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Many drugs are not able to enter the brain due to the presence of the blood-brain barrier (BBB) and therefore cannot be used in the treatment of diseases of the brain. Since it is now known that the brain is under immunological surveillance, we hypothesized that phagocytic cells of the innate immune system, mainly neutrophils and monocytes, can be exploited as transporters of drugs to the brain. To target circulating mononuclear phagocytic cells, negatively-charged nano-sized liposomes were formulated encapsulating serotonin, a BBB impermeable neurological drug. Brain uptake, biodistribution, and the mechanism of brain transport were examined in vitro and in rats and rabbits by utilizing double-radiolabeled (3)H (in the membrane) and (14)C-serotonin (in the core), and liposomes with fluorescent markers (membrane and core). The brain uptake of liposomal serotonin was significantly higher (0.138%+/-0.034 and 0.097%+/-0.011, vs. 0.068%+/-0.02 and 0.057%+/-0.01, 4 h and 24 h after IV administration in rats, serotonin liposomes and in solution, respectively). The same brain uptake of both empty and serotonin liposomes, the co-localization in the brain of both markers, and the unchanged ratio of (3)H:(14)C suggest that intact liposomes entered the brain. Since treatment of animals by liposomal alendronate resulted with inhibition of monocytes but not of neutrophils, and with no brain delivery, it is suggested that monocytes are the main transporters of liposomes to the brain.

Brain development in humans occurs stagewise in correlation with the onsets of the main Piagetian stages of reasoning development. This allows a description of cognitive development as at least partially resulting from and dependent upon biological events occurring in the brain. Evidence shows that some eventual brain structures depend on a combination of biological events and instructional inputs. This contributes to the instruction dependence of the higher cognitive functions. Such a description thereby permits some novel working hypotheses about normal cognitive development and how to foster it as well as suggests alternative ways of creating intervention programs for children from deprived environments., (Copyright 2001 Academic Press.)

Stages of increased cerebral blood flow accompany stages of rapid brain growth The existence of stages of rapid brain growth implies the existence of associated stages of increased cerebral blood flow (CBF) to supply the substances and energy needed for the added brain weight. Studies in the literature give developmental data for CBF in humans which show stages of increased cerebral blood flow at ages starting just preceding and/or coincident with the ages of the rapid brain growth stages. Confirmation of the implication for one of the earliest stages is also found in PET data. Additionally, data for rodents show a similar association of stages of increasing CBF and their brain growth stages. Thus, to the accuracy of the data, the implication is confirmed. Finding stages in cerebral blood flow predicts the existence of stages of brain growth. In addition; finding correlated blood flow stages also supports the age spans of the stages of rapid brain growth in both species. Such correlations also suggest that measurements of blood flow anywhere in the body might serve to reveal rapid growth stages in particular localities or organs if the blood flow shows significant stages. The ratio of energy consumed in brain to that in total body decreases from close to 100% at birth to the adult value of about 20% by age 18 years.

Brain weight and performance on a spatial-location test were measured from birth to weaning on mouse strains CD1, Balb/c, and their F1 cross. For CD1, onsets of both the last rapid-brain-growth stage and nonzero scores on the spatial-location test were around age 17 days; asymptotes of both were reached about age 23 days. Balb/c and F1 had at least 5- to 6-day delays of both onsets and asymptotes. For the strains studied, onset of nonzero performance on the spatial-location test may be a provisional indicator of onset of significant and rapid brain growth after age 15 days. The delayed F1 brain growth stage could indicate that control of brain growth about age 20 days resides in an inhibitory factor present in Balb/c but not in CD1.

Starting at parturition and continuing until weaning, mothers of five mouse litters received tap water while five others had 10 mg PbAc/ml in their drinking water. The offspring receiving lead from the mothers had significantly lower body weights after the first days of receiving lead; their slowed body growth led to a 2-day delay of onset (usually at 16-18 days) of their last rapid body growth stage. They also had significantly smaller brain weights between age 14 days and weaning (23 days). The onset of rapid brain growth was delayed from its usual onset at 16-18 days to about 22-23 days before rising to about the same value as the control mice at 26 days. Thus, the initial effect on brain growth is decidedly greater than on body growth, though brain weight later reaches close to the control value.

