Breastfeeding, the use of docosahexaenoic acid-fortified formulas in infancy and neuropsychological function in childhood.

OBJECTIVE: To investigate the relation between breastfeeding, use of docosahexaenoic acid (DHA)-fortified formula and neuropsychological function in children. DESIGN: Prospective cohort study. SETTING: Southampton, UK. SUBJECTS: 241 children aged 4 years followed up from birth. MAIN OUTCOME MEASURES: IQ measured by the Wechsler Pre-School and Primary Scale of Intelligence (3rd edn), visual attention, visuomotor precision, sentence repetition and verbal fluency measured by the NEPSY, and visual form-constancy measured by the Test of Visual-Perceptual Skills (Non-Motor). RESULTS: In unadjusted analyses, children for whom breast milk or DHA-fortified formula was the main method of feeding throughout the first 6 months of life had higher mean full-scale and verbal IQ scores at age 4 years than those fed mainly unfortified formula. After adjustment for potential confounding factors, particularly maternal IQ and educational attainment, the differences in IQ between children in the breast milk and unfortified formula groups were severely attenuated, but children who were fed DHA-fortified formula had full-scale and verbal IQ scores that were respectively 5.62 (0.98 to 10.2) and 7.02 (1.56 to 12.4) points higher than children fed unfortified formula. However, estimated total intake of DHA in milk up to age 6 months was not associated with subsequent IQ or with score on any other test. CONCLUSIONS: Differences in children's intelligence according to type of milk fed in infancy may be due more to confounding by maternal or family characteristics than to the amount of long-chain polyunsaturated fatty acids they receive in milk.

Myopia and polymorphisms in genes for matrix metalloproteinases.

PURPOSE: To investigate the relation between myopia and variations in three genes coding for matrix metalloproteinases, enzymes that degrade matrix proteins and modulate scleral extensibility. METHODS: Three hundred sixty-six men and women, from Sheffield, United Kingdom, were genotyped for the 1G/2G polymorphism in the MMP-1 gene, the 5A/6A polymorphism in the MMP-3 gene and the Arg-->Gln polymorphism in exon 6 of the MMP-9 gene and assessed for refractive error. RESULTS: Risk of myopia was increased in people homozygous for the 5A allele of the MMP-3 gene (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-9.0) compared to those who were homozygous for the 6A allele, and in people homozygous for the Gln allele in exon 6 of the MMP-9 gene (OR, 2.8; 95% CI, 1.1-7.0) compared to those who were homozygous for the Arg allele. People who were homozygous for the 2G allele of the MMP-1 gene had an odds ratio for myopia of 2.3 (95% CI, 0.9-6.1), compared with those who were homozygous for the 1G allele, although this relation did not reach statistical significance. Risk of myopia increased progressively with the dose of these three alleles, showing a greater than 10-fold difference across the range. CONCLUSIONS: The results suggest that common variations in three of the genes that control breakdown of matrix proteins in the sclera may contribute to the development of simple myopia.

Dietary patterns in infancy and cognitive and neuropsychological function in childhood.

BACKGROUND: Trials in developing countries suggest that improving young children's diet may benefit cognitive development. Whether dietary composition influences young children's cognition in developed countries is unclear. Although many studies have examined the relation between type of milk received in infancy and subsequent cognition, there has been no investigation of the possible effect of variations in the weaning diet. METHODS: We studied 241 children aged 4 years, whose diet had been assessed at age 6 and 12 months. We measured IQ with the Wechsler Pre-School and Primary Scale of Intelligence, visual attention, visuomotor precision, sentence repetition and verbal fluency with the Developmental Neuropsychological Assessment (NEPSY), and visual form-constancy with the Test of Visual Perceptual Skills. RESULTS: In sex-adjusted analyses, children whose diet in infancy was characterised by high consumption of fruit, vegetables and home-prepared foods ('infant guidelines' dietary pattern) had higher full-scale and verbal IQ and better memory performance at age 4 years. Further adjustment for maternal education, intelligence, social class, quality of the home environment and other potential confounding factors attenuated these associations but the relations between higher 'infant guidelines' diet score and full-scale and verbal IQ remained significant. For a standard deviation increase in 'infant guidelines' diet score at 6 or 12 months full-scale IQ rose by .18 (95% CI .04 to .31) of a standard deviation. For a standard deviation increase in 'infant guidelines' diet score at 6 months verbal IQ rose by .14 (.01 to .27) of a standard deviation. There were no associations between dietary patterns in infancy and 4-year performance on the other tests. CONCLUSIONS: These findings suggest that dietary patterns in early life may have some effect on cognitive development. It is also possible that they reflect the influence of unmeasured confounding factors.

