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PubMed1984

General toxicity testing: sense and non-sense, science and policy.

The dramatic increase in the number and variety of industrial chemicals in addition to natural compounds, and the increased public concern about their health effects, has in the last few decades led to a remarkable development in number and types of toxicity tests employed to assess safety of chemicals. Not too many years ago, toxicity tests were relatively simple in design and conduct. They were sometimes inadequate in a number of aspects. Toxicity testing has now become an unbalanced mixture of sound science and policy. Many times companies wishing to market products internationally are faced with a plethora of different national regulatory requirements. In this presentation attention is given to requirements for toxicity data and the need for harmonization in guidelines while avoiding rigid protocols. The wisdom and necessity of conducting all currently required tests will be considered. The relevance of certain biochemical, hematological, and pathological parameters is discussed as is the relevance of Good Laboratory Regulation for toxicity testing. The importance of a scientific evaluation of all chemical biological data derived from modern sensibly designed toxicity tests with respect to extrapolation and safety assessment is emphasized. Future development in certain areas of toxicity research is stressed and examples are given.

Animals↗
PubMed1988

Methodological issues in social support and social network research.

With the plethora of articles describing a relationship between social support and/or social network and health status, it was considered useful to take stock of the current status of research in this area, focusing on two critical methodological issues: clarity of definition, and validity and reliability of the measurement instruments. Of the 33 instruments reviewed only modest agreement was found in conceptual definition, and frequently the concepts were not defined or ill-defined. Of particular concern is the definitional confusion between social support and social network. Variables used to operationalize these concepts confirm this lack of specificity and ambiguity in definition. As for validity and reliability, many of the investigators reported no data on these issues; others provided information that only modestly supported the validity or reliability of their instrument. The conclusion of this assessment suggests the need to clarify the essential elements of social support and social networks in order to better distinguish between the behavioral (support) and structural (network) variables that may be affecting health status. A question is also raised as to the likelihood of a single questionnaire being designed that would accurately measure the perceptions of support or supportive behaviors in the variety of supportive research that will continue to be studied. Finally, more rigorous standards need to be used by investigators in establishing the validity and reliability of the instruments in order to improve their predictive utility.

Data Collection↗
PubMed1991

Current methodological refinements for the acquisition of life history information in fishes: paradigms from pan-oceanic billfishes.

1. Many factors contribute to hinder progress in estimating and verifying age, growth, and life history strategies of billfishes. It is necessary to discern growth of an individual fish to circumvent problems in substantiating age, growth, longevity and age at maturity. These biological characteristics allow us to discover what life history periods are critical to survival and reproduction. 2. Two theoretical approaches may be considered for studying the age of billfish: Age may be delineated in terms of the passage of time (chronological age), or may be examined as the progression of physiological development (physiological age). 3. Hard tissues such as otoliths, spines, vertebrae and post-mitotic tissues contain a plethora of biological and ecological information documenting a fish's chronological and physiological age and individual life history. In calcified tissues, this information can be obtained when the proper techniques are used to investigate the structural and chemical components of billfish hard parts. Chemical analyses of stable isotopes and elemental concentrations in calcified tissues suggest that calcified tissues contain hydrographic, nutritional and migrational information--life history information. 4. Utilization of structural and chemical analyses of billfish otoliths, vertebrae, and other hard parts, enables specific phases of growth to be linked to environmental occurrences. Measurement of the metabolically accumulated cellular pigment, lipofuscin, in post-mitotic tissue may make it possible to define physiological age or readiness. Internal and external structural and chemical analyses of otoliths, vertebrae, and other hard parts, combined with biochemical assays of post-mitotic tissue will greatly enhance studies of life history. The methods presented provide insights into means by which life history knowledge can be obtained.

Aging↗
PubMed1991

Stereology: a method for analyzing images.

This review deals with notions of shape, sizes, numbers, densities and orientation in space, all basic concepts in stereology. With the initiation by Delesse in 1847, but mainly since the beginning of the XXth century, many stereological methods have been published allowing us to relate two-dimensional measurements easily obtainable on flat histological images with three-dimensional characteristics of the structure analysed. Looking at these methods, the neurobiologist, generally impermeable to concepts of sampling, statistical bias, efficiency, cost of effort and distribution-free, is discountenanced and continues old laboratory usages and customs. Furthermore, for the last ten years, the advent of a plethora of new powerful tools, considered as assumption-free and more efficient than the previous ones, increase the risk proportionately the disarray of the potential user. The purpose of this review is to present synthetically all traditional and actual aspects of stereology in order to guide the reader in the labyrinth of this speciality. The necessarily short exposition is compensated by many references to which the beginner or the initiated can refer.

