Identification of the novel allele, HLA-B*14:56, in a Brazilian individual.

Novel allele, HLA-B*14:56, generated by a gene conversion event was identified in a Brazilian individual.

A novel allele, HLA-B*51:220, identified in an individual from south of Brazil.

Novel allele, HLA-B*51:220 generated by a gene conversion event was identified in a Brazilian individual.

Single molecule real-time DNA sequencing of HLA genes at ultra-high resolution from 126 International HLA and Immunogenetics Workshop cell lines.

The hyperpolymorphic HLA genes play important roles in disease and transplantation and act as genetic markers of migration and evolution. A panel of 107 B-lymphoblastoid cell lines (B-LCLs) was established in 1987 at the 10th International Histocompatibility Workshop as a resource for the immunogenetics community. These B-LCLs are well characterised and represent diverse ethnicities and HLA haplotypes. Here we have applied Pacific Biosciences' Single Molecule Real-Time (SMRT) DNA sequencing to HLA type 126 B-LCL, including the 107 International HLA and Immunogenetics Workshop (IHIW) cells, to ultra-high resolution. Amplicon sequencing of full-length HLA class I genes (HLA-A, -B and -C) and partial length HLA class II genes (HLA-DRB1, -DQB1 and -DPB1) was performed. We typed a total of 931 HLA alleles, 895 (96%) of which were consistent with the typing in the IPD-IMGT/HLA Database (Release 3.27.0, January 20, 2017), with 595 (64%) typed at a higher resolution. Discrepant types, including novel alleles (n = 10) and changes in zygosity (n = 13), as well as previously unreported types (n = 34) were observed. In addition, patterns of linkage disequilibrium were distinguished by four-field resolution typing of HLA-B and HLA-C. By improving and standardising the HLA typing of these B-LCLs, we have ensured their continued usefulness as a resource for the immunogenetics community in the age of next generation DNA sequencing.

Neonatal fatty acid profiles are correlated with infant growth measures at 6 months.

Rapid weight gain in infancy and low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA) at birth are associated with increased adiposity later in life. The association between placental LCPUFA delivery and weight gain in infancy is poorly understood. We sought to determine the relationships between maternal phenotype, placental fatty acid transporter expression and offspring growth patterns over the first 6 months. Placental tissue and cord blood were collected at term delivery from women with uncomplicated pregnancies. Offspring body composition measurements were recorded 1 day and 6 months after birth. Body mass index (BMI) z-scores were determined using World Health Organization 2006 reference data. Body phenotype patterns were compared among offspring who had an increase in BMI z-score and those who had a decrease. High skinfold thickness at birth and positive change in BMI z-scores during infancy were associated with low neonatal n-3 LCPUFA plasma levels (r=-0.46, P=0.046) and high saturated fatty acids levels (r=0.49, P=0.034). Growth of skinfolds over 6 months of age was associated with placental fatty acid transporter gene expression. Change in BMI z-score in the first 6 months of life correlated with arm muscle area growth, a measure of lean mass (r=0.62, P=0.003), but not with growth in skinfold thickness. Early infancy weight gain was associated with poor plasma LCPUFA status at birth, and fat deposition in infancy was related to changes in placental lipid handling. Thus, neonatal fatty acid profiles may influence the trajectory of infant growth and fat and lean mass deposition.

Late preterm birth, post-term birth, and abnormal fetal growth as risk factors for severe mental disorders from early to late adulthood.