Grip strength, body composition, and mortality.

BACKGROUND: Several studies in older people have shown that grip strength predicts all-cause mortality. The mechanisms are unclear. Muscle strength declines with age, accompanied by a loss of muscle mass and an increase in fat, but the role that body composition plays in the association between grip strength and mortality has been little explored. We investigated the relation between grip strength, body composition, and cause-specific and total mortality in 800 men and women aged 65 and over. METHODS: During 197374 the UK Department of Health and Social Security surveyed random samples of men and women aged 65 and over living in eight areas of Britain to assess the nutritional state of the elderly population. The survey included a clinical examination by a geriatrician who assessed grip strength and anthropometry. We used Cox proportional hazards models to examine mortality over 24 years of follow-up. RESULTS: Poorer grip strength was associated with increased mortality from all-causes, from cardiovascular disease, and from cancer in men, though not in women. After adjustment for potential confounding factors, including arm muscle area and BMI, the relative risk of death in men was 0.81 (95% CI 0.700.95) from all-causes, 0.73 (95% CI 0.600.89) from cardiovascular disease, and 0.81 (95% CI 0.660.98) from cancer per SD increase in grip strength. These associations remained statistically significant after further adjustment for fat-free mass or % body fat. CONCLUSION: Grip strength is a long-term predictor of mortality from all-causes, cardiovascular disease, and cancer in men. Muscle size and other indicators of body composition did not explain these associations.

The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years.

OBJECTIVE: We investigated the effects of head growth prenatally, during infancy, and during later periods of development on cognitive function at the ages of 4 and 8 years. METHODS: We studied 633 term-born children from the Avon Longitudinal Study of Parents and Children cohort whose head circumference was measured at birth and at regular intervals thereafter. Their cognitive function was assessed with the Wechsler Preschool and Primary Scale of Intelligence at the age of 4 years and with the Wechsler Intelligence Scale for Children at the age of 8 years. Linear regression analysis was used to calculate postnatal head growth between successive time points, conditional on previous size, and to examine the relationship between head growth during different periods of development and later IQ. RESULTS: When the influence of head growth was distinguished for different periods, only prenatal growth and growth during infancy were associated with subsequent IQ. At 4 years, after adjustment for parental characteristics, full-scale IQ increased an average of 2.41 points for each 1-SD increase in head circumference at birth and 1.97 points for each 1-SD increase in head growth during infancy, conditional on head size at birth. At 8 years, head circumference at birth was no longer associated with IQ, but head growth during infancy remained a significant predictor, with full-scale IQ increasing an average of 1.56 points for each 1-SD increase in growth. CONCLUSION: The brain volume a child achieves by the age of 1 year helps determine later intelligence. Growth in brain volume after infancy may not compensate for poorer earlier growth.

Maternal diet during pregnancy and carotid intima-media thickness in children.

OBJECTIVE: Autopsy studies show that intimal lipid accumulations in arteries are often present at birth, suggesting that the prenatal environment plays a role in the pathogenesis of atherosclerosis. In animal models, a restricted or unbalanced maternal diet during gestation can influence susceptibility to atherosclerosis, but the relation in humans between maternal diet during pregnancy and atherogenesis is unknown. METHODS AND RESULTS: We measured carotid intima-media thickness (IMT) in 216 nine-year-old children whose mothers had participated in a study of nutrition during pregnancy. IMT was greater in boys, in children who were heavier, in those with higher systolic blood pressure, and in those who took less exercise. Increased IMT was associated with a lower maternal energy intake in early (P=0.029) or late (P=0.006) pregnancy, after adjustment for these factors. Mean IMT of children whose mothers were in the lowest quarter of the distribution of energy intake in late pregnancy was 0.027 mm (95% confidence interval, 0.004 to 0.049) greater than that of those whose mothers were in the highest quarter of the distribution. CONCLUSIONS: Lower maternal energy intake during pregnancy may increase the susceptibility to atherogenesis of the child.

