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The greater longevity of humans over other mammalian species is provided, in large part, by the complex neural circuitry of the brain. Assurance of the integrity of this circuitry is partly provided by its neural plasticity. The brain is also protected from adverse systemic phenomena by the blood-brain and blood-cerebrospinal fluid barriers. However, these barriers do not protect the brain from adverse phenomena that originate within the central nervous system. The brain and immune systems share many analogous characteristics; and an immunogenic compartment of the brain is described here that also has the capacity to assure the integrity of its neural circuits and its autonomy. Finally, the role of this compartment in aging and in aging-dependent diseases is discussed.

Cerebral amyloid angiopathy (CAA) occurs in humans along with the neuritic amyloid plaques in Alzheimer's disease, in several familial (inherited) syndromes, and in a sporadic form that increases in prevalence with age to attain a rate of about 60% after age 90. In the non-Alzheimer conditions, it is often accompanied by cerebral hemorrhage and sometimes also by dementia. We report here the experimental induction of cerebrovascular amyloid (CVA) in thyroglobulin (Tg)-immunized rabbits. The vascular deposits in these rabbits are comparable to that seen in humans in that they primarily involve arterioles, venules, and capillaries and exhibit microscopic and ultrastructural characteristics similar to the human lesion. Prominent congophilic vascular lesions in the brain were seen in three out of six Tg-immunized rabbits, whereas less striking basement membrane thickening was evident in three other experimental animals, probably reflecting individual variations in vascular responses to actively induced Tg immunity. Occasional primitive amyloid plaques were also encountered adjacent to vascular lesions. These observations are of particular interest since in other experimental models, cerebral vascular amyloid deposits have not been observed, thus suggesting that immunopathogenic events induced by active Tg immunization may be unique in their effects on the cerebral vasculature.

This article continues the report of a study at the St Louis Comprehensive Neighborhood Health Center in which definitive blood lead levels were routinely determined in pediatric patients younger than 5 years of age. Data on changes during the 1980s in population, housing, and soil lead levels also are provided for possible correlation with changes in blood lead levels. From 1976 through 1993, there has been a progressive decline in annual mean blood lead levels and in the percentage of patients at several ranges indicative of different degrees of risk for brain damage. Comparisons of blood lead levels in residents of other neighborhoods in the city of St Louis show that most predominantly black neighborhoods and a single predominantly poor white neighborhood are particularly high-risk areas. In the study catchment area, the total population has decreased but the number of children younger than 5 years of age has increased. The latter has resulted in about a doubling of admissions to our health center in 1993. There also has been a decline in occupied housing units, an increase in unoccupied units (probably unfit for habitation), and the demolition of more than 6700 units. There also has been a remarkable citywide reduction in soil lead levels, somewhat more marked in the study catchment area than in some other areas of the city. The reduction in the lead burden in children in the study catchment area appears to be associated with the decline in housing units and the decline in soil lead levels.

This article presents data on total cholesterol (TC) determinations carried out in black patients of an inner-city neighborhood health center. In the pediatric group (under age 18), TC determinations were carried out only in over-weight children. In adults, they were performed routinely on all new admissions. During 1992, a total of 1158 TC determinations were made, 385 in males and 773 in females. Age-related changes in mean TC were compared between black males and females, between males in our population and those in the general population, and between females in the two populations. Age-related changes in the proportion of cases in our population also were analyzed in the desirable, borderline, and high-risk TC levels. Our objective was to determine if these data could account for the higher black mortality rates from coronary heart disease (CHD) than in the general population. The data show that mean TC levels and risk ratios are not substantially different in our population than in the general population. The differences in CHD mortality rates in the two populations, therefore, cannot be attributed to TC levels.

This study compares the prevalence rates of 5 common age-dependent diseases in non-demented and demented subjects. Control and dementia populations were approximately age-matched and their numbers also approximated. Prevalence rates for hypertension, myocardial infarction (MI), stroke, cancer and diabetes were determined. The rates of two or more coexisting diseases in the same patient were also compared. Two populations were studied: one was designated the autopsy series, and the other the hospital series. In the autopsy series, the rate of cardiomegaly/hypertension was 1.3 times higher in the control than in the dementia population, and for MI it was 1.7 times higher in the former than in the latter. The rate for stroke was higher in the control group by only a factor of 1.1, for cancer by only a factor of 1.2, and for diabetes the rates were almost identical in the two populations. The rate differences were statistically significant only with respect to cardiomegaly and MI. When the non-vascular and vascular dementias were compared, the rates in the latter were higher by only a factor of 1.3 for cardiomegaly, stroke, cancer and diabetes; for MIs, the rates were about the same in the two dementia categories. The data for two or more coexisting diseases were almost identical in control and dementia autopsy populations. In the hospital series, the hypertension rate was 1.6 times higher in the control than in the Alzheimer's disease (AD) group; for MI, the control group was higher by a factor of 1.5.(ABSTRACT TRUNCATED AT 250 WORDS)