BACKGROUND: Late preterm births constitute the majority of preterm births. However, most evidence suggesting that preterm birth predicts the risk of mental disorders comes from studies on earlier preterm births. We examined if late preterm birth predicts the risks of severe mental disorders from early to late adulthood. We also studied whether adulthood mental disorders are associated with post-term birth or with being born small (SGA) or large (LGA) for gestational age, which have been previously associated with psychopathology risk in younger ages. METHOD: Of 12 597 Helsinki Birth Cohort Study participants, born 1934-1944, 664 were born late preterm, 1221 post-term, 287 SGA, and 301 LGA. The diagnoses of mental disorders were identified from national hospital discharge and cause of death registers from 1969 to 2010. In total, 1660 (13.2%) participants had severe mental disorders. RESULTS: Individuals born late preterm did not differ from term-born individuals in their risk of any severe mental disorder. However, men born late preterm had a significantly increased risk of suicide. Post-term birth predicted significantly increased risks of any mental disorder in general and particularly of substance use and anxiety disorders. Individuals born SGA had significantly increased risks of any mental and substance use disorders. Women born LGA had an increased risk of psychotic disorders. CONCLUSIONS: Although men born late preterm had an increased suicide risk, late preterm birth did not exert widespread effects on adult psychopathology. In contrast, the risks of severe mental disorders across adulthood were increased among individuals born SGA and individuals born post-term.

Maternal hypertensive disorders during pregnancy: adaptive functioning and psychiatric and psychological problems of the older offspring.

OBJECTIVE: To study whether pre-eclampsia and hypertension without proteinuria during pregnancy are associated with adaptive functioning, and psychiatric and psychological problems, of older offspring. DESIGN: Retrospective longitudinal cohort study. SETTING: Participants in the Helsinki Birth Cohort 1934-44 Study. POPULATION: A cohort of 778 participants born after normotensive, pre-eclamptic, or hypertensive pregnancies, defined based on the mother's blood pressure and urinary protein measurements at maternity clinics and birth hospitals. METHODS: Pearson's chi-squared tests and multivariable logistic regression. MAIN OUTCOME MEASURES: Achenbach System of Empirically Based Assessment Older Adult Self-Report scores, completed at age 69.3 years (SD 3.1 years). RESULTS: Compared with offspring born after normotensive pregnancies, offspring born after pre-eclamptic pregnancies had increased odds of reporting total problems (aOR 4.00, 95%CI 1.64-9.77) and problems of particular concern to clinicians (critical items; aOR 5.28, 95%CI 1.87-14.96), as well as: anxious/depressed, functional impairment, memory, thought, and irritable/disinhibited problems on syndrome scales; depressive, somatic, and psychotic problems on Diagnostic and Statistical Manual of Mental Disorders scales; and adjustment problems in relationship satisfaction with spouse/partner. Maternal hypertension without proteinuria was not consistently associated with adjustment and problems (total problems, aOR 1.08, 95%CI 0.75-1.57; critical items, aOR 1.58, 95%CI 0.91-2.72). CONCLUSIONS: Maternal hypertensive disorders in pregnancy, during a period of expectant treatment, carry an increased risk of problems in adaptive functioning and mental wellbeing in the offspring seven decades later. Being the longest follow-up on transgenerational consequences of maternal hypertensive disorders reported thus far, our study points to the life-time increased risk of an adverse intrauterine environment.

Sex differences in regional specialisation across the placental surface.

There may be regional specialisation in structure and function across the placental surface. In Riyadh, Saudi Arabia, the length and the breadth of the placental surface at birth were highly correlated, but the breadth was more closely associated with the size of the baby. To replicate this we studied 321 pregnant Saudi women in the town of Baish. We measured the size of the newborn babies and their placentas. The association of the length and breadth of the placental surface on the baby's body size differed in boys and girls. Among boys the breadth had a stronger association with all birth measurements except crown-heel length. This was similar to the findings in Riyadh. Placental surface length was related to crown-heel length. For each centimetre in surface length, crown-heel length increased by 0.27 cm (95% CI 0.09-0.44, p = 0.004). Among girls placental surface breadth was related to crown-heel length, whereas surface length was related to birth weight, head and thigh circumferences. For each centimetre in surface breadth, crown-heel length increased by 0.33 cm (0.13-0.53, p = 0.001). We conclude that, within Saudi Arabia, there are both geographical and sex differences in regional specialisation across the placental surface. In the adverse circumstances of Baish, linked to the mothers' short stature, boys were smaller at birth than girls. Boys may have compensated for under-nutrition by increasing the depth of spiral artery invasion rather than by recruiting additional spiral arteries. Girls may have had more effective regional specialisation across the placental surface.