Birth weight and cardiac structure in children.

OBJECTIVE: Epidemiologic studies have shown associations between impaired fetal growth and risk for coronary heart disease in adults. The underlying mechanisms are unknown. We investigated whether restricted intrauterine growth affects cardiac structure. METHODS: We performed echocardiography on 216 9-year-old children who were measured previously at birth. The diameter of the coronary left and right main branches was derived from the widest dimension; total coronary artery diameter was calculated by adding the diameters of the left and right coronary arteries. Aortic root diameter, left atrial diameter, left ventricular diameter, left ventricular outflow tract diameter, and left ventricular mass were measured. RESULTS: On average, children who had weighed less at birth had a smaller total coronary artery diameter, aortic root diameter, and left ventricular outflow tract diameter after adjustment for gender, gestational age, current height and weight, and maternal height and prepregnant weight. For each SD increase in birth weight, total coronary diameter rose by 0.10 mm, log aortic root diameter rose by 1.5%, and log left ventricular outflow tract diameter rose by 1.6%. CONCLUSION: Impaired fetal growth may have long-term effects on cardiac structure. This may help to explain why adults whose birth weight was low are at greater risk for coronary heart disease.

Circulating levels of MCP-1 and eotaxin are not associated with presence of atherosclerosis or previous myocardial infarction.

The chemokines are a family of signalling proteins that participate in regulation of the immune system and have been implicated in the pathogenesis of vascular diseases. Deleting the gene encoding the chemokine MCP-1 in mouse models of atherosclerosis reduces lipid lesion formation and circulating chemokines are upregulated in man immediately following myocardial infarction (MI) or coronary angioplasty. We have therefore investigated whether circulating levels of two chemokines (MCP-1 and eotaxin) differ between subjects with and without atherosclerosis. We have used three different methods of measuring the presence and extent of atherosclerosis in human subjects: duplex ultrasonography of the carotid arteries and clinical diagnosis of coronary heart disease on individuals from the general population and coronary angiography on patients with suspected heart disease. There was no difference in the levels of circulating MCP-1 or eotaxin, measured by ELISA, between subjects with and without atherosclerosis. Furthermore, any increase in circulating MCP-1 following acute MI must be short-lived, since chemokine levels were not different in subjects who had had an MI previously compared to those who had not. We conclude that although there may be a transient increase in circulating chemokine levels following coronary angioplasty, there is no difference in the levels of circulating MCP-1 or eotaxin in subjects with and without atherosclerosis.

An epidemiological study of renal pathology in tuberous sclerosis complex.

OBJECTIVES: To report the frequency of renal symptoms and complications of patients with tuberous sclerosis complex (TSC), to describe the ultrasonographic appearance of the kidneys in a population-based sample, and to investigate the relationship between a history of renal haemorrhage and renal lesions identified by ultrasonography. PATIENTS AND METHODS: As part of an epidemiological study, 179 patients with TSC were identified as living in the Wessex Region in the South of England. Patients were interviewed and examined in their homes, to elicit the presence of renal symptoms or a history of renal complications. Renal ultrasonography was used in consenting patients in their homes. RESULTS: There was a history of renal complications in 16 (9%) patients; 149 consented to interview and examination, and 19 gave a history of renal symptoms in the previous year; 124 had renal ultrasonography; 86 (69%) had renal angiomyolipomas and 37 (30%) had renal cysts. Large lesions (>3 cm in diameter) were strongly associated with a history of symptomatic bleeding, although significant haemorrhage occurred in a 6-year-old child with small angiomyolipomas. CONCLUSIONS: The formation of angiomyolipoma in TSC is common. Polycystic kidney disease, renal carcinoma and renal failure, although rare, occur in TSC. Most patients with angiomyolipomas have neither complications nor symptoms. There was no appreciable difference between the sexes in the risk of developing these lesions. Although less commonly seen in the very young, there is no identifiable relationship after adolescence between age and the risk of having a renal angiomyolipoma. Bleeding tends to occur from large lesions (>3 cm) but most such patients have remained asymptomatic to date.

