Size at birth and its relation to muscle strength in young adult women.

OBJECTIVE: To assess the relationship between development in utero, assessed by birth weight, and muscle strength in young adult women as assessed by grip strength. METHODS: A total of 1563 participants aged 20-40 years in the Southampton Women's Survey had their grip strength measured during pregnancy. At recruitment to the survey the women had been asked to recall their birth weight or obtain it from their parents. For 536 women born in Southampton, birth weight was obtained from hospital records. Grip strength was related to birth weight using multiple linear regression analysis, adjusting for age, height, weight and reported physical activity. RESULTS: Grip strength increased with age, height, weight, physical activity and birth weight. In the mutually-adjusted model, grip strength increased by 1.10 kg per kilogram of birth weight (95% CI: 0.58-1.61 kg). In women with hospital birth weight data the relationship strengthened to 1.44 kg per kilogram of birth weight (95% CI: 0.50-2.38 kg). CONCLUSIONS: Grip strength in women in their twenties and thirties is at or approaching its peak. The association between grip strength and birth weight was remarkably similar to findings from other studies of women at younger and older ages. This indicates that in utero development has consequences for muscle strength throughout the life course, even allowing for the increase to peak muscle strength and then its decline as a woman ages.

Birth weight, infant weight gain, and cause-specific mortality: the Hertfordshire Cohort Study.

Low birth weight, a marker of adverse intrauterine circumstances, is known to be associated with a range of disease outcomes in later life, including coronary heart disease, hypertension, type 2 diabetes, and osteoporosis. However, it may also decrease the risk of other common conditions, most notably neoplastic disease. The authors describe the associations between birth weight, infant weight gain, and a range of mortality outcomes in the Hertfordshire Cohort. This study included 37,615 men and women born in Hertfordshire, United Kingdom, in 1911-1939; 7,916 had died by the end of 1999. For men, lower birth weight was associated with increased risk of mortality from circulatory disease (hazard ratio per standard deviation decrease in birth weight = 1.08, 95% confidence interval: 1.04, 1.11) and from accidental falls but with decreased risk of mortality from cancer (hazard ratio per standard deviation decrease in birth weight = 0.94, 95% confidence interval: 0.90, 0.98). For women, lower birth weight was associated with a significantly (p < 0.05) increased risk of mortality from circulatory and musculoskeletal disease, pneumonia, injury, and diabetes. Overall, a one-standard-deviation increase in birth weight reduced all-cause mortality risk by age 75 years by 0.86% for both men and women.

Early growth and death from cardiovascular disease in women.

OBJECTIVE: To determine whether the link suggested between growth in utero and during infancy and death from cardiovascular disease in men is also present in women. DESIGN: Follow up study of women and men whose birth weight and weight at 1 year of age had been recorded. SETTING: Hertfordshire, England. SUBJECTS: 5585 women and 10,141 men born during 1911-30. MAIN OUTCOME MEASURES: Standardised mortality ratios for cardiovascular disease. RESULTS: Among women and men death rates from cardiovascular disease fell progressively between the low and high birth weights groups (chi 2 = 4.3, p = 0.04 for women, chi 2 = 8.5, p < 0.005 for men). Cardiovascular deaths in men but not women were also strongly related to weight at 1 year, falling progressively between the low and high weight groups (chi 2 = 27.5, p < 0.0001). The highest cardiovascular death rates in women were among those with below average birth weight but above average weight at 1 year. In men the highest rates were among those with below average birth weight and below average weight at 1 year. CONCLUSION: Relations between cardiovascular disease and birth weight are similar in men and women. In men cardiovascular disease is also related to weight gain in infancy.

The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life.

OBJECTIVE: To determine how fetal growth is related to death from cardiovascular disease in adult life. DESIGN: A follow up study of men born during 1907-24 whose birth weights, head circumferences, and other body measurements were recorded at birth. SETTING: Sheffield, England. SUBJECTS: 1586 Men born in the Jessop Hospital. MAIN OUTCOME MEASURE: Death from cardiovascular disease. RESULTS: Standardised mortality ratios for cardiovascular disease fell from 119 in men who weighed 5.5 pounds (2495 g) or less at birth to 74 in men who weighed more than 8.5 pounds (3856 g). The fall was significant for premature cardiovascular deaths up to 65 years of age (chi 2 = 5.0, p = 0.02). Standardised mortality ratios also fell with increasing head circumference (chi 2 = 4.6, p = 0.03) and increasing ponderal index (weight/length3) (chi 2 = 3.8, p = 0.05; for premature deaths chi 2 = 6.0, p = 0.01). They were not related to the duration of gestation. Among men for whom the ratio of placental weight to birth weight was in the highest fifths the standardised mortality ratio was 137. CONCLUSION: These findings show that reduced fetal growth is followed by increased mortality from cardiovascular disease. They suggest that reduction in growth begins early in gestation. They are further evidence that cardiovascular disease originates through programming of the body's structure, physiology, and metabolism by the environment during fetal life. Maternal nutrition may have an important influence on programming.

Early growth and abdominal fatness in adult life.