Small head circumference at birth and early age at adiposity rebound.

AIMS: The adiposity rebound is the age in childhood when body mass index is at a minimum before increasing again. The age at rebound is highly variable. An early age is associated with increased obesity in later childhood and adult life. We have reported that an early rebound is predicted by low weight gain between birth and 1 year of age and resulting low body mass index at 1 year. Here, we examine whether age at adiposity rebound is determined by influences during infancy or is a consequence of foetal growth. Our hypothesis was that measurements of body size at birth are related to age at adiposity rebound. METHODS: Longitudinal study of 2877 children born in Helsinki, Finland, during 1934-1944. RESULTS: Early age at adiposity rebound was associated with small head circumference and biparietal diameter at birth, but not with other measurements of body size at birth. The mean age at adiposity rebound rose from 5.8 years in babies with a head circumference of ≤33 cm to 6.2 in babies with a head circumference of >36 cm (P for trend = 0.007). The association between thinness in infancy and early rebound became apparent at 6 months of age. It was not associated with adverse living conditions. In a simultaneous regression, small head circumference at birth, high mother's body mass index and tall maternal stature each had statistically significant trends with early adiposity rebound (P = 0.002, <0.001, 0.004). CONCLUSION: We hypothesize that the small head size at birth that preceded an early adiposity rebound was the result of inability to sustain a rapid intra-uterine growth trajectory initiated in association with large maternal body size. This was followed by catch-up growth in infancy, and we hypothesize that this depleted the infant's fat stores.

Placental programming of chronic diseases, cancer and lifespan: a review.

Particular paths of fetal growth are now known to predict a range of disorders in adult life. This is thought to reflect fetal programming, the phenomenon whereby nutrition and other influences during development set the body's organs and systems for life. The thesis of this review is that normal variations in the processes of placental development lead to variations in the supply of nutrients to the fetus and programme a small number of key systems that are linked to later disease. A baby's growth and nutrition depend both on the function of the placenta, reflected in its gross morphology at birth, and on the mother's lifetime nutrition, reflected in her height and weight. In many studies, the effects of placental size and shape on later disease have been examined within different categories of mother's body size. The review shows that variations in gross placental morphology at birth predict a wide range of disorders in later life. Any particular placental phenotype seems to predict a limited number of diseases. Further research into the links between the processes of placentation and the morphology of the placenta at birth is now required. We need to know more about the relative importance of nutrient flow, nutrient balance and the timing of nutritional events in determining disorders in later life. We also need to understand why, compared to other placental mammals, the human placenta is so variable in its morphology and functional capacity.

Intergenerational effects of in utero exposure to Ramadan in Tunisia.

UNLABELLED: We have reported that changes in the lifestyle of pregnant women during Ramadan affect more than one generation. In a series of newborn babies in Saudi Arabia, those whose mothers had been in utero during Ramadan differed from those whose mothers had not been in utero during Ramadan. These were unexpected findings and require replication. METHODS: We examined body size at birth in 1,321 babies (682 boys and 639 girls) born in Gafsa, a small city in Tunisia. RESULTS: Babies whose mothers had been in utero during Ramadan were smaller and thinner, and had smaller placentas, than those whose mothers had not been in utero during Ramadan. After adjustment for sex, the babies were 93 g lighter (95% confidence interval, 32-153, P=0.003) than those whose mother had not been in utero during Ramadan, their mean ponderal index was 0.52 kg/m(3) lower (0.24-0.79, P<0.001) and their placental weight was 21 g lower (5-37, P=0.01). The findings did not differ by trimester of maternal exposure to Ramadan. They were similar in boys and girls and in primiparous and multiparous mothers CONCLUSION: This study provides further evidence that changes in lifestyle during Ramadan have intergenerational effects.

Early life stress and blood pressure levels in late adulthood.

