Subependymal nodules, giant cell astrocytomas and the tuberous sclerosis complex: a population-based study.

OBJECTIVES: (1) In a population-based study of tuberous sclerosis (TSC), to identify the number of patients presenting with symptomatic giant cell astrocytomas (GCAs); (2) within a subset of this population, to identify the number who would be diagnosed with GCAs on predetermined radiological criteria. METHODS: Patients with TSC in Wessex (a geographical region of England) were identified, and their medical history determined. A subset were invited to have a cranial MRI if they did not have a history of a symptomatic GCA and if they were likely to tolerate cranial imaging without a general anaesthetic. Scans were performed according to a standard protocol on a single scanner and were reported blindly by a neuroradiologist. RESULTS: 179 people were identified with TSC. Ten of these had a history of treatment for a symptomatic GCA. Forty-one of the remainder had a cranial MRI. Thirty-nine of these had subependymal nodules, of whom 24 (59%) had at least one (maximum 11) that showed enhancement with gadolinium. In seven (17%), the lesion was >1 cm, and all of these lesions showed gadolinium enhancement. CONCLUSIONS: In this study, the proportion of patients with TSC who had a history of symptomatic GCA was 5.6%. In the subset without such a history, who underwent imaging, the number diagnosed as having a GCA on radiological criteria was much higher (59% gadolinium enhancement and 17% >1 cm in size). Screening for GCAs (performing scans on asymptomatic patients with TSC) would therefore identify large numbers of patients who had not presented with symptoms. This finding leads us to recommend that screening should not be undertaken.

Maternal vitamin D status during pregnancy and child outcomes.

OBJECTIVE: To investigate whether exposure to high maternal concentrations of 25(OH)-vitamin D in pregnancy poses any risk to the child. DESIGN: Prospective study. SETTING: Princess Anne Maternity Hospital, Southampton, UK. SUBJECTS: A group of 596 pregnant women were recruited. A total of 466 (78%) children were examined at birth, 440 (74%) at age 9 months and 178 (30%) at age 9 years. METHODS: Maternal 25 (OH)-vitamin D concentrations were measured in late pregnancy. Anthropometry of the child was recorded at birth, 9 months and 9 years. At 9 months, atopic eczema was assessed. At 9 years, children had an echocardiogram and a dual energy x-ray absorptiometry scan, blood pressure, arterial compliance and carotid intima-media thickness were measured and intelligence and psychological function assessed. RESULTS: There were no associations between maternal 25(OH)-vitamin D concentrations and the child's body size or measures of the child's intelligence, psychological health or cardiovascular system. Children whose mothers had a 25(OH)-vitamin D concentration in pregnancy >75 nmol/l had an increased risk of eczema on examination at 9 months (OR 3.26, 95% CI 1.15-9.29, P=0.025) and asthma at age 9 years (OR 5.40, 95% CI, 1.09-26.65, P=0.038) compared to children whose mothers had a concentration of <30 nmol/l. CONCLUSION: Exposure to maternal concentrations of 25(OH)-vitamin D in pregnancy in excess of 75 nmol/l does not appear to influence the child's intelligence, psychological health or cardiovascular system; there could be an increased risk of atopic disorders, but this needs confirmation in other studies.

The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex.

BACKGROUND: The aetiology of the learning difficulty in tuberous sclerosis is debated. It may be related to the amount of tubers in the brain or caused by the infantile spasms that occur in early life. AIMS: To examine the relative contributions to final intelligence (IQ) made by both cerebral tubers and infantile spasms. METHODS: As part of an epidemiological study of tuberous sclerosis in the south of England, patients were recruited who were able to undergo magnetic resonance imaging (MRI) without the need for an anaesthetic. Epilepsy history was determined by interview and review of clinical records. IQ was assessed using either Wechsler intelligence scales or Raven's matrices. RESULTS: A total of 41 patients consented to have an MRI scan. IQ scores were normally distributed about a mean of 91. Twenty six patients had a positive history of epilepsy, and 11 had suffered from infantile spasms. There was a significant relation between the number of tubers and IQ. Infantile spasm status partly confounded the relation between tubers and IQ, but did not render the relation statistically insignificant. The relation between infantile spasms and learning difficulty remained strong even when controlling for the number of tubers.

Serum insulin-like growth factor-I concentrations in late middle age: no association with birthweight in three UK cohorts.

