Biological Insults Research Articles

Predicting the Developmental Outcome of Two-Year-Old Children Born Exposed to Methadone: Impact of Social-Environmental Risk Factors

Suggests that conclusions drawn concerning the development of drug-exposed children have been too extreme in either condemning the children as damaged or proclaiming them unaffected. Results from a longitudinal study of the development of methadone-exposed and comparison-group children are presented. Social-environmental risk factors, sex of child, and maternal communication are used to predict the children's developmental (outcome at age 2 years. No significant differences in outcomes between the groups were found. For the methadone group only, cumulative environmental risk factors predicted poorer developmental outcome. We note that the problematic neurobehavioral profile of some drug-exposed children can result from either biological insult associated with drug exposure or environmental risk factors including maternal communication. The importance of early intervention for drug-exposed and comparison children and their families is emphasized.

Deficient cumulative learning: An animal model of retarded cognitive development

Biological insults that produce profound mental retardation (MR) in humans have generally been found to produce little cognitive dysfunction in animal models. Based on the fact that impaired transfer of learning is one of the hallmark characteristics of mentally retarded humans, we proposed that this discrepancy may largely reflect the common use of a single learning task as the critical cognitive index rather than an assessment of cumulative learning. Consistent with this hypothesis, rats exposed to prenatal hyperphenylalaninemia (a model of maternal PKU) evidenced significant impairment when tested on a series of 10 problems designed to allow for positive transfer of learning. This same treatment, however, did not alter learning rate of the individual tasks that comprised this series when presented singly to experimentally naive animals. Deficient transfer of learning contributed significantly to the impairment observed in the maternal PKU group. These results support the hypothesis that the assessment of cumulative learning is an important component of animal models of impaired cognitive development.

The molecular biology of carcinogenesis.

Carcinogenesis may result from the action of any one or a combination of chemical, physical, biologic, and/or genetic insults to cells. The process of carcinogenesis may be divided into at least three stages: initiation, promotion, and progression. The first stage of carcinogenesis, initiation, results from an irreversible genetic alteration, most likely one or more simple mutations, transversions, transitions, and/or small deletions in DNA. The reversible stage of promotion does not involve changes in the structure of DNA but rather in the expression of the genome mediated through promoter-receptor interactions. The final irreversible stage of progression is characterized by karyotypic instability and malignant growth. Critical molecular targets during the stages of carcinogenesis include proto-oncogenes, cellular oncogenes, and tumor suppressor genes, alterations in both alleles of the latter being found only in the stage of progression. Although many of these critical target genes have been identified, the ultimate number and characteristics of molecular alterations that define neoplasia have not been elucidated.

Stimulation of human monocyte β-glucan receptors by glucan particles induces production of TNF-α and IL-1β

β-glucans are pharmacologic agents that rapidly enhance host resistance to a variety of biologic insults through mechanisms involving macrophage activation. To determine whether stimulation of the β-glucan receptors on human monocytes resulted in cytokine production, monolayers of monocytes were incubated with purified yeast glucan particles and measured for tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA and protein. By Northern blot analysis, TNF-α mRNA was detected within 30 min of incubation with glucan particles, peaked at 2 h, and remained elevated for at least 8 h. Glucan induction of IL-1β mRNA followed a similar time-course of initiation and accumulation. By enzyme-linked immunosorbent assays (ELISAs), significant levels of TNF-α and IL-1β were present in supernatants of glucan-treated cells within 1 h and plateau levels of both cytokines were approached within 4 h. At particle-to-cell ratios of from 0.4 to 18, glucan particles induced dose-dependent increases in TNF-α and IL-1β mRNA and corresponding increases in TNF-α and IL-1β proteins. Exposure of monocytes to glucan particles for 0–30 min and washing before continued incubation for 4 h in particle-free buffer induced production and secretion of TNF-α and IL-1β in a time-dependent fashion compatible with phagocytosis. The pretreatment of monocyte monolayers with trypsin reduced glucan-induced production of TNF-α and IL-1β in a dose-dependent manner with 5 μg/ml of trypsin effecting reductions of greater than 50%. Thus, glucan particles induce human monocyte production of TNF-α and IL-1β by a mechanism that is dependent on trypsin-sensitive β-glucan receptors.

Plasma homovanillic acid as a predictor of response to neuroleptics.

Fourteen schizophrenic subjects were evaluated for degree of psychosis before and after treatment with the antipsychotic drug haloperidol and for plasma homovanillic acid concentration after four and 28 days of treatment. A significant correlation was found between an increase in homovanillic acid concentration on day 4 or a decrease from day 4 to day 28 and the degree of improvement after four weeks of treatment. Thus, those patients who had the greatest change in plasma homovanillic acid in response to neuroleptic blockade showed the greatest improvement. These and other observations have led us to propose that the central dopaminergic system, through adaptive changes in activity, serves as a physiologic buffer system protecting against destabilization of mental function from diverse biologic or psychologic insults.

Calcium and osteoporosis.