Severe stress experienced in early life may have long-term consequences on adult physiological functions. We studied the long-term effects of separation on blood pressure levels in non-obese subjects who were separated temporarily in childhood from their parents during World War II (WWII). The original clinical study cohort consists of people born during 1934-1944 in Helsinki, Finland. This substudy includes 1361 non-obese subjects (body mass index <30 kg m(-2)). Of these, 192 (14.1%) had been evacuated abroad during WWII. The remaining subjects served as controls. Blood pressure levels and use of blood pressure medication were studied. The separated subjects had significantly higher systolic blood pressure values than the non-separated (148.6+21.5 vs 142.2+19.6 mm Hg, P<0.0001) in adult life. Those subjects separated in early childhood had markedly higher systolic and diastolic blood pressure values in adult life compared with the non-separated (154.6 vs 142.5 mm Hg; 95% confidence interval (CI) 2.6-14.7; P<0.005 and 90.8 vs 87.7 mm Hg; 95% CI 1.0-7.3; P<0.02, respectively). Systolic blood pressure was also higher in the group separated for a duration of <1 year (151.7 vs 142.2 mm Hg; 95% CI 0.0-12.4; P<0.05) compared with the non-separated. Besides being separated, age at separation and duration of separation also influenced blood pressure levels in adult life. This could be due to early hormonal and metabolic programming, during plastic periods in early life, influencing blood pressure levels in adult life.

Resource allocation in utero and health in later life.

The way that a fetus obtains and allocates nutritional resources has profound consequences for its life-long health. Under the new developmental model for the origins of chronic disease, the causes to be identified are linked to normal variations in the processes of feto-placental development, that are associated with differences in the supply of nutrients to the baby. These differences programme the function of a few key systems that are linked to chronic disease, including the immune system, anti-oxidant defences, inflammation, and the number and quality of stem cells. There is not a separate cause for each different disease. Which chronic disease originates during development may depend more on timing than on qualitative differences in experience.

The breadth of the placental surface but not the length is associated with body size at birth.

Studies of pregnancies complicated by preeclampsia led to the suggestion that the surface of the placenta is aligned along two axes, measured by its breadth and length. It was hypothesised that tissue along the breadth serves as a nutrient sensor, responding to the mother's nutritional state and fetal nutritional demands, while tissue along the length has different functions. To develop this hypothesis we measured the breadth and length of the placental surface in 401 neonates born in the King Khalid Hospital, Riyadh, Saudi Arabia, and related these measurements to the baby's body size. The breadth and length of the placental surface were highly correlated (coefficient = 0.7). Nevertheless, in a simultaneous regression with both measurements, only the breadth was associated with neonatal body size. There were strong trends of increasing birth weight, ponderal index, and the circumferences of the head, chest, abdomen and thigh with increasing placental breadth. In contrast no measurement of baby's body size was related to placental length. Birth weight increased by 125 g per cm increase in placental breadth (95% confidence interval 88 to 162, p < 0.001) but only by 20 g per cm increase in placental length (-13 to 53, p = 0.2). The corresponding figures for head circumference were 0.28 cm (0.17-0.39, p < 0.001) and 0.03 (-0.07 to 0.14, p = 0.5). The associations between placental breadth and neonatal body size were strongest if the mother's height was below the median (157 cm). The associations between a larger breadth of the placental surface and a larger baby are consistent with the hypothesis that tissue along the breadth plays a key role in nutrient transfer from mother to baby. Mothers who are short in stature are known to have lower rates of protein turnover in pregnancy. In these circumstances the ability of the placenta to transfer amino acids to the fetus may be critical.

Immune response gene profiles in the term placenta depend upon maternal muscle mass.

Maternal thinness leads to metabolic challenges in the offspring, but it is unclear whether reduced maternal fat mass or muscle mass drives these metabolic changes. Recently, it has been shown that low maternal muscle mass--as measured by arm muscle area (AMA)--is associated with depressed nutrient transport to the fetus. To determine the role of maternal muscle mass on placental function, we analyzed the gene expression profiles of 30 human placentas over the range of AMA (25.2-90.8 cm(2)) from uncomplicated term pregnancies from the Southampton Women's Survey cohort. Eighteen percent of the ∼60 genes that were highly expressed in less muscular women were related to immune system processes and the interferon-γ (IFNG) signaling pathway in particular. Those transcripts related to the IFNG pathway included IRF1, IFI27, IFI30, and GBP6. Placentas from women with low muscularity are, perhaps, more sensitive to the effects of inflammatory cytokines than those from more muscular women.