Artifacts↗
PubMed1996

Preferential partner selection in an evolutionary study of Prisoner's Dilemma.

Partner selection is an important process in many social interactions, permitting individuals to decrease the risks associated with cooperation. In large populations, defectors may escape punishment by roving from partner to partner, but defectors in smaller populations risk social isolation. We investigate these possibilities for an evolutionary Prisoner's Dilemma in which agents use expected payoffs to choose and refuse partners. In comparison to random or round-robin partner matching, we find that the average payoffs attained with preferential partner selection tend to be more narrowly confined to a few isolated payoff regions. Most ecologies evolve to essentially full cooperative behavior, but when agents are intolerant of defections, or when the costs of refusal and social isolation are small, we also see the emergence of wallflower ecologies in which all agents are socially isolated. Between these two extremes, we see the emergence of ecologies whose agents tend to engage in a small number of defections followed by cooperation thereafter. The latter ecologies exhibit a plethora of interesting social interaction patterns.

Algorithms↗
PubMed1983

Morphological alterations in dorsal root ganglion neurons and supporting cells of organotypic mouse spinal cord-ganglion cultures exposed to taxol.

Explants of 14-day fetal mouse spinal cord with attached dorsal root ganglia, which had become differentiated over 2-3 weeks in culture, were exposed to 1-2 microM taxol for up to 6 days. The culture medium was supplemented with nerve growth factor (300 units/ml) during exposure to the drug. By 3-6 days in taxol, unusually numerous microtubules were seen in peripheral perikaryal and proximal neuritic regions of ganglion neurons. Microtubules also engirdled massive aggregations of pleomorphic vesicular/cisternal elements in many neurons. These aggregates were visible as unusual 'clear' spheroidal regions in the living cells, and were often as large as the nuclei. Some of the elements comprising these striking vesicular/cisternal accumulations appeared to be portions of disrupted Golgi complexes normally polarized around the cytocentrum, as well as hypertrophied smooth endoplasmic reticulum formations. In other neuronal areas, Golgi complexes and other organelles were altered or disrupted to lesser degrees. Ordered microtubular arrays occurred along endoplasmic reticulum cisternae both in neuron somata and neurites. Over time, a plethora of microtubules assembled throughout the perikarya in various orientations apparently unrelated to microtubule organizing centers. Unlike the effects of other plant alkaloids that interact with tubulin, there was no discernible increase in filaments, although their distribution appeared altered. Concentric ordered microtubular-macromolecular lamellated complexes were seen only in neurites. Neuronal nuclei were misshapen, often displaced, and displayed fine structure reminiscent of chromatolysis. Satellite and Schwann cells contained atypically abundant microtubules, abnormal cisternae, disrupted Golgi complexes, and increased lysosomes. Some nuclei displayed abnormal chromatin, and in rare cases even microtubules. We suggest that taxol alters the distribution, integrity, and/or organization of organelle systems in dorsal root ganglion cells by engendering unusually abundant microtubules in abnormal groupings and aberrant locations in these cells.

Alkaloids↗
PubMed1996

Growth factor-induced c-fos expression defines distinct subsets of midbrain dopaminergic neurons.