BACKGROUND: Small body size at birth and during infancy is associated with an increased risk of adult osteoporosis and cardiovascular disease. Fetal programming of the growth hormone-insulin-like growth factor (GH-IGF) axis may provide a mechanism for these epidemiological findings. AIMS: To determine whether measurements of GH and IGF-I in late middle age were related to size at birth and in infancy. METHODS: Overnight urinary GH excretion and fasting serum IGF-I were measured in 309 men and 193 women from Hertfordshire (born 1920-1930) for whom birthweight and weight at 1 year were recorded. Serum IGF-I was measured in men and women from Preston (n=254, born 1935-1943) and Sheffield (n=215, born 1939-1940) whose birthweight and other birth measurements were recorded. RESULTS: Urinary GH and serum IGF-I were not related to birthweight, other measurements at birth, or weight at 1 year. CONCLUSION: In contrast to previous studies in children or young adults, these data do not support the hypothesis that IGF-I concentrations are programmed by intra-uterine events, as assessed by birthweight, in late middle age.

Glucocorticoid metabolism and the Metabolic Syndrome: associations in an elderly cohort.

OBJECTIVE: The phenotype of the Metabolic Syndrome (hypertension, insulin resistance and hyperlipidaemia) bears similarities to Cushing's Syndrome, in which the cause of these features is elevated cortisol production. We have investigated relationships between glucocorticoid production and features of the Metabolic Syndrome in a cohort of elderly subjects. DESIGN: A cross-sectional analysis was carried out of a subset of a birthweight cohort from Sheffield. METHODS: 92 men and 40 women (aged 69-75 y) representative of the original cohort were investigated. Features of the Metabolic Syndrome (blood pressure, BMI, waist hip ratio, fasting glucose, insulin and triglycerides) were recorded and urinary glucocorticoid metabolites were measured by gas chromatography mass spectrometry. RESULTS: Total glucocorticoid metabolites were correlated with the overall phenotype of the Metabolic Syndrome (P = 0.002), whereas specific pathways of metabolism (activity of 11 beta-hydroxysteroid dehydrogenases and A-ring reductases) did not show significant associations. Specifically total glucocorticoid production increased with increasing systolic blood pressure (r = 0.21, P = 0.013), fasting glucose (r = 0.19, P = 0.02) and insulin (r = 0.23, P = 0.025). Glucocorticoid production was greater with increasing abdominal girth (r = 0.19, P = 0.033), but there was no association with enhanced metabolism via a specific pathway. Within this cohort, birthweight was not associated with total glucocorticoid metabolites. However, decreasing birthweight (P = 0.022), increasing obesity (P = 0.026) and increasing total glucocorticoid production (P = 0.009) were all independent predictors of fasting glucose. CONCLUSIONS: These data support the concept that cortisol production is enhanced in the Metabolic Syndrome, although they did not confirm the recent evidence that increased cortisol secretion is predicted by low birthweight.

Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age.

BACKGROUND: People who are small at birth tend to have higher blood pressure in later life. However, it is not clear whether it is fetal growth restriction or the accelerated postnatal growth that often follows it that leads to higher blood pressure. METHODS AND RESULTS: We studied blood pressure in 346 British men and women aged 22 years whose size had been measured at birth and for the first 10 years of life. Their childhood growth was characterized using a conditional method that, free from the effect of regression to the mean, estimated catch-up growth. People who had been small at birth but who gained weight rapidly during early childhood (1 to 5 years) had the highest adult blood pressures. Systolic pressure increased by 1.3 mm Hg (95% CI, 0.3 to 2.3) for every standard deviation score decrease in birth weight and, independently, increased by 1.6 mm Hg (95% CI, 0.6 to 2.7) for every standard deviation score increase in early childhood weight gain. Adjustment for adult body mass index attenuated the effect of early childhood weight gain but not of birth weight. Relationships were smaller for diastolic pressure. Weight gain in the first year of life did not influence adult blood pressure. CONCLUSIONS: Part of the risk of adult hypertension is set in fetal life. Accelerated weight gain in early childhood adds to this risk, which is partly mediated through the prediction of adult fatness. The primary prevention of hypertension may depend on strategies that promote fetal growth and reduce childhood obesity.

Plasma antioxidant vitamins and carotenoids and age-related cataract.