Sir Richard Doll Lecture. Developmental origins of chronic disease.

Coronary heart disease, type 2 diabetes, breast cancer and many other chronic diseases are unnecessary. Their occurrence is not mandated by genes passed down to us through thousands of years of evolution. Chronic diseases are not the inevitable lot of humankind. They are the result of the changing pattern of human development. We could readily prevent them, had we the will to do so. Prevention of chronic disease, and an increase in healthy ageing require improvement in the nutrition of girls and young women. Many babies in the womb in the Western world today are receiving unbalanced and inadequate diets. Many babies in the developing world are malnourished because their mothers are chronically malnourished. Protecting the nutrition and health of girls and young women should be the cornerstone of public health. Not only will this prevent chronic disease, but it will produce new generations who have better health and well-being through their lives.

Enhanced beta cell proliferation in mice overexpressing a constitutively active form of Akt and one allele of p21Cip.

AIMS/HYPOTHESIS: The ability of pancreatic beta cells to proliferate is critical both for normal tissue maintenance and in conditions where there is an increased demand for insulin. Protein kinase B(Akt) plays a major role in promoting proliferation in many cell types, including the insulin-producing beta cells. We have previously reported that mice overexpressing a constitutively active form of Akt(caAkt (Tg)) show enhanced beta cell proliferation that is associated with increased protein levels of cyclin D1, cyclin D2 and cyclin-dependent kinase inhibitor 1A (p21(Cip)). In the present study, we sought to assess the mechanisms responsible for augmented p21(Cip) levels in caAkt(Tg) mice and test the role of p21(Cip) in the proliferative responses induced by activation of Akt signalling. METHODS: To gain a greater understanding of the relationship between Akt and p21(Cip), we evaluated the mechanisms involved in the modulation of p2(Cip) by Akt and the in vivo role of reduced p21(Cip) in proliferative responses induced by Akt. RESULTS: Our experiments showed that Akt signalling regulates p21(Cip) transcription and protein stability. caAkt(Tg) /p21(Cip+/-) mice exhibited fasting and fed hypoglycaemia as well as hyperinsulinaemia when compared with caAkt(Tg) mice. Glucose tolerance tests revealed improved glucose tolerance in caAkt(Tg)/p21(Cip+/-) mice compared with caAkt (Tg). These changes resulted from increased proliferation, survival and beta cell mass in caAkt(Tg)/p21(Cip+/-) compared with caAkt(Tg) mice. CONCLUSIONS/INTERPRETATION: Our data indicate that increased p21(Cip) levels in caAkt(Tg) mice act as a compensatory brake, protecting beta cells from unrestrained proliferation. These studies imply that p21(Cip) could play important roles in the adaptive responses of beta cells to proliferate in conditions such as in insulin resistance.

Inputs and losses by surface runoff and subsurface leaching for pastures managed by continuous or rotational stocking.

Pasture management practices can affect forage quality and production, animal health and production, and surface and groundwater quality. In a 5-yr study conducted at the North Appalachian Experimental Watershed near Coshocton, Ohio, we compared the effects of two contrasting grazing methods on surface and subsurface water quantity and quality. Four pastures, each including a small, instrumented watershed (0.51-1.09 ha) for surface runoff measurements and a developed spring for subsurface flow collection, received 112 kg N ha(-1) yr(-1) and were grazed at similar stocking rates (1.8-1.9 cows ha(-1)). Two pastures were continuously stocked; two were subdivided so that they were grazed with frequent rotational stocking (5-6 times weekly). In the preceding 5 yr, these pastures received 112 kg N ha(-1) yr(-1) after several years of 0 N fertilizer and were grazed with weekly rotational stocking. Surface runoff losses of N were minimal. During these two periods, some years had precipitation up to 50% greater than the long-term average, which increased subsurface flow and NO(3)-N transport. Average annual NO(3)-N transported in subsurface flow from the four watersheds during the two 5-yr periods ranged from 11.3 to 22.7 kg N ha(-1), which was similar to or less than the mineral-N received in precipitation. Flow and transport variations were greater among seasons than among watersheds. Flow-weighted seasonal NO(3)-N concentrations in subsurface flow did not exceed 7 mg L(-1). Variations in NO(3)-N leached from pastures were primarily due to variable precipitation rather than the effects of continuous, weekly rotational, or frequent rotational stocking practices. This suggests that there was no difference among these grazing practices in terms of NO(3)-N leaching.

