participated in the study. MEASUREMENTS: We measured salivary cortisol and, for 215 individuals, plasma cortisol and ACTH concentrations in conjunction with a standardized psychosocial stressor (Trier Social Stress Test). RESULTS: There was a linear relationship between low birth weight and low plasma ACTH but no linear relationship with cortisol. There were, however, quadratic relationships between birth weight and salivary (mixed model P = 0.001) and plasma cortisol (P = 0.005) but not with plasma ACTH (P = 0.1). The lowest peak salivary cortisol concentrations were seen in the lowest third of birth weights (adjusted for gestational age and sex): 12.9 nmol/liter (95% confidence interval of mean 11.2-15.0), compared with 17.1 nmol/liter (14.8-19.8) in the middle and 14.1 nmol/liter (12.6-15.7) in the highest third of birth weights. Corresponding figures for plasma cortisol were 418 nmol/liter (380-459), 498 nmol/liter (455-545), and 454 nmol/liter (428-482), and for plasma ACTH 8.17 pmol/liter (6.98-9.57), 12.42 pmol/liter (10.64-14.51), and 11.50 (10.06-13.14), respectively. Results for areas under the curve were similar. CONCLUSIONS: We found an inverse U-shaped relationship between birth weight and cortisol concentrations during psychosocial stress. The lowest cortisol and ACTH concentrations were seen in subjects with the lowest birth weights. These results support the hypothesis that both hyper- and hypocortisolism may be programmed during the fetal period.

The effects of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene on glucose/insulin metabolism interact with prenatal exposure to famine.

OBJECTIVE: An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism. RESEARCH DESIGN AND METHODS: We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-gamma2 genotype among 675 term singletons born around the time of the 1944-1945 Dutch famine. RESULTS: A significant interaction effect between exposure to famine during midgestation and the PPAR-gamma2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-gamma2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation. CONCLUSIONS: The effects of the PPAR-gamma2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic beta-cell maldevelopment and carrier type of the Ala allele in the PPAR-gamma2 gene.

Impaired insulin secretion after prenatal exposure to the Dutch famine.

OBJECTIVE: We previously reported that people prenatally exposed to famine during the Dutch Hunger Winter of 1944-1945 have higher 2-h glucose concentrations after an oral glucose tolerance test in later life. We aimed to determine whether this association is mediated through alterations in insulin secretion, insulin sensitivity, or a combination of both. RESEARCH DESIGN AND METHODS: We performed a 15-sample intravenous glucose tolerance test in a subsample of 94 normoglycemic men and women from the Dutch Famine Birth Cohort. We used the disposition index, derived as the product of insulin sensitivity and the first-phase insulin response to glucose as a measure of the activity of the beta-cells adjusted for insulin resistance. In all analyses, we adjusted for sex and BMI. RESULTS: Glucose tolerance was impaired in people who had been prenatally exposed to famine compared with people unexposed to famine (difference in intravenous glucose tolerance test K(g) value -21% [95% CI -41 to -4]). People exposed to famine during midgestation had a significantly lower disposition index (-53% [-126 to -3]) compared with people unexposed to famine. Prenatal exposure to famine during early gestation was also associated with a lower disposition index, but this difference did not reach statistical significance. CONCLUSIONS: Impaired glucose tolerance after exposure to famine during mid-gestation and early gestation seems to be mediated through an insulin secretion defect.

Air pollution in early life and adult mortality from chronic rheumatic heart disease.

Background: Chronic rheumatic heart disease (RHD) remains a globally important cause of heart disease. The reasons for the continuing high prevalence of this disease are obscure, but it may have its origins in the poor social and economic conditions with which the disease has been consistently and strongly linked. Mortality studies from the UK have suggested the importance of adverse environmental factors in early life; these studies demonstrated specific geographical associations between high rates of chest infection during infancy and subsequent RHD. They raised the possibility that early air pollution, which is known to be strongly linked with chest infection during infancy, may predispose to RHD. Methods: We related estimates of air pollution and social conditions developed by Daly in 1951-52 for 78 urban areas in England and Wales to their subsequent RHD mortality rates at ages 35-74 in men and women during 1993-2012. Results: There were strong relationships between domestic air pollution and RHD [relative risk per standard deviation (SD) increase in pollution 1.168, 95% confidence interval (CI): 1.128 to 1.210, P < 0.001). Inclusion of published data on social class, education, crowding and population density in multiple regression analyses showed that the air pollution association was independent of these; only overcrowding was separately linked with RHD. Conclusions: We present the first evidence of an association between air pollution in early life and RHD. Although there are several limitations to this study, the strength and consistency of the results, together with their biological plausibility, suggest a causal link. This deserves attention because it may have important consequences for the control of RHD in resource-poor countries where widespread use of biomass fuels and domestic pollution remain a problem.

Prevalence and prognostic value of echocardiographic screening for rheumatic heart disease.

Objective: Rheumatic heart disease (RHD) remains a major health problem in many low-income and middle-income countries. The use of echocardiographic imaging suggests that subclinical disease is far more widespread than previously appreciated, but little is known as to how these mild forms of RHD progress. We have determined the prevalence of subclinical RHD in a large group of schoolchildren in Aswan, Egypt and have evaluated its subsequent progression. Methods: Echocardiographic screening was performed on 3062 randomly selected schoolchildren, aged 5-15 years, in Aswan, Egypt. Follow-up of children with a definite or borderline diagnosis of RHD was carried out 48-60 months later to determine how the valvular abnormalities altered and to evaluate the factors influencing progression. Results: Sixty children were initially diagnosed with definite RHD (19.6 per 1000 children) and 35 with borderline disease (11.4 per 1000); most had mitral valve disease. Of the 72 children followed up progression was documented in 14 children (19.4%) and regression in 30 (41.7%) children. Boys had lower rates of progression while older children had lower rates of regression. Functional defects of the valve even in the presence of structural features were associated with lower rates of progression and higher rates of regression than structural changes. Conclusions: RHD has a high prevalence in Egypt. Although a high proportion of the abnormalities originally detected persisted at follow-up, both progression and regression of valve lesions were demonstrated.