OBJECTIVE: To investigate the relationships between plasma concentrations of antioxidant vitamins and carotenoids and nuclear, cortical, and posterior subcapsular cataracts in a group of elderly men and women. DESIGN: Cross-sectional survey. PARTICIPANTS: Three hundred seventy-two men and women, aged 66 to 75 years, born and still living in Sheffield, England. METHODS: The Lens Opacities Classification System (LOCS) III was used to grade nuclear, cortical, and posterior subcapsular lens opacities. Fasting blood samples were taken to assess plasma concentrations of vitamin C, vitamin E, alpha-carotene, beta-carotene, lycopene, lutein, zeaxanthin, and beta-cryptoxanthin. MAIN OUTCOME MEASURES: Logistic regression analyses of the associations between plasma vitamin concentrations and cataract subtype, adjusting for age, gender, and other risk factors. RESULTS: After adjustment for age, gender, and other risk factors, risk of nuclear cataract was lowest in people with the highest plasma concentrations of alpha-carotene (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.3-0.9, P for trend 0.006) or beta-carotene (OR, 0.7; 95% CI, 0.4-1.4, P for trend 0.033). Risk of cortical cataract was lowest in people with the highest plasma concentrations of lycopene (OR, 0.4; 95% CI, 0.2-0.8, P for trend 0.003), and risk of posterior subcapsular cataract was lowest in those with higher concentrations of lutein (OR, 0.5; 95% CI, 0.2-1.0, P for trend 0.012). High plasma concentrations of vitamin C, vitamin E, or the carotenoids zeaxanthin and beta-cryptoxanthin were not associated with decreased risk. CONCLUSIONS: These findings suggest that a diet rich in carotenoids may protect against cataract development, but because they are based on observational data, they need to be confirmed in randomized controlled trials.

A hypothesis about a mechanism for the programming of blood pressure and vascular disease in early life.

1. There is now a great deal of evidence that people whose weight at birth was low tend to have higher blood pressure and increased risk of death from cardiovascular disease as adults. 2. We argue that, in fetuses whose growth is impaired, synthesis of elastin in the walls of the aorta and large arteries is deficient and that this deficiency leads to permanent changes in the mechanical properties of these vessels. 3. Over a lifetime, such changes could predispose an individual to higher blood pressure and cardiovascular disease.

Associations of micro-albuminuria with intra-uterine growth retardation.

BACKGROUND/AIM: Micro-albuminuria is associated with insulin resistance and a high blood pressure and predicts an increased risk of cardiovascular disease in both diabetic and non-diabetic populations. Relationships have been described for micro-albuminuria with both low birth weight and short stature in adulthood. We have tested the hypothesis that micro-albuminuria in non-diabetic adults may be associated with markers of intra-uterine growth retardation. METHODS: We measured the urinary albumin excretion rate in 818 men and women from three populations, in whom detailed records of birth weight were available, of whom 354 had records of length at birth to provide an estimate of the ponderal index. RESULTS: The albumin excretion rates were higher in men than in women (5.1 vs. 3.8 microg/min) and were related to age (r = 0.23, p < 0.001) and body mass index (r = 0.08, p = 0.02) as well as fasting plasma glucose and blood pressure. Considered as a continuous variable, the albumin excretion rate was not related to any measure of size at birth or to adult height. Fifty-four subjects (6.6%) were micro-albuminuric (albumin excretion rate > or = 20 microg/min), and these subjects were thinner at birth than normo-albuminuric subjects (12.9 vs. 13.8 oz/in3, p = 0.09). Compared to those subjects whose ponderal index had been in the upper third of the distribution, people whose ponderal index had been in the lower third of the distribution had an odds ratio for micro-albuminuria of 3.1 (p for trend 0.05). CONCLUSION: The association between micro-albuminuria, insulin resistance, and coronary heart disease may be a consequence of growth retardation representing a common antecedent.

Patterns of prescribing of nutritional supplements in the United Kingdom.

BACKGROUND AND AIMS: A large number of prescriptions are issued for nutritional supplements under British National Formulary classifications 9.4.1 (foods for special diets) and 9.4.2 (enteral feeds), but little is known about the characteristics of the patients who receive them. We used the General Practice Research Database to examine patterns of prescribing of these supplements. METHODS: We selected patients who had been prescribed supplements under classifications 9.4.1 and 9.4.2 during 1996-1997. Descriptive statistics were used to examine how prescribing varied. RESULTS: 28644 patients received prescriptions during 1996-1997. Among the 27413 (96%) patients prescribed supplements for oral use, 14750 received supplements for enteral nutrition alone, 8122 received supplements for special diets alone and 4541 had both types of supplement. 51% of patients receiving supplements for special diets were <18 years. The commonest diagnoses among such children were milk intolerance (24%) and malnutrition (17%). 94% of patients receiving supplements for enteral nutrition were adult, 52% of whom had cancer or cardiovascular disease. Only 4% of patients had weight and height recorded prior to first prescription. CONCLUSIONS: The GPRD provides valuable information on the characteristics of patients prescribed nutritional supplements. But because only limited data are available on their nutritional status prior to supplementation, it is hard to assess whether general practitioners are prescribing these supplements appropriately.

