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.

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).

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.

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.

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.

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.

Retinopathy in type 1 diabetes mellitus: Major differences between rural and urban dwellers in northwest Ethiopia.

AIM: To audit levels of diabetes-related eye disease in Type 1 diabetes mellitus (T1DM) patients in northwest Ethiopia. In particular to establish whether, despite identical clinical goals, major differences between the physically demanding life-style of rural subsistence farmers and the sedentary life-style of urban dwellers would influence the prevalence of diabetes-related eye complications. METHODS: A robust infrastructure for chronic disease management that comprehensively includes all rural dwellers was a pre-requisite for the investigation. A total of 544 T1DM were examined, representing 80% of all T1DM patients under regular review at both the urban and rural clinics and representative of patient age and gender (62.1% male, 37.9% female) of T1DM patients from this region; all were supervised by the same clinical team. Eye examinations were performed for visual acuity, cataract and retinal changes (retinal photography). HbA1c levels and the presence or absence of hypertension were recorded. RESULTS/CONCLUSIONS: Urban and rural groups had similar prevalences of severe visual impairment/blindness (7.0% urban, 5.2% rural) and cataract (7.3% urban, 7.1% rural). By contrast, urban dwellers had a significantly higher prevalence of retinopathy compared to rural patients, 16.1% and 5.0%, respectively (OR 2.9, p<0.02, after adjustment for duration, age, gender and hypertension). There was a 3-fold greater prevalence of hypertension in urban patients, whereas HbA1c levels were similar in the two groups. Since diabetic retinopathy is closely associated with microvascular disease and endothelial dysfunction, the possible influences of hypertension to increase and of sustained physical activity to reduce endothelial dysfunction are discussed.

The relationship between umbilical cord length and chronic rheumatic heart disease: a prospective cohort study.

BACKGROUND: One previous, preliminary study reported that the length of the umbilical cord at birth is related to the risk of developing chronic rheumatic heart disease in later life. We sought to replicate this finding. DESIGN: Prospective, population-based birth cohort. METHODS: We traced 11,580 individuals born between 1915 and 1929 in Uppsala, Sweden. We identified cases with a main or secondary diagnosis of chronic rheumatic heart disease in the Swedish national inpatient, outpatient or death registers. Archived obstetric records provided data on umbilical cord length, gestational age, birthweight and placental weight. RESULTS: There were 136 patients with chronic rheumatic heart disease (72 men and 64 women) with a mean age at first hospital admission of 68 years (range 36-92). There was evidence of a positive association between umbilical cord length and risk of subsequent chronic rheumatic heart disease. The overall hazard ratio in the Swedish study (1.13, 95% confidence interval 1.01 to 1.27) was similar to that of the previous study, with some suggestion of larger effect in men than in women. No other birth characteristics were predictive except for weak evidence of a protective effect of higher birthweight in men. CONCLUSIONS: People with longer umbilical cords at birth are more likely to develop chronic rheumatic heart disease in later life. As longer umbilical cords have more spiral arteries and a higher vascular resistance, we hypothesize that the increased pressure load on the heart leads to changes in endothelial biology and increased vulnerability to the autoimmune process initiated by infection with ß-haemolytic streptococci.

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 paradox of overnutrition in aging and cognition.

Populations of many countries are becoming increasingly overweight and obese, driven largely by excessive calorie intake and reduced physical activity; greater body mass is accompanied by epidemic levels of comorbid metabolic diseases. At the same time, individuals are living longer. The combination of aging and the increased prevalence of metabolic disease is associated with increases in aging-related comorbid diseases such as Alzheimer's disease, cerebrovascular dementia, and sarcopenia. Here, correlative and causal links between diseases of overnutrition and diseases of aging and cognition are explored.

The relationship between depression, anxiety and cardiovascular disease: findings from the Hertfordshire Cohort Study.

BACKGROUND: Previous studies suggest a link between depression, anxiety and cardiovascular disease (CVD). The aim of the study was to determine the relationship between depressive and anxiety symptoms and CVD in a population based cohort. METHODS: In total 1578 men and 1,417 women from the Hertfordshire Cohort Study were assessed for CVD at baseline and after 5.9 ± 1.4 years. Depressive and anxiety symptoms were measured using the HADS scale. RESULTS: Baseline HAD-D score, but not HAD-A, was significantly associated with baseline plasma triglycerides, glucose and insulin resistance (men only) and HDL cholesterol (women only). After adjustment for CVD risk factors, higher baseline HAD-D scores were associated with increased odds ratios for CVD (men: 1.162 [95% CI 1.096-1.231]; women: 1.107 [1.038-1.181]). Higher HAD-A scores associated with increased CVD in men only. High HAD-D scores predicted incident CVD (adjusted OR 1.130 [1.034-1.235]), all-cause mortality (adjusted HR 1.081, [1.012-1.154]) and cardiovascular mortality (adjusted HR 1.109 [1.002-1.229]) in men but not in women. LIMITATIONS: The use of a self-report measure of depressive and anxiety symptoms, 'healthy' responder bias and the low number of cardiovascular events are all limitations. CONCLUSIONS: Depressive and anxiety symptoms are commoner in people with CVD. These symptoms are independent predictors of CVD in men. Although HAD-D score was significantly associated with several cardiovascular risk factors, this did not fully explain the association between HAD-D and CVD.