The second part of this study deals with blood lead (PbB) levels in 541 pregnant women and 351 nonpregnant women of childbearing age residing in the health center's catchment area. Each blood sample was analyzed for erythroprotoporphyrin (EP) and PbB. Comparisons of these data were made with national data on women of childbearing age and with children in our catchment area, as well as with children nationally. Mean PbB and prevalence rates at greater than or equal to 10 and greater than or equal to 15 micrograms/dL were higher in the nonpregnant women of the catchment area than in the pregnant women. For comparison with women nationally, the data on these two groups were combined because national data did not clearly distinguish between pregnant and nonpregnant women. The women in the catchment area showed mean PbB and prevalence rates at the two ranges noted above that were not only higher than in white women but also generally higher than in black women nationally. Thus, this rank order was similar to that reported earlier for children. The comparisons between women and children living in the same environment showed that the children have significantly higher mean PbBs and prevalence rates at the two ranges than the women. The physiological and environmental bases for these differences are discussed. As in the study on children, the EP is also not adequate as a screening procedure for identifying women with PbB levels greater than or equal to 25 and greater than or equal to 15 micrograms/dL.

A sharply focused study is presented defining the demographic characteristics of the catchment area of a St Louis health center and determining the blood lead (PbB) levels in children from 1977 to 1989. The sources of lead exposure are examined, and the adequacy of erythroprotoporphyrin (EP) determinations are evaluated to identify children with toxic levels. Mean PbB levels and prevalence rates at higher ranges were not only substantially higher in the catchment area population than in white children, but also significantly higher than in black children nationally. Since 1980, mean PbB declined progressively in the catchment area children, but it was not until 1989 that the mean PbB had declined to the 1980 level in white children nationally. PbB parameters in the catchment area children were not only higher than in children in other St Louis neighborhoods, but also higher than in children living in towns adjacent to a lead smelting operation. The environmental sources of lead considered here do not appear to fully account for the higher PbB levels in the children in the catchment area. Nutritional factors also need to be considered. Furthermore, the EP lacks both sensitivity and specificity for identifying children with PbB levels greater than or equal to 25 micrograms/dL and greater than or equal to 15 micrograms/dL. While this study identifies a community that has experiences a high prevalence of lead toxicity in its children, it also suggests that nationwide and even citywide estimates of the prevalence of lead toxicity based on EP screening may be significantly lower than actual prevalences.

Fischer 344 male rats showed a low average level (less than ++) of in vivo as well as in vitro neuron binding antibody at 3, 15, and 26 months. However, a significant increase with age in average intensity of binding was observed with both the in vivo and the in vitro conditions. If a criterion of ++ is used as an antibody binding level likely to have biological consequences, the percent of in vivo cases showing foci of ++ or greater intensity also rises with age from 20 to 80%; a criterion of +++ gives an in vivo rise with age of only from 10 to 20%. The in vitro incidence with the ++ criterion is already 80% at three months and rises to 90%; with the +++ criterion the incidence with age rises from 20 to 80%. No evidence was obtained to support the concept that there is a weakening of the blood-brain-barrier in 26 month rats either by the systemic injection of trypan blue or by a comparison of intensity of antibody binding between extra- and intra-barrier neurones.

In vivo and in vitro IgG binding to neurons was determined by the direct and indirect immunofluorescence and immunoperoxidase techniques in 90- and 500-day-old female Wistar rats. The sera were also tested against other organs of 90- and 300-day-old rats, and an absorption technique was carried out with minced thymus. Only 1 90-day-old rat showed positive in vivo neuron binding. One serum of a young (6.7%) and 17 sera of old (42.5%) rats were positive by the in vitro procedures. The 1 young and 4 of the old positive sera cross-reacted with thymocytes, and when 3 of these were subjected to absorption, neuron igG binding capacity was removed. Significant cross-reactivity with other organs could not be demonstrated. These observations indicate that in these rats there are at least two kinds of serum neuron binding IgG which significantly increase with age; one of these cross-reacts with thymus and the other does not.