Growth factors are considered pivotal for the development, maintenance, and function of mesencephalic dopaminergic neurons. Recent studies have identified a plethora of growth factors which support the survival and differentiation of embryonic dopaminergic neurons. However, the exact cellular targets of these growth factors, and, thus, their precise mechanisms of action, remain largely unknown. To identify these cellular targets, we analysed, at the single cell level, growth factor-induced c-fos expression in dissociated mesencephalic cell cultures derived from a fos-lac Z transgenic mouse line. Pharmacological interference with cell-cell communication was utilized to control for direct growth factor effects. beta-Galactosidase-expressing cells were phenotypically characterized by immunocytochemistry to specific neural cell markers. Glia cell line-derived neurotrophic factor, basic fibroblast growth factor, brain-derived neurotrophic factor, and neurotrophin-3 directly induced Fos expression in differently sized, yet overlapping, populations of tyrosine hydroxylase-immunoreactive dopaminergic neurons. In an additional subpopulation of dopaminergic neurons, neurotrophin-3 induced fos-lac Z expression indirectly through a glutamate-mediated activation of N-methyl-D-aspartate receptors. Consistent with their proposed glial-mediated mode of action, transforming growth factor alpha and platelet-derived growth factor induced Fos expression predominantly in glia but only in a very small number of dopaminergic neurons. These findings demonstrate that individual dopaminergic neurons represent the direct targets of different sets of extracellular growth factors. Our findings further establish that growth factors affect dopaminergic neurons by indirect mechanisms which require specific cell-cell communication. These data also suggest a potential role for growth factors in the establishment of the morphological and functional diversity of midbrain dopaminergic neurons.

Animals↗
PubMed1991

A novel hypothesis concerning the mechanisms of activation, and of control, of periodontal bone loss.

Chronic inflammatory periodontitis fulfills the classical definition of an infectious disease in that it is a disease of the host caused by the activities of one or more parasites. Typically, the etiology of an infectious disease has been defined as the specific microbe which incites the disease process, even though the quality and nature of host responses to the pathogen may underlie much of the pathology seen. This approach in the study of the etiology of chronic periodontitis has not resulted in the identification of a single 'periodontopathogen', but rather is leading to the realization that multiple sets of microbes may induce the same endpoint, albeit some possibly more efficiently than others. The premise of this paper is that a different view of the literature in the area, with the primary emphasis on the mechanisms of damage and resistance to periodontitis, reveals a probable commonality, rather than a plethora of diseases. The concept of a mechanism-based etiology, rather than of a microbe-based one, deserves consideration for this complex, host-parasite interaction. The novel hypothesis presented here is that the common virulence factor of chronic periodontitis is lipopolysaccharide (LPS), that the central damaging mediator is a cyclooxygenase product of arachidonic acid (probably prostaglandin E2), and that the critical resistance mechanism that limits disease activity is the effective, peripheral neutralization of LPS by emigrated polymorphonuclear neutrophils.

Alveolar Bone Loss↗
PubMedDate not supplied

Prenatal diagnosis of central nervous system abnormalities.

Fetal anomalies have been the subject of innumerable publications both in the prenatal and neonatal literature. This has significantly increased in the last 10 years, mainly because of the advent of high-resolution ultrasound equipment and improvement of scanning techniques. In addition, guidelines issued by professional organizations involved in prenatal diagnosis have encouraged a more universal approach to the imaging and documentation of prenatal findings. The fetal central nervous system is the most frequently investigated organ system, mainly because of its easy accessibility and prominence even in the early stages of embryologic development. The biparietal diameter was the first fetal measurement to be widely used in determining gestational age. As investigators gained more experience, the appearance of ultrasound images achieved the resolution that allows direct comparisons with gross specimens and more recent sophisticated techniques of computed tomography and magnetic resonance imaging. Now endovaginal ultrasound can document early first trimester development and compare it to known embryologic landmarks. Interest in demonstrating the ultrasound counterpart of central nervous system structures in the early stages of development has resulted in a plethora of articles proving the unique ability of ultrasound in imaging the developing fetus. In view of all these developments, the beginning ultrasound specialist is faced with the challenge and responsibility not only of being familiar with the literature but also of the mastery of scanning techniques that allow accurate prenatal diagnosis. It is therefore helpful to review key developmental milestones in embryologic life and correlate them with the corresponding prenatal ultrasound appearance. In addition, the changing appearance of the developing fetus has created a need for a systematic approach in the evaluation of structures so routine protocols can be established. This has been the subject of other publications that allow the novice to draw from the cumulative experience of different centers around the world. It is important to pay attention to the specifics described in the literature when duplicating results in one's laboratory. The frustration of not being able to reproduce results is common, especially when technical limitations prevent imaging under ideal conditions. This is especially true in patients who are first seen in the later third trimester with no prior prenatal care.(ABSTRACT TRUNCATED AT 400 WORDS)

Brain↗
PubMed1995

Markers for immunotoxic effects in rodents and man.