Birth weight and later risk of depression in a national birth cohort.

BACKGROUND: Low birth weight increases the risk of childhood behavioural problems, but it is not clear whether poor foetal growth has a long-term influence on susceptibility to depression. AIMS: To examine the relation between birth weight and risk of psychological distress and depression. METHOD: At age 16 years 5187 participants in the 1970 British Cohort Study completed the 12-item General Health Questionnaire to assess psychological distress. At age 26 years 8292 participants completed the Malaise Inventory to assess depression and provided information about a history of depression. RESULTS: Women whose birth weight was 3.5 kg. Birth weight was not associated with a reported history of depression or with risk of psychological distress at age 16 years. In men there were no associations between any measurement and the full range of birth weight but, compared with men of normal birth weight, those born weighing

Critical periods of brain growth and cognitive function in children.

There is evidence that IQ tends to be higher in those who were heavier at birth or who grew taller in childhood and adolescence. Although these findings imply that growth in both foetal and postnatal life influences cognitive performance, little is known about the relative importance of brain growth during different periods of development. We investigated the relationship between brain growth in different periods of pre- and postnatal life and cognitive function in 221 9-year-old children whose mothers had taken part in a study of nutrition in pregnancy and whose head circumference had been measured at 18 weeks gestation, birth and 9 months of age. Cognitive function of the children and their mothers was assessed with the Wechsler Abbreviated Scale of Intelligence. Full-scale IQ at age 9 years rose by 1.98 points [95% confidence interval (CI) 0.34 to 3.62] for each SD increase in head circumference at 9 months and by 2.87 points (95% CI 1.05 to 4.69) for each SD increase in head circumference at 9 years of age, after adjustment for sex, number of older siblings, maternal IQ, age, education, social class, duration of breastfeeding and history of low mood in the post-partum period. Postnatal head growth was significantly greater in children whose mothers were educated to degree level or of higher socio-economic status. There was no relation between IQ and measurements of head size at 18 weeks gestation or at birth. These results suggest that brain growth during infancy and early childhood is more important than growth during foetal life in determining cognitive function.

Variation in the matrix metalloproteinase-1 gene and risk of coronary heart disease.

AIMS: Matrix metalloproteinase-1 (MMP-1), a proteolytic enzyme able to degrade types I and III collagens, is present in atherosclerotic lesions but absent from the normal blood vessel wall. The recent observation that, in a transgenic mouse model, MMP-1 gene expression slows the development and progression of atherosclerotic plaques suggests that it may play a role in human atherogenesis. We investigated whether coronary heart disease was associated with a functional polymorphism in the human MMP-1 gene. In addition, we examined a polymorphism in the human MMP-3 gene that was previously reported to be associated with progression of coronary atherosclerosis. METHODS AND RESULTS: We genotyped 471 Caucasian men and women, aged 66-75 years, from Sheffield, UK, for the 1G/2G polymorphism in the MMP-1 gene and the 5A/6A polymorphism in the MMP-3 gene and ascertained the prevalence of coronary heart disease. People homozygous for the more transcriptionally active 2G allele of the MMP-1 gene had a reduced risk of coronary heart disease (OR 0.5, 95% CI 0.3 to 0.9) compared to people homozygous for the less transcriptionally active 1G allele. Heterozygotes had an intermediate risk (OR 0.7, 95% CI, 0.5 to 1.1). We found no association between the 5A/6A polymorphism in the MMP-3 gene and risk of coronary heart disease. CONCLUSION: Sequence variants at the MMP-1 genomic locus may influence risk of coronary heart disease in humans.

Foetal and postnatal head growth and risk of cognitive decline in old age.