Growth from birth to adulthood and peak bone mass and density data from the New Delhi Birth Cohort.

UNLABELLED: Growth in early life may predict adult bone health. Our data showed that greater height and body mass index (BMI) gain in utero and infancy are associated with higher peak bone mass, and greater BMI gain in childhood/adolescence with higher peak bone density. These associations are mediated by attained adult height and BMI. INTRODUCTION: To study the relationship of height and BMI during childhood with adult bone mineral content (BMC), areal density (aBMD) and apparent density (BMAD, estimated volumetric density). METHODS: Participants comprised 565 men and women aged 33-39 years from the New Delhi Birth Cohort, India, whose weight and height were recorded at birth and annually during infancy (0-2 years), childhood (2-11 years) and adolescence (11 years-adult). Lumbar spine, femoral neck and forearm BMC and aBMD were measured using dual X-ray absorptiometry; lumbar spine and femoral neck BMAD were calculated. RESULTS: Birth length, and height and height gain during infancy, childhood and adolescence were positively correlated with adult BMC (p≤0.01 all sites except birth length with femoral neck). Correlations increased with height from birth to 6 years, then remained constant for later height measurements. There were no associations with BMAD. BMI at birth, and during childhood and adolescence was also positively correlated with BMC (p < 0.01 all sites). BMI at 11 years, and BMI gain in childhood and adolescence, were correlated with aBMD and BMAD (p < 0.001 for all); these correlations strengthened with increasing age of BMI measurement. The associations with height and BMI in early life became non-significant after adjustment for adult height and BMI. CONCLUSIONS: Greater skeletal growth and BMI gain in utero and during infancy are associated with higher peak BMC, and greater BMI gain in childhood and adolescence is associated with higher peak aBMD and BMAD. These associations are mediated by the attainment of adult height and BMI, respectively.

OS103. Hypertensive disorders during pregnancy and cognitive decline of the offspring up to old age: the helsinki birth cohort study.

INTRODUCTION: Hypertensive disorders affect the fetal developmental milieu and may point to mechanisms by which prenatal adversity is associated with lower cognitive ability in subsequent life. OBJECTIVES: We tested whether hypertensive disorders during pregnancy predict age-related change in cognitive ability in the offspring up to old age. METHODS: Using mothers' blood pressure and urinary protein measurements from the maternity clinics and birth hospitals, we defined normotensive or hypertensive pregnancies in mothers of 398 men, who participated in the Helsinki Birth Cohort 1934-44 Study. The men underwent the Finnish Defense Forces basic ability test twice, first, during compulsory military service at age 20.1 (SD=1.4) years and, then, in a re-test at age 68.5 (SD=2.9) years. The test yields a total score and subscores for tests measuring verbal, arithmetic and visuospatial reasoning. Scores were standardized with a mean of 100 and standard deviation of 15. RESULTS: Men born after pregnancies complicated by a hypertensive disorder, compared with men born after normotensive pregnancies, scored 3.84 (95% Confidence Interval, 0.77 to 6.91) points lower on total cognitive ability at 68.5 years, and displayed a greater decline in total cognitive ability (2.31, 0.23 to 4.39) after 20.1 years. Of the subscores, associations were strongest for arithmetic reasoning. CONCLUSION: Maternal hypertensive disorders in pregnancy predict lower cognitive ability and greater cognitive decline up to old age. Multidisciplinary research is essential in order to uncover the mechanisms linking hypertensive pregnancy disorders with lower cognitive abilities in the offspring.