STUDY OBJECTIVE: The aim was to determine whether abdominal fatness in adult men is associated with retarded growth in fetal life and infancy. DESIGN: This was a follow up study of (1) men born during 1920-30 whose birthweights and weights at one year were recorded at the time by health visitors; and (2) men born during 1935-43 whose size at birth was measured in detail. The main outcome measure was the ratio of waist circumference to hip girth. SETTING: Hertfordshire and Preston, England. SUBJECTS: Subjects were 845 men born in east Hertfordshire who still live there; and 239 men born in Preston who still live in or close to the city. MAIN RESULTS: After allowing for body mass index, mean waist to hip ratio fell with increasing birthweight and rose as the ratio of placental weight to birthweight increased. These trends were independent of duration of gestation and therefore reflected retarded fetal growth. Waist to hip ratio also fell with increasing weight at one year. All these trends were independent of adult height, alcohol consumption, smoking, social class, and age. CONCLUSIONS: The tendency to store fat abdominally, which is known to increase the risk of cardiovascular disease and diabetes independently of obesity, may be a persisting response to adverse conditions and growth failure in fetal life and infancy.

Targeting autoantigen to B cells prevents the induction of a cell-mediated autoimmune disease in rats.

Immunization protocols that induce high levels of delayed-type hypersensitivity are often associated with low levels of antibody production, whereas alternative immunization strategies can produce the opposite effect. This reciprocal relationship appears to depend, at least in part, on the fact that T cell-derived lymphokines that are predominantly involved in one type of response inhibit the development of those T cells that promote the alternative one. Such a regulatory mechanism is likely to be bistable in that whenever one form of response is established, spontaneous development of the alternative one will be inhibited. We have applied this concept to the control of a cell-mediated autoimmune disease in rats. By covalently linking the autoantigen to anti-IgD antibody, we have targeted it to B cells for presentation to antigen-specific T cells. This form of presentation favors antibody production and may be expected to antagonize the cell-mediated disease-inducing response to the same antigen. To test this hypothesis, use was made of the fact that experimental allergic encephalomyelitis (EAE), when induced with the encephalitogenic peptide of guinea pig myelin basic protein, is purely a cell-mediated disease. The experiments show that Lewis rats, immunized with the peptide in its encephalitogenic form, were protected from disease when simultaneously injected with the peptide coupled to anti-IgD monoclonal antibodies. Control experiments showed that neither peptide nor anti-IgD alone were protective, and the peptide covalently coupled to irrelevant antibodies also failed to protect. Spleen cells from animals protected from disease by the anti-IgD-peptide conjugate, when activated in vitro with the encephalitogen, were able to transfer EAE to naive recipients. The results demonstrate that a cell-mediated immune response can be controlled by appropriate targeting of the specific antigen without inducing T cell anergy and suggest a potential strategy for preventing autoimmune diseases that are essentially cell-mediated in type.

Fetal and placental size and risk of hypertension in adult life.

OBJECTIVE: To study the effect of intrauterine growth and maternal physique on blood pressure in adult life. DESIGN: A follow up study of infants born 50 years previously whose measurements at birth were recorded in detail. SETTING: Preston, Lancashire. SUBJECTS: 449 Men and women born in hospital in Preston during 1935-43 and still living in Lancashire. MAIN OUTCOME MEASURES: Placental weight, birth weight, and blood pressure at age 46 to 54 years. RESULTS: In both sexes systolic and diastolic pressures were strongly related to placental weight and birth weight. Mean systolic pressure rose by 15 mm Hg as placental weight increased from less than or equal to 1 lb (0.45 kg) to greater than 1.5 lb and fell by 11 mm Hg as birth weight increased from less than or equal to 5.5 lb to greater than 7.5 lb. These relations were independent so that the highest blood pressures occurred in people who had been small babies with large placentas. Higher body mass index and alcohol consumption were also associated with higher blood pressure, but the relations of placental weight and birth weight to blood pressure and hypertension were independent of these influences. CONCLUSIONS: These findings show for the first time that the intrauterine environment has an important effect on blood pressure and hypertension in adults. The highest blood pressures occurred in men and women who had been small babies with large placentas. Such discordance between placental and fetal size may lead to circulatory adaptation in the fetus, altered arterial structure in the child, and hypertension in the adult. Prevention of hypertension may depend on improving the nutrition and health of mothers.

Weight in infancy and death from ischaemic heart disease.

Environmental influences that impair growth and development in early life may be risk factors for ischaemic heart disease. To test this hypothesis, 5654 men born during 1911-30 were traced. They were born in six districts of Hertfordshire, England, and their weights in infancy were recorded. 92.4% were breast fed. Men with the lowest weights at birth and at one year had the highest death rates from ischaemic heart disease. The standardised mortality ratios fell from 111 in men who weighed 18 pounds (8.2 kg) or less at one year to 42 in those who weighed 27 pounds (12.3 kg) or more. Measures that promote prenatal and postnatal growth may reduce deaths from ischaemic heart disease. Promotion of postnatal growth may be especially important in boys who weigh below 7.5 pounds (3.4 kg) at birth.

The autonomy of CD8+ T cells in vitro and in vivo.