Studies of elderly people have shown that scores on tests of cognitive function tend to be higher in those with larger head circumferences. One explanation for these findings is that optimal brain development in utero and in the first years of life may protect against cognitive decline in old age, though the relative importance of these two periods of brain growth is unclear. We assessed change in cognitive function over a 3.5-year period in 215 men and women aged 66-75 years whose head circumference had been recorded at birth and as adults. Cognitive function was tested in the initial study and at follow-up with the AH4 intelligence test and the Wechsler Logical Memory test. We found no associations between head circumference at birth and score on the cognitive function tests or change in score over time. However, people who had a larger head circumference as an adult gained significantly higher scores on the intelligence test on both testing occasions and were less likely to show a decline in memory performance over the follow-up period. People whose head circumference was in the top quarter of the distribution had an odds ratio for decline in immediate recall on the Logical Memory test of 0.2 (95% confidence interval 0.1-0.6) and an odds ratio for decline in delayed recall of 0.3 (95% confidence interval 0.1-0.9) compared with those whose head circumference was in the bottom quarter, after adjustment for age, sex and potential risk factors. These results suggest that brain development during infancy and early childhood is important in determining how well cognitive abilities are preserved in old age.

Lutein and zeaxanthin status and risk of age-related macular degeneration.

PURPOSE: To investigate the relation between plasma concentrations of lutein and zeaxanthin and age-related macular degeneration in a group of elderly men and women. METHODS: The Wisconsin Age-Related Maculopathy Grading System was used to grade features of early and late macular degeneration in 380 men and women, aged 66 to 75 years, from Sheffield, United Kingdom. Fasting blood samples were taken to assess plasma concentrations of lutein and zeaxanthin. RESULTS: Risk of age-related macular degeneration (early or late) was significantly higher in people with lower plasma concentrations of zeaxanthin. Compared with those whose plasma concentrations of zeaxanthin were in the highest third of the distribution, people whose plasma concentration was in the lowest third had an odds ratio for risk of age-related macular degeneration of 2.0 (95% confidence interval [CI] 1.0-4.1), after adjustment for age and other risk factors. Risk of age-related macular degeneration was increased in people with the lowest plasma concentrations of lutein plus zeaxanthin (odds ratio [OR] 1.9, 95% CI 0.9-3.5) and in those with the lowest concentrations of lutein (OR 1.7, 95% CI 0.9-3.3), but neither of these relations was statistically significant. CONCLUSIONS: These findings provide support for the view that zeaxanthin may protect against age-related macular degeneration.

Relation between size at birth and risk of age-related macular degeneration.

PURPOSE: To determine whether poor fetal growth, as determined by size at birth, is associated with increased risk of age-related macular degeneration. METHODS: A total of 660 men and women born in Sheffield, United Kingdom, between 1922 and 1930 and whose size at birth was available were traced and invited to take part in the study. Of these, 392 attended for ophthalmic examination. Age-related macular degeneration in these volunteers was determined by the Wisconsin Age-Related Maculopathy Grading System. RESULTS: The mean birth weight of subjects with macular degeneration (early or late) was heavier than that of those without (7.6 lb vs. 7.3 lb, respectively; P = 0.03). After adjustment for age, gender, and risk factors for macular degeneration, a significantly increased risk of macular degeneration was found in subjects with higher birth weight (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.1-2.0 for each SD [1 lb, 5 oz] increase in birth weight). Other parameters describing size at birth showed a weaker relation or no relation with macular degeneration, but one of the measures of fetal proportion (head circumference-to-birth weight ratio) was significantly associated with risk of macular degeneration. Subjects with macular degeneration had a significantly lower head circumference-to-birth weight ratio than did those without (11.2 vs. 12.0 respectively, P = 0.01). CONCLUSIONS: The finding that age-related macular degeneration was associated with increased rather than decreased birth weight was unexpected. Failure of the developing fetus's normal brain-sparing mechanism is a possible explanation for our finding of a lower head circumference-to-birth weight ratio among subjects with macular degeneration.

Validation of a device to measure arterial pulse wave velocity by a photoplethysmographic method.