There is growing interest and concern in society about the capacity of chemicals to impair immune responses and trigger autoimmune disease. Methods to investigate chemical-induced immunosuppression have been developed and validated in the mouse and rat. Animal models that are suitable to investigate the ability of chemicals to induce autoimmune disease are virtually lacking. From the plethora of tests to assess immunity in man, panels of biomarkers to study immunotoxicity in humans have been proposed. Such studies in humans are considerably more complex than in animals as non-invasive tests are limited, responses in the population are heterogeneous, and exposure levels are often low. Human risk assessment is therefore mostly based on animal studies. As examples of compounds affecting biomarkers in animals and man, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and hexachlorobenzene are discussed.

Animals↗
PubMed1995

Function and activation of the transcription factor NF-kappa B in the response to toxins and pathogens.

The ubiquitous transcription factor NF-kappa B regulates the expression of a plethora of genes. In most cell types the dimeric DNA-binding form of the transcription factor is retained in the cytoplasm by physical association with the inhibitory I kappa B molecules. Five distinct DNA-binding subunits have so far been identified in vertebrates, which share a N-terminal homology region responsible for DNA-binding and dimerization. Exposure of cells to a variety of pathogenic and/or toxic agents leads to the generation of hydrogen peroxide and the inducible phosphorylation of I kappa B, which is a prerequisite for its proteolytic degradation. The DNA-binding subunits can subsequently enter the nucleus, bind to their cognate DNA and activate transcription.

Animals↗
PubMed1994

Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee.

The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity rate, mortality rate (10% to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

Clinical Trials as Topic↗
PubMedDate not supplied

Mechanisms of CNS injury in behavioral dysfunction.

Advances in the neurosciences have led to a greater understanding of the anatomical, biochemical, and molecular loci involved in injury to, and adaptation of, the central nervous system. Recent research has permitted the elucidation of the mechanisms for some neurotoxicants whose actions have been studied for decades, as in the example of the pyrethroid insecticides. In contrast, the mechanism of the neurotoxicity of the organophosphate insecticides and nerve gases has been known for many years, but our understanding of the many resulting sequelae has been markedly increased by recent discoveries. Two examples illustrate the strengths and weaknesses of such methods in predicting neurotoxicity. Studies of the parkinsonian-like toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (a by-product of synthesis of illicit opiates) exemplify the best application of current methods in neurotoxicology. It has been shown that the expression of MPTP toxicity requires both metabolism of MPTP to the proximal toxicant 1-methyl-4-phenylpyridinium (MPP+) and active uptake into central dopamine neurons. The discovery of binding sites of MPP+ in these cells has clarified how dopamine neurons are destroyed, thereby causing neurological signs. This illustrates two key concepts: first, the bioconversion of compounds to proximal toxicants is often ignored, and second, these events are unlikely to be detectable by in vitro studies that focus on a few biochemical endpoints. Another useful example was that of erythrosin (FD&C Red No. 3), in which numerous in vitro studies suggested that this food color was a potential neurotoxicant. However, this was shown to be an artifact of the ability of this color to disrupt biomembranes at high in vitro concentrations, and this idea was supported by negative data from both behavioral and clinical studies. Thus, the plethora of possible molecular and biochemical targets in the central nervous system (receptors, second messenger events, transmitter-modulator synthesis, storage and release, membrane maintenance, etc.) preclude the likelihood of developing a single test or a battery of neurochemical or biochemical tests that will be able to screen for neurotoxicants randomly or efficiently. Use of in vitro methods is likely to detect both false positives and negatives. While the availability of theoretical or phenomenological data provides the best start to the application of available biochemical and molecular techniques, predictions of neurotoxicity best can come from theoretical comparison of the structure of suspect compounds (and hypothesized metabolites) with known target sites in the CNS.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Arachidonic acid and free fatty acids as second messengers and the role of protein kinase C.

In addition to serving as the precursor to a plethora of eicosanoids and other bioactive molecules, arachidonate may function as a bona fide second messenger. A number of studies have documented the ability of arachidonate to regulate the function of multiple targets in vitro systems. This has been particularly well established and studied with the activation of protein kinase C by arachidonate in a mechanism distinct from activation by diacylglycerol. In cells, arachidonate induces a number of activities, many of which may be independent of further metabolism to eicosanoids; suggesting possible direct action of arachidonate. This review summarizes the current state of knowledge on the possible second messenger function of arachidonate with specific emphasis on the regulation of protein kinase C.