It has become increasingly apparent that the pathogenesis of osteoporosis is complex, poorly understood, and ill-defined. Calcium deficiency and/or calcium malabsorption and the homeostatic response to this biological insult may ultimately prove to be one of the pivotal factors in conditioning or modulating the skeletal response to senescence. Until we know more about the prevention and potential reversibility of age-related changes in bone cell function, hormonal secretion and metabolism, and dietary patterns that prove deleterious to skeletal health, clinicians will be confronted with an ever-increasing population of aging, fracture-prone, osteoporotic patients. Because calcium supplements improve the calcium balance of perimenopausal and postmenopausal women and because improvements in calcium balance can be correlated with increased skeletal mass, it appears desirable to focus our efforts on diets and/or calcium supplements that guarantee an adequate supply of this essential mineral. Because calcium replacement may simply retard bone resorption and may not restore bone already lost by the fracture-prone, osteoporotic female, dietary analyses and appropriate modification of calcium intakes should be made at least in the third and fourth decades of life, with the goal of retarding the inexorable loss of skeletal tissue as early as possible.

PKU, learning, and models of mental retardation.

Experimental phenylketonuria was induced in male rats by daily injections of alpha-methylphenylalanine and phenylalanine on postnatal Days 3-31. Beginning at 8 weeks of age, the animals were subjected to a test of observational learning followed by a test of latent learning (two tests of "advantageous" learning). The animals subjected to the PKU treatment early in life showed significant learning deficits in both tests. The importance of these studies lies in the fact that unlike conventional tests of learning, tests of advantageous learning are sensitive to the kinds of biological insults which cause mental retardation in humans. This differential sensitivity evident in studies of animal models of cognitive pathology is analogized to the areas of dysfunction which characterize human mental retardation. Suggestions for the development of appropriate models of intellectual development are made.

Twinning handedness and embryology.

It is hypothesized that in some pairs of monozygotic twins, the biological insult occasioning the split may also cause a reversal of predetermined handedness and that this cannot happen if the split occurs before the ovum itself has acquired laterality. The use of the word 'split' here is not meant to give support to the concept of mirror-imaging.

A strategy for developing novel drugs for the treatment of schizophrenia.

Antipsychotic drugs currently in use have been developed as antidopaminergic agents; that is, normalization of psychotic symptoms occurs through a reduction in dopaminergic activity, usually by blockade of postsynaptic dopamine receptors. Based on this current understanding of the mechanism of action of antipsychotic drugs, it is suggested that one physiological role of the dopaminergic system is to down-regulate in the face of biological or psychological insult, as a means of maintaining mental stability. An attempt to develop new drugs to improve the efficiency of this down-regulative system as an alternative to conventional drugs that block dopamine receptors is proposed.

Hypothermia induction and survival in hamsters: the role of temperature acclimation and an anesthetic (Holothane).

Abstract In summary, it has been shown that a reduction of biological insult during hypothermic induction with light anesthesia (halothane) will greatly enhance the survival ability of hamsters in hypothermia. Heat acclimation and cold acclimation prior to hypothermia drastically alter the thermogenic capacity of these animals at low body temperatures while apparently not altering the hypothermic survival capabilities. Normalization and shortening of induction times was also achieved with the halothane-helox method which will permit future comparative studies where it is essential to eliminate effects caused by variations in the induction time.

Biological and Environmental Determinants of Early Development,

I found this an exciting book, not so much because of any breakthroughs in our understanding of child development, but because of the broad look at development that it encompasses in traveling from the subcellular level to the body politic. Equally fascinating is that no matter at which end of this spectrum one begins, the underlying theme of structure leads to function leads to behavior appears to apply equally well. A number of chapters deal with the effects of various biological insults on the developing nervous system and the methods available to study them, such as staining techniques, tissue culture, and the use of enzyme markers. There is a good review of Drugs in Pregnancy and Their Effects on Pre- and Postnatal Development by Kelsey, with an interesting observation that nurses working in operating rooms have a higher rate of miscarriage, suggesting a relationship to the anesthetic agents being used

THE FINE STRUCTURE OF THE HAMSTER SEMINAL VESICLE WITH SPECIAL REFERENCE TO PIGMENT FORMATION.

This study describes the fine structure of the hamster seminal vesicle. Intact, sexually mature young and aged animals were used to obtain the results presented. The epithelium of the hamster seminal vesicle contains numerous large electron-dense structures, with a single limiting membrane, with many internal granules and, in the aged animals, myelin-like figures. Based on histochemical results presented in this study, and those of others, it is suggested that this material is a lipofuscin pigment. This substance is of special interest inasmuch as in the hamster seminal vesicle epithelium, pigment is a more sensitive indicator of circulating androgen than is, as in the case of the rat seminal vesicle, regression of cell height. It is possible that this pigment takes origin as breakdown products of mitochondria, the endoplasmic reticulum and the Golgi apparatus. The relation of “pro-pigment granules” and lysosomes is discussed. Results indicate that pigment is formed at sites of increased catabolism in response to a biological insult to the cell.