Birth weight and perceived stress reactivity in older age.

Stress reactivity is a disposition that underlies individual differences in stress responses, thereby affecting vulnerability for the development of disease. Besides genetic and early postnatal environmental factors, stress reactivity has been shown to be influenced by an adverse prenatal developmental environment, but it is unclear if such effects persist into older age. We tested associations between fetal growth and perceived stress reactivity in 421 participants from the Hertfordshire Cohort at age 66-75 years. Regression analysis showed a U-shaped association between birth weight and perceived stress reactivity with increased levels of stress reactivity at the lower and upper end of the birth weight distribution. These effects were stable after adjustment for markers of early adversity and recent adversity and chronic stress. Although the effects were small, they are consistent with findings from studies in younger cohorts, and demonstrate that such effects can persist into older age.

Epilepsy, poverty and early under-nutrition in rural Ethiopia.

PURPOSE: The incidence of epilepsy in Ethiopia is high compared with industrialised countries, but in most cases the cause of epilepsy is unknown. Childhood malnutrition remains widespread. We performed a case-control study to determine whether epilepsy is associated with poverty and markers of early under-nutrition. METHODS: Patients with epilepsy (n=112), aged 18-45years, were recruited from epilepsy clinics in and around two towns in Ethiopia. Controls with a similar age and gender distribution (n=149) were recruited from patients and relatives attending general outpatient clinics. We administered a questionnaire to define the medical and social history of cases and controls, and then performed a series of anthropometric measurements. Unconditional logistic regression was used to estimate multivariate adjusted odds ratios. Multiple linear regression was used to estimate adjusted case-control differences for continuously distributed outcomes. RESULTS: Epilepsy was associated with illiteracy/low levels of education, odds ratio=3.0 (95% confidence interval: 1.7-5.6), subsistence farming, odds ratio=2.6 (1.2-5.6) and markers of poverty including poorer access to sanitation (p=0.009), greater overcrowding (p=0.008) and fewer possessions (p<0.001). Epilepsy was also associated with the father's death during childhood, odds ratio=2.2 (1.0-4.6). Body mass index was similar in cases and controls, but patients with epilepsy were shorter and lighter with reduced sitting height (p<0.001), bitrochanteric diameter (p=0.029) and hip size (p=0.003). Patients with epilepsy also had lower mid-upper arm circumference (p=0.011) and lean body mass (p=0.037). CONCLUSION: Epilepsy in Ethiopia is strongly associated with poor education and markers of poverty. Patients with epilepsy also had evidence of stunting and disproportionate skeletal growth, raising the possibility of a link between early under-nutrition and epilepsy.

Population mutation scanning of human GHR by meltMADGE and identification of a paucimorphic variant.

Current studies of human genetic diversity are focused in two areas: first, detection of rare mutations in highly selected clinical cases; and second, in common single-nucleotide polymorphism (SNP) and haplotype effects in the general population. Less frequent SNPs and "paucimorphisms" remain underexplored, although lower frequency coding SNPs are more likely to have functional impact. We have developed a cost-efficient mutation scanning technology, meltMADGE, for population mutation scanning. Previous research in GHR has explored its role in extreme (-3 SD) growth retardation and, subsequently, "moderate" (-2 SD) growth retardation cases. Here, we describe meltMADGE assays for the entire coding region of GHR. As a first step we have established long polymerase chain reaction subbanks for GHR from 2423 unselected subjects and have applied meltMADGE scanning assays of exons 4 and 5 to these subbanks. A novel paucimorphism present at 439+30A>C (allele frequency: 0.0021) in intron 5 (location chr5:42,695,221 in GRCh37/hg19) was identified in 10 individuals, confirmed by sequencing and analysis made for major phenotypic effects. This approach is relevant to the deep sampling of populations for less frequent sequence diversity, some of which is expected to exert significant phenotypic effects.

Evidence for developmental programming of cerebral laterality in humans.