We aimed to validate a new method for measuring arterial pulsewave transit time and pulsewave velocity (a measure of arterial elasticity), based on the principle of photoplethysmography (PPG), and to compare transcutaneous values with those obtained by intra-arterial measurements. Three validation experiments are described. (a) PPG pulse wave delay times (defined as the time interval between the ECG R wave and the foot of the arterial pulse wave measured at the wrist or ankle) were compared to values obtained simultaneously from an established methodology (Doppler ultrasound). (b) Aortic pulsewave delay times in 17 subjects obtained non-invasively by the PPG method were compared with those obtained from the intra-arterial pressure wave. (c) Repeatability measurements of PWV on the same subjects were carried out over two timescales (minutes and hours) in the arm, the leg and the trunk. The Doppler and PPG delay times correlated well, as did intra-arterial and transcutaneous values. Repeatability at short timescales was good (coefficients of variation (CV) < 6% for all measurement sites) and, at the longer timescale, was satisfactory (CVs in the aorta, the arm and leg were 6.3, 13.1 and 16.0, respectively). The PWV values agreed well with others in the literature. We conclude that the PPG technique provides a complement to existing methods for the non-invasive measurement of arterial compliance. Its simplicity and ease of use make it suitable for large-scale epidemiological studies.

Size at birth and carotid atherosclerosis in later life.

Several studies have shown that low birthweight is associated with a higher risk of stroke and coronary heart disease in later life. Increased atherogenesis may be one underlying mechanism, but few studies have examined this directly. We used duplex ultrasonography to assess the extra-cranial carotid arteries of 389 elderly men and women born and still living in Sheffield, UK, whose recorded birth measurements were available. Men and women who had weighed 6.5 lbs or less at birth had a higher risk of having carotid stenosis >30% than those who weighed over 7.5 lbs, but this trend was not statistically significant (OR 1.8, 95% CI 1.0-3.3). Women who had been lighter or who had a smaller head circumference at birth tended to have an increased intima-media thickness, but these relations ceased to be statistically significant after adjustment for gestational age and cardiovascular risk factors. In men, by contrast, an increased intima-media thickness was associated with having been heavier at birth (P=0.049) or having had a larger abdominal circumference at birth (P=0.040), after adjustment for gestational age and cardiovascular risk factors. These results provide little evidence that impaired fetal growth increases susceptibility to atherogenesis.

Left ventricular mass and arterial compliance: relation to coronary heart disease and its risk factors in South Indian adults.

BACKGROUND: Rates of coronary heart disease (CHD) in India are rising, and are now similar to those in Western countries. The prevalence of conventional CHD risk factors such as hypercholesterolaemia, hypertension, smoking and obesity, tend to be lower in Indian than Western populations, and fail to explain these high rates of disease. Increased left ventricular (LV) mass and decreased arterial compliance predict a higher risk of CHD in Western populations, but there are no published data from India. We have measured LV mass and arterial compliance, and examined their relation to CHD and other known risk factors, in men and women living in Mysore, South India. METHODS: We examined 435 men and women born in Mysore during 1934-1953. LV mass was measured by echocardiography and arterial compliance (derived from pulse wave velocity, PWV) was measured by a non-invasive optical method in three arterial segments. RESULTS: The mean LV mass was 149 g (S.D. 37) in men and 125 g (S.D. 32) in women. The mean PWV was 4.14 m/s in the aorto-radial, 3.28 m/s in the aorto-femoral and 13.59 m/s in the femoro-popliteal-posterior tibial segments. LV mass and PWV were positively correlated with each other and with systolic and diastolic blood pressures, non-insulin dependant diabetes mellitus, fasting plasma glucose, insulin, proinsulin concentrations and serum triglyceride concentrations (p<0.05 for all), independently of age, sex and body size. In addition, LV mass correlated negatively with fasting serum HDL-cholesterol (p=0.02). Higher LV mass was associated with an increased risk of CHD (p=0.05). CONCLUSIONS: The mean LV mass in this Indian population is low compared with Western populations, though as in the West, increased LV mass is associated with an increased risk of CHD. Greater LV mass and reduced arterial compliance are associated with higher levels of many known CHD risk factors especially with those which form the Insulin Resistance Syndrome.