Antioxidant vitamin status and carotid atherosclerosis in the elderly.

BACKGROUND: The oxidative modification of LDL is thought to play a crucial role in the initiation of atherosclerosis. Antioxidant vitamins can protect LDL from oxidation, and high intakes or blood concentrations of these vitamins have been linked with a reduced risk of cardiovascular disease. Few data are available on the importance of antioxidant vitamins in earlier stages of atherogenesis. OBJECTIVE: We investigated the cross-sectional relation between antioxidant vitamin status and carotid atherosclerosis in a group of elderly persons. DESIGN: The study sample comprised 468 men and women aged 66-75 y living in Sheffield, United Kingdom. Duplex ultrasonography was used to measure intima-media thickness and the degree of stenosis in the extracranial carotid arteries. Antioxidant vitamin status was assessed by measuring fasting plasma concentrations of vitamin C, vitamin E, and beta-carotene. RESULTS: In the men, after adjustment for age and cardiovascular disease risk factors, a 20% higher plasma vitamin C concentration was associated with a 0.004-mm smaller intima-media thickness; a 20% higher beta-carotene concentration was associated with a 0.005-mm smaller intima-media thickness. Compared with men with high blood concentrations of beta-carotene or cholesterol-adjusted vitamin E, those with low blood concentrations of these vitamins were 2.5 times as likely to have carotid stenosis of >30%. We found no significant trends between plasma concentrations of antioxidant vitamins and either measure of carotid atherosclerosis in the women. CONCLUSION: A high antioxidant vitamin status may help to prevent the initiation and progression of early atherosclerotic lesions in men.

Intrauterine programming of adult body composition.

Epidemiological studies suggest an association between weight in infancy and the risk of osteoporosis in later life. The extent to which this reflects environmental influences on skeletal growth and metabolism before birth or during the first year of postnatal life remains uncertain. We therefore examined the association between birth weight and adult body composition (bone, lean, and fat mass) in a cohort of 143 men and women, aged 70-75 yr, who were born in Sheffield, UK, and still lived there. The subjects underwent assessment of body composition by dual energy x-ray absorptiometry. Neonatal anthropometric information included birth weight, birth length, head size, and abdominal circumference. There were significant (P < 0.01) positive associations between birth weight and adult, whole body, bone, and lean mass among men and women. These were mirrored in significant (P < 0.03) associations between birth weight and bone mineral content at the lumbar spine and femoral neck. Associations between birth weight and whole body fat were weaker and not statistically significant. The associations of birth weight with whole body bone mineral and lean mass remained statistically significant after adjustment for age, sex, and adult height. They also remained significant after adjustment for cigarette smoking, alcohol consumption, dietary calcium intake, and physical inactivity. These data are in accord with previous observations that anthropometric measures in infancy are associated with skeletal size in adulthood. The presence of these relationships at birth adds to the evidence that bone and muscle growth may be programmed by genetic and/or environmental influences during intrauterine life.

Relation between size at birth and age-related cataract.

PURPOSE: To determine whether poor fetal growth, as determined by size at birth, is associated with an increased risk of age-related cataract. METHODS: A total of 741 men and women born in Sheffield, England between 1922 and 1930 and whose size at birth was available were traced and invited to take part in the study. Of these, 392 (53%) attended for ophthalmic examination. Lens opacity in these volunteers was graded using the Lens Opacities Classification System (LOCS) III. RESULTS: After adjusting for age, gender, gestational age, and risk factors for cataract there were no consistent associations between size at birth and age-related cataract. However, the odds ratio for nuclear cataract (opalescence) among subjects whose birth weight was more than 8 lb was 2.4 (95% CI 1.2 to 5.0) compared with those who weighed under 6 lb 12 oz at birth. Risk of cortical cataract by contrast fell with increasing birth weight, but the trend was not significant and became weak after adjusting for gestational age and other risk factors for cataract. No relation was evident between risk of posterior subcapsular cataract and size at birth. CONCLUSIONS: There is no consistent association between size at birth and age-related cataract. The higher risk of nuclear cataract with increased birth weight was contrary to the expected trend. The apparent difference in direction of the relation between birth weight and different subtypes of cataract may be a chance finding but warrants further exploration.

Renal function, plasma homocysteine and carotid atherosclerosis in elderly people.