Animals↗
PubMed1996

The associations of psychopathology in epilepsy: a community study.

There is a plethora of studies documenting the association between psychosocial disadvantage and epilepsy but a paucity of studies explaining the precise nature of that relationship. Previous studies have been hampered by methodological problems including small sample size and selection bias. This study examined the aetiology of psychopathology in epilepsy in a cross-sectional community study. A significant proportion of patients were anxious and depressed and many reported side effects of their medication. Stepwise multiple regression techniques were employed to examine the relationship between clinical, demographic and psychosocial variables. Results indicated that psychosocial variables were the best predictors of each other but when these were taken into account, patient perceived seizure severity was an important predictor variable in understanding the relationship between epilepsy and psychosocial functioning.

Adult↗
PubMedDate not supplied

Dopamine and norepinephrine activity in schizophrenia. An integrative perspective.

The dopamine (DA) hypothesis of schizophrenia stated that increased DA activity is the primary cause of schizophrenia. Recently, even though increased DA activity is in fact involved in psychotic symptoms and antipsychotic drug response, it has become clear that decreased DA activity is present in remitted and chronic states and may relate to deficit symptoms and cortical lesions. In addition, the norepinephrine (NE) system seems to be involved in symptomatology, antipsychotic drug response, course, and outcome in schizophrenia. This review supports the hypothesis that a disturbance in DA and NE activity regulates schizophrenic behavior. A plethora of DA- and NE-related findings in schizophrenic patients are reviewed in relationship to each other according to basic science data and to presently entertained hypotheses, with emphasis on a neural developmental disturbance interacting with a genetic predisposition shaped by environmental factors.

Brain↗
PubMedDate not supplied

The role of the acute-phase protein alpha 1-antichymotrypsin in brain dysfunction and injury.

The crystal structure of proteolytically modified human ACT has been solved at 2.7-A resolution (Baumann et al., 1991). The final model consists of 374 amino acids, 126 solvent molecules and 5 sugar residues. Asn70 is glycosylated and Asn104 is probably glycosylated. The role of carbohydrates in serpin function may be 3-fold: secretion, removal from circulation and recognition by receptors for complex uptake (Travis et al., 1990). Experiments with recombinant, non-glycosylated ACT have shown that glycosylation has no effect on the association rates of ACT with its target proteases (Rubin et al., 1990). The X-ray diffraction studies also revealed that a certain ACT region is involved in DNA binding, although the physiologic relevance of this binding is still unknown. Using a plethora of techniques, scientists are starting to understand the role of ACT in health and disease. It is 14 years since ACT was first purified (Travis et al., 1978) and 9 years since its gene was cloned (Chandra et al., 1983). We have learned considerably about this protease inhibitor in humans and rodents; in inflammation, cancer and AD; as binding to proteases (irreversibly), to the A beta (irreversibly) and to DNA. However, there are still open avenues for research. These include: finding the proteases that ACT inhibits in brain, identifying the cellular receptors which bind ACT-protease complexes and elucidating the DNA-binding phenomenon. Recently, 4 mutations have been found in APP. The first mutation at position 22 of A beta was detected in HCHWA-D by Levy et al. (1991).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Reaction↗
PubMed1994

Fibrillin secretion and microfibril assembly by Marfan dermal fibroblasts.

The Marfan syndrome has been linked to the FBN1 gene encoding the microfibrillar glycoprotein fibrillin. To date, there have been no descriptions of microfibrillar abnormalities characteristic of this connective tissue disorder, although biochemical analyses have highlighted apparent abnormalities in fibrillin synthesis, secretion and processing. We have conducted a biochemical and ultrastructural investigation of fibrillin expression and assembly by a panel of dermal fibroblast lines from patients with Marfan syndrome and related diseases. The study has highlighted marked differences between cells in terms of secretion and aggregation of newly-synthesised fibrillin. In addition, electron microscopic visualization of fibrillin assemblies has clearly demonstrated for the first time the plethora of microfibrillar abnormalities that underlie this heterogeneous disorder. These data emphasize the molecular complexity that is a feature of the diverse clinical phenotypes exhibited by Marfan patients.

Autoradiography↗