Experiments have been carried out in vitro and in vivo to determine to what extent CD8+ T cells in the rat can function independently of any helper activity from CD4+ cells. We have identified the culture conditions required for the autonomous proliferation of CD8+ T cells in the rat mixed leucocyte culture (MLC) and in particular have studied both the kinetics of the response and the effect of replacing the homologous serum, used in our previous MLC experiments, with fetal calf serum (FCS). The results obtained using FCS show that, early in the MLC, CD8+ T-cells proliferate at a comparable rate to the CD4+ subset but that, within 48-72 hr, the proliferation rate of the CD8+ cells ceases to increase with time. In contrast, the proliferation of the CD4+ T cells appears to be limited only by the exhaustion of the culture medium. The results also show that the proliferative responses of both CD4+ and CD8+ T cells are inhibited in homologous serum but that it is the CD8+ subset that is more affected. When CD8+ T cells, in homologous serum, are co-cultured with irradiated CD4+ T cells the proliferative activity is increased, indicating that the helper activity of the CD4+ T cells can over-ride the inhibitory effect of the serum. In vivo we have compared the abilities of injected CD4+ and CD8+ T cells to mediate rejection of skin allografts on nude rats. Grafts were rejected more rapidly on recipients of low doses of CD4+ T cells than on rats given 200 times as many CD8+ T cells. Thoracic duct lymphocytes (TDL) obtained 5 weeks after CD8+ T-cell injection always contained a population of CD4+ T cells, even when the injected CD8+ T-cell inoculum contained less than 0.1% CD4+ cells as contaminants. Evidence was obtained that these CD4+ T cells found in TDL displayed alloreactivity in MLC. Further, the intentional injection of very low doses of CD4+ cells led, after 5 weeks, to frequencies of CD4+ T cells, in thoracic duct lymph, equal to that obtained by the injection of 200 times as many cells of the same phenotype. It appears that, in T-cell-deficient rats, CD4+ cells can expand over 2000 times in a few weeks. Such expansion may explain the relatively slow rejection of skin allografts observed in these experiments when nude rats were injected with putatively pure populations of CD8+ T cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Appendicitis epidemic following introduction of piped water to Anglesey.

The extension of piped water supplies in Anglesey, North Wales, 30 years ago and the consequent introduction of domestic hot water systems was followed by an epidemic of appendicitis. This occurred while appendicitis rates were falling elsewhere in Britain. The diet of Anglesey is unremarkable. This is further evidence that epidemics of appendicitis occur during the transition to 'western' hygiene, an important component of which is the provision of domestic hot water systems and fixed baths.

The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents.

Neural grafts from day 17-19 fetal rats or mice survived well when transplanted into syngeneic, or immunodeficient hosts, thus demonstrating that there are no non-immunological barriers to cross-species transplantation of neuronal tissue in rats and mice. However, intraventricular grafts from rat to mouse, or vice versa, in immunocompetent animals were rejected in less than 30 days. By this time all graft tissue had been destroyed and scavenged, presumably by the macrophages seen infiltrating the grafts within 10 days of grafting. Rat allografts from major histocompatibility complex disparate donors disparate donors survived well as did grafts between rats differing only at minor histocompatibility loci. However, allografts from donors that differed from recipients at both major and minor histocompatibility complex loci had a variable survival time. When neural tissue was grafted into immunologically primed recipients, it was rejected as was similar tissue grafted beneath the kidney capsule of an allogeneic host. Concomitant grafting of allogeneic tissue under the kidney capsule and into the third ventricle was followed by rejection in both sites. A striking observation in these studies was the induction of Class I major histocompatibility complex antigens on grafted neuronal tissue. High levels of antigen expression were correlated with a vigorous host response and poor graft survival but lower levels were not indicative of impending graft destruction. Whilst the brain can be regarded as an immunologically privileged site, the privilege is not absolute and caution needs to be exercised in the interpretation of results from allogeneic or xenogeneic grafts.

Early cellular events in a systemic graft-vs.-host reaction. II. Autoradiographic estimates of the frequency of donor lymphocytes which respond to each Ag-B-determined antigenic complex.

A graft-vs.-host (GVH) reaction was initiated by the intravenous injection of parental strain (AO) lymphocytes into irradiated (AO times HO)F1 or (AO times DA)F1 hybrids. The proportion of donor T cells which had responded to the F1 hybrid antigens within 24 h was estimated by two methods. (a) Donor lymphocytes were labeled with [3H]uridine in vitro before injection. The proportion of labeled cells which had morphologically transformed in the recipient's spleen was 17-19%. In both series of experiments syngeneic transfers were performed in which case the proportion of transformed cells was 1-2.4%. A similar low proportion was found after parental to F1 transfer in a non-Ag-B strain combination. These figures were used to calculate the frequency of responding cells in the injected population given three additional pieces of information: (a) the extent of selection in the spleen which transformed the estimate to 4.5%-6.0% responders; (b) division of donor cells was shown to be negligible under the conditions of the experiment; and (c) the nonspecific recruitment of lymphocytes was shown to be negligible. A speculative model of antigen recognition by T cells which accounts for the high proportion of responders is outlined.