This study utilizing immunocytochemical techniques consists of two segments, 1) an analysis of the changes with age in the hormone content of normal, involuting, macro- and microfollicles, as well as calcitonin (C) cells, and 2) an analysis of the components of the lesion characteristic of lymphocytic thyroiditis. Involuting and macro- (cystic) follicles show a decline in hormone content with age, while microfollicles show a variable pattern with some showing a high and others a low content, as well as some showing an absence of hormone. There also appears to be an increase with age in hormone-containing C cell micronodules, but we were unable to demonstrate a decline in hormone content of individual C cells. Studies on the in vivo binding of immunoglobulins, as an indicator of thyroid antibody binding, showed an increase with age in IgG and IgM binding to follicular epithelium. Much stronger reactions were observed in the epithelium of microfollicles than in that of involuting or macrofollicles. There were also examples of presumptive in vivo antibody binding by C cell micronodules. We were unable to demonstrate an imbalance of helper/suppressor T cell ratio in the thyroiditis lesion, but did find that some lymphocytes contain thyroid hormones, suggesting that the latter may act as cytokines and assist in the perpetuation of the lesion. The epithelial expression of human lymphocyte antigens (HLA) was strong in microfollicles and weak or absent in involuting or macrofollicles in sections with lymphocytic thyroiditis. It was also strong in the epithelium of a microfollicular adenoma without a lymphocytic infiltrate while weak or absent in the epithelium of adjacent normal follicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Two types of follicular change in the thyroid are described. The first represents an involutional change in which colloid cysts (macrofollicles) are often found. The second represents a hyperplastic-dysplastic (microfollicular) lesion. Two types of change in calcitonin (C) cells are also described, one of which may represent an involutional process, although this is not certain. The second is a hyperplastic (micronodular) lesion, but without evidence of dysplasia. An infiltration of lymphocytes is also commonly encountered. Only about 15% of cases after age 60 are free of the follicular and lymphoid lesions. Both the macro- and microfollicular lesions show a statistically significant increase with age, as do the lymphoid lesion and its derivative Hashimoto's thyroiditis. C cell micronodules also appear to increase with age, but there are too few such cases for a reliable statistical analysis. An analysis of combinations of the follicular and lymphoid lesions show a particularly frequent association of the microfollicular and lymphoid lesions. Evidence is presented suggesting that many microfollicular lesions may represent clones of mutated cells, and that the lymphocytes may be targeted to these microfollicles. Lymphocytes were rarely found in association with C cell micronodules. Within individual thyroids there is considerable variation in the proportion of each lesion when combinations are present. Thus with advancing age there is an increasing heterogeneity of thyroid structure that may confound attempts to correlate structural and physiological changes with age.

In serial studies of immunopathologic changes in an animal model of thyroiditis 52 rabbits were immunized with either bovine, porcine or human thyroglobulin (Tg) in Freund's complete adjuvant, while another 47 animals served as noninjected or adjuvant injected controls. The immunized animals were divided into two groups, one receiving an initial series of only three Tg injections while the other received, in addition, challenging injections over an 8-week period. The immunized animals were killed over a period of 6-34 months after the last Tg injection, and untreated controls were killed at comparable ages. In Tg immunized animals, lymphocytic thyroiditis was encountered in 25 per cent and thyroid amyloid in 17 per cent; glomerular amyloid was encountered in 44 per cent with diffuse lesions in 8 per cent, nodular lesions in 17 per cent and a mixture of the two in 19 per cent. That the thyroid and glomerular hyaline deposits contained amyloid was shown by various histochemical criteria, as well as by the presence of typical fibrils on electron microscopy. Immunohistochemical studies indicated that the amyloid was predominantly of the AA type. Rabbits receiving challenging Tg injections, in addition to the initial series, showed only thyroiditis and nodular glomerular lesions most of which were amyloid. Whilst the vast majority of rabbits with lymphocytic or amyloidotic responses showed both thyroid and renal lesions, a small percentage of animals showed only a lesion of one or the other of these two organs. It is of interest that the thyroid and renal amyloid lesions, described for the first time with induced thyroglobulin immunity, were not detected in other earlier short term investigations.