Data in the literature show that in humans the fraction of the total electroencephalographic (EEG) energy that appears in the alpha frequencies rises from about zero at birth to about 70% in adults. This rise is shown to occur mainly in 5 stages, the ages of which correlate with those of stages of increase in brain weight. Supporting the correlation are data on gender dimorphism in humans in both brain weight and EEG development, as well as limited data on development in kittens, rats, mice, and guinea pigs.

The football field, an ideal setting for research in trauma by radiotelemetry, has allowed collection of data on man's response to impact. The physiologic response adds a new dimension to the measurement of impact tolerance. The present study has demonstrated the protective response of the athlete and explains how he is able to dissipate forty times more kinetic energy than his helmet is capable of absorbing.

In a 1974 survey of data on human brain and head growth statistically significant peaks in growth rates of human brains were found around ages 11 years and 15 years. In addition, correlations were found in that almost all studies had non-significant peaks around ages 3, 7, 11-12 and 15 years; troughs were found at the intermediate ages (5, 9, and 13 years). More recent data include a very extensive collection of head circumference data from a dozen countries which showed statistically significant peaks around ages 7, 12, and 15 years. Confirmation of those results have been found in data on cortical thickness, photographs of neuronal arbors, and the percent of EEG energy found in the alpha-frequencies (8-13 cps). The proposed peak around age 3 years cannot be decided from existing brain weight and head circumference data bases, but the EEG data and the cortical thickness data supply significant support. Overall, there are statistically significant peaks in brain growth rates at age 7, 11-12, and 15 years, though the latter holds only for males at present. The significance of the stages for development of brain functions is being explored.

A relation between head circumference and brain weight of humans is generally believed to exist, but the literature contains only two studies which exhibit a quantitative aspect of the relation, showing that brain weight is proportional to the cube of the head circumference from birth through age 3.5 years. By assembling data from autopsy records, we have been able to show that this cubic relationship holds through brain maturation at around age 18 years.

The recent dramatic development of molecular neurobiology has focused almost entirely on biological events in individual brain cells, and it seems that many of the goals of such work will soon be attained. Yet, when we attain those goals, we will still have to ask how this information will enable us to understand the properties of brain cell collectivities and their presumptive roles in higher brain functions. Even general ideas about those functions are not yet well defined. Therefore, it seems worthwhile to start studying correlations of the molecular events to these higher functions to help delineate the molecular aspects that need study. It is readily appreciated that we cannot tell what other animal species see, hear, taste, smell and feel when touching something, though we can foresee the time when we will be able to detail the biochemical and biophysical consequences of all inputs to those senses. Thus, however deep our understanding of the biology of those species, we are unable to establish relations between their biological responses to inputs and their presumptive mental perceptions. Even though humans can use language to talk about those perceptions, we cannot even verify whether someone else's perceptions are the same as our own, as with the old question of whether two individuals see the same thing when viewing something blue. Questions about still higher mental functions of human brains are even less accessible to analysis and can be approached at best, by using correlations. In this article are a number of such questions and their current correlation-level answers.

Study of data in the literature on rat and mouse brain growth from birth to weaning reveals a stagewise growth in average brain weight. Rapid growth occurs in the intervals between days 0-6, 8-12, and 17-23 after birth. Slow growth periods then lie in the intervals 6-8, 12-17, and after 23 days. The first slow growth period is signalled by events occurring at its end: substantial acceleration of synthesis of RNA, DNA, protein, and myelin. The second slow growth period is characterized by at least a 3-day interval during which there is very little increase in average brain weight compared with what occurs just before and just after that period; the correlation among 12 studies is highly significant. Implications are discussed for cross-species' extrapolation of findings about brain development.