Adverse fetal environments are associated with depression, reduced cognitive ability and increased stress responsiveness in later life, but underlying mechanisms are unknown. Environmental pressures on the fetus, resulting from variations in placental function and maternal nutrition, health and stress might alter neurodevelopment, promoting the development of some brain regions over others. As asymmetry of cerebral activity, with greater right hemisphere activity, has been associated with psychopathology, we hypothesized that regional specialization during fetal life might be reflected persistently in the relative activity of the cerebral hemispheres. We tested this hypothesis in 140 healthy 8-9 year-old children, using tympanic membrane temperature to assess relative blood flow to the cerebral hemispheres at rest and following psychosocial stress (Trier Social Stress Test for Children). Their birth weight and placental weight had already been measured when their mothers took part in a previous study of pregnancy outcomes. We found that children who had a smaller weight at birth had evidence of greater blood flow to the right hemisphere than to the left hemisphere (r = -.09, P = .29 at rest; r = -.18, P = .04 following stress). This finding was strengthened if the children had a relatively low birth weight for their placental weight (r = -.17, P = .05 at rest; r = -.31, P = .0005 following stress). Our findings suggest that lateralization of cerebral activity is influenced persistently by early developmental experiences, with possible consequences for long-term neurocognitive function.

Maternal prenatal licorice consumption alters hypothalamic-pituitary-adrenocortical axis function in children.

Overexposure to glucocorticoids has been proposed as a mechanism by which prenatal adversity 'programs' the function of the hypothalamic-pituitary-adrenocortical axis (HPAA), thereby increasing the risk of adult diseases. Glycyrrhizin, a natural constituent of licorice, potently inhibits 11ß-hydroxysteroid dehydrogenase type 2, the feto-placental barrier to the higher maternal cortisol levels. We studied if maternal consumption of glycyrrhizin in licorice associates with HPAA function in children. Diurnal salivary cortisol and salivary cortisol during the Trier Social Stress Test for Children (TSST-C) were measured in children (n=321, mean age=8.1, SD=0.3 years) whose mothers consumed varying levels of glycyrrhizin in licorice during pregnancy; exposure-level groups were labeled high (≥500 mg/week), moderate (250-499 mg/week) and zero-low (0-249 mg/week). In comparison to the zero-low exposure group, children in the high exposure group had 19.2% higher salivary cortisol awakening peak, 33.1% higher salivary cortisol awakening slope, 15.4% higher salivary cortisol awakening area under the curve (AUC), 30.8% higher baseline TSST-C salivary cortisol levels, and their salivary cortisol levels remained high throughout the TSST-C protocol (P-values <0.05). These effects appeared dose-related. Our findings lend support to prenatal 'programming' of HPAA function by overexposure to glucocorticoids.

Poor sleep and altered hypothalamic-pituitary-adrenocortical and sympatho-adrenal-medullary system activity in children.

CONTEXT: Neuroendocrine alterations, with well-known links with health, may offer insight into why poor sleep is associated with poor health. Yet, studies testing associations between sleep and neuroendocrine activity in children are scarce. OBJECTIVE: The aim of this study was to determine whether actigraphy-based sleep pattern is associated with hypothalamic-pituitary-adrenocortical axis and sympatho-adrenal-medullary system activity in children. DESIGN AND SETTING: We conducted a cross-sectional study in a birth cohort in Helsinki, Finland. PARTICIPANTS: We studied 282 8-yr-old children. MAIN OUTCOME MEASURES: We measured diurnal salivary cortisol and salivary cortisol and alpha-amylase (a sympatho-adrenal-medullary system marker) responses to the Trier Social Stress Test for Children (TSST-C). RESULTS: Children with short (77.4%) displayed higher diurnal cortisol levels across the entire day (P < 0.03), higher cortisol levels after the TSST-C stressor (P < 0.04), and higher overall alpha-amylase levels across the entire TSST-C protocol (P < 0.05). The effects were not confounded by factors that may alter sleep or hormonal patterns. CONCLUSIONS: Poor sleep may signal altered neuroendocrine functioning in children. The findings may offer insight into the pathways linking poor sleep with poor health.

Minireview: transgenerational inheritance of the stress response: a new frontier in stress research.

It is well established in animal models that the prenatal environment can have a major impact on stress axis function throughout life. These changes can predispose to various metabolic, cardiovascular, and neurobiological pathophysiologies. Emerging evidence indicates that the same programming effects occur in humans. It is now becoming clear that the pathophysiological effects are not confined to the first-generation offspring and that there is transgenerational memory of fetal experience that can extend across multiple generations. The complex mechanisms by which transgenerational transmission of stress responsiveness occur are rapidly becoming a focus of investigation. Understanding these fundamental biological processes will allow for development of intervention strategies that prevent or reverse adverse programming of the stress response.