If disease is only case casually related to aging, the prevailing strategy of dealing with each disease category is appropriate; if they are linked causally, the current strategy may not only be inappropriate but prove futile. The extent to which optimal gerontologic care can delay the onset of biologic deterioration, together with the use of short-lived animal models for research, may eventually resolve this issue.

The effects of age, sex, and irradiation on the genesis of amyloidosis, neuron-binding antibody (NBA), and the concomitant appearance of these two phenomena were studied in a colony of Syrian hamsters. In nonirradiated controls amyloidosis increased in prevalence with age after 12 months, and prevalence was higher in females than in males. Irradiation had the effect of advancing the appearance of amyloidosis to the 7-12 months group but did not intensify the amyloidotic process. IgG binding to the nucleus or cytoplasm of neurons was rare, and, despite the fact that IgM and IgA binding to these structures was present in about one-third of the animals, there was neither an aging nor an irradiation effect. The only statistically significant findings with respect to the concomitant occurrence of amyloid and NBA were negative correlations between nuclear IgM and IgA binding and amyloidosis. Of the various species thus far studied, the hamster is the first in which there has been no aging effect in respect to NBA.

This study compares the lifespan changes in respect to several brain-body weight parameters between several rat strains and human population groups. In the rat, following an initial potential decline, these parameters remain essentially constant throughout the lifespan. In the human, following a similar postnatal decline, there is a further progressive decline after about age 50. However, this decline with age disappears when correction is made for percent body fat. Thus, while both brain and body weight decline with age in humans, they do not decline proportionately. In both species brain and body weights are greater in males than in females, but when the data are translated into the several brain-body parameters females generally show higher indices than males, and this correlates with their superior longevity. These findings are discussed in respect to the role of the brain in aging.

The direct immunoperoxidase technique was used to assess IgG and IgM nuclear and cytoplasmic binding to the mouse brain as a function of age, brain damage, and stress. Nuclear IgM binding was found to increase in older animals (over 30 months of age). There was also heightened nuclear and cytoplasmic binding 1 week after a frontal cortex lesion in mice approximately 2 months of age. Mice with brain lesions, however, did not show greater binding some months later and, if allowed to die from natural causes, actually showed less IgM nuclear binding than control animals. No association was found between lifespan and binding or between stress per se and binding. The capacity of the blood-brain barrier to repair itself after injury is discussed, and these findings are compared to earlier data based on indirect measurement procedures.

The multiplication of Rickettsia mooseri in fertile eggs is speeded up and quantitatively increased by single dose x-radiation given either 24 hours before or 48 hours after inoculation. This effect is noted at all dosage levels studied, ranging from 100 to 1500 r. The rickettsiostatic effects of high incubation temperature (40 degrees C.) and of streptomycin are neutralized by radiation, but the rickettsiostatic actions of PABA, penicillin, and aureomycin are not altered. Possible mechanisms of action and implications of the observed effects are discussed.

Groups of 10 day old embryonate eggs were given 250, 500, 750, and 1000 r of x-radiation, and oxygen consumption determinations were made subsequently at various intervals during a period of 90 hours. In general, the effect of radiation was moderately stimulatory, but after 90 hours the respiratory rates of the 250 and 1000 r groups were well below those of the control groups. The most striking effect, noted in 3 separate experiments, was the occurrence of a "3 step staircase" type of oxygen consumption curve in all irradiated groups, the levelling off periods apparently occurring between the 4th and 14th, the 24th and 36th, and the 42nd and 66th hours after exposure. These curves were in striking contrast to those shown by groups of non-irradiated eggs, which were practically of the straight line type.

Groups of embryonated eggs infected with the PR8 strain of influenza virus A were incubated at 34 degrees , 37.5 degrees , and 40 degrees C. At frequent intervals, for periods ranging up to 96 hours, pooled allantoic fluids were tested simultaneously for infectivity and hemagglutination. After about 12 hours of virus growth, fluids often showed infectivity titres greater than 10(-5), but were incapable of causing hemagglutination. At later time intervals, marked disagreement between the two tests for viral activity was noted at all temperatures, but most strikingly at 40 degrees C. Hemagglutination titres were highest and best sustained in eggs incubated at 34 degrees C., while incubation at 37.5 degrees C. resulted in the highest and best sustained infectivity titres. Hemagglutination titre determinations do not reflect accurately the rate of influenza virus multiplication. Possible reasons for the lack of correspondence between hemagglutination and infectivity are discussed.