Although epidemiological studies suggest that people with minor impairment of renal function are at higher risk of stroke and coronary heart disease, the mechanisms underlying this relation are unclear. One explanation may lie with observations that deterioration in renal function is accompanied by elevations in plasma homocysteine concentrations. There is evidence that moderate hyperhomocysteinemia may play a causal role in atherosclerotic disease. We investigated the relations between renal function, plasma homocysteine and atherosclerosis of the carotid arteries in 128 men and women aged 69-74 years. Renal function was assessed by creatinine clearance and serum creatinine. Duplex ultrasonography was used to quantify the degree of stenosis in the extracranial carotid arteries. Severity of carotid atherosclerosis was greatest in men and women with the poorest renal function, whether measured by creatinine clearance or serum creatinine. After adjustment for plasma homocysteine, pulse pressure and other cardiovascular risk factors, the odds ratio for having carotid stenosis >30% was 4.3 (95% CI 1.4-12.9) in those whose creatinine clearance rate was 55 ml/min or less compared with those whose creatinine clearance rate was >73 ml/min. Even small decrements in renal function were associated with increased risk; people whose creatinine clearance rate was between 56 and 73 ml/min had an odds ratio of 3.8 (95% CI 1.2-11.9). Plasma homocysteine concentrations were significantly higher in people with poorer renal function, but they did not explain the associations we found between carotid atherosclerosis and creatinine clearance or serum creatinine.

Reproducibility of peer review in clinical neuroscience. Is agreement between reviewers any greater than would be expected by chance alone?

We aimed to determine the reproducibility of assessments made by independent reviewers of papers submitted for publication to clinical neuroscience journals and abstracts submitted for presentation at clinical neuroscience conferences. We studied two journals in which manuscripts were routinely assessed by two reviewers, and two conferences in which abstracts were routinely scored by multiple reviewers. Agreement between the reviewers as to whether manuscripts should be accepted, revised or rejected was not significantly greater than that expected by chance [kappa = 0.08, 95% confidence interval (CI) -0.04 to -0.20] for 179 consecutive papers submitted to Journal A, and was poor (kappa = 0.28, 0.12 to 0. 40) for 116 papers submitted to Journal B. However, editors were very much more likely to publish papers when both reviewers recommended acceptance than when they disagreed or recommended rejection (Journal A, odds ratio = 73, 95% CI = 27 to 200; Journal B, 51, 17 to 155). There was little or no agreement between the reviewers as to the priority (low, medium, or high) for publication (Journal A, kappa = -0.12, 95% CI -0.30 to -0.11; Journal B, kappa = 0.27, 0.01 to 0.53). Abstracts submitted for presentation at the conferences were given a score of 1 (poor) to 6 (excellent) by multiple independent reviewers. For each conference, analysis of variance of the scores given to abstracts revealed that differences between individual abstracts accounted for only 10-20% of the total variance of the scores. Thus, although recommendations made by reviewers have considerable influence on the fate of both papers submitted to journals and abstracts submitted to conferences, agreement between reviewers in clinical neuroscience was little greater than would be expected by chance alone.

Blood pressure, arterial compliance, and left ventricular mass: no relation to small size at birth in south Indian adults.

OBJECTIVE: To determine whether reduced fetal growth leads to raised blood pressure, reduced arterial compliance, and increased left ventricular mass in an Indian population. DESIGN: A retrospective cohort study of men and women (age range 40-61 years) whose weight, length, and head circumference at birth were recorded. SETTING: The Holdsworth Memorial Hospital, Mysore, South India. SUBJECTS: 435 men and women born in the hospital between 1934 and 1953. MAIN OUTCOME MEASURES: Systolic and diastolic blood pressures; compliance in four arterial segments derived from pulse wave velocity, measured by a non-invasive optical method; and left ventricular mass measured using M mode echocardiography. RESULTS: Small size at birth was not associated with increased adult blood pressure or left ventricular mass, or with reduced arterial compliance. Systolic blood pressure and left ventricular mass were higher in subjects who were greater in length at birth, rising by 1.64 mm Hg (95% confidence interval (CI) -0.08 to +3.37 mm Hg) and 1.63 g/m(2) (95% CI 0.13 to 3.13 g/m(2)), respectively, per one inch (2.5 cm) increase in birth length, independently of adult size. Arterial compliance was reduced in people whose mothers were lighter and had smaller pelvic (external conjugate) diameters. CONCLUSIONS: The higher prevalence of coronary heart disease in Indian men and women of lower birth weight, shown in an earlier study of the same cohort, cannot be explained by changes in blood pressure, arterial compliance, and left ventricular mass. The association of raised blood pressure and left ventricular mass with longer birth length suggests that the way in which the intrauterine environment influences coronary heart disease differs between Indian and Western populations.