THE BIOSYNTHESIS OF p-AMINOBENZOIC ACID.
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Journal Article↗
Biomedical subjects
B Weiss
Publications and source records attributed to B Weiss.
Covalent coupling of rat liver phenylalanine hydroxylase.
Optimal conditions have been determined for the coupling of rat liver phenylalanine hydroxylase (Phe H) to cyanogen bromide-Sepharose 4B. When 8 mg of ligand was reacted with 100 mg of matrix, 20 to 30 percent of the initial enzyme activity was covalently bound along with 90 percent of the protein. The coupled enzyme showed greater thermal stability from 40 degrees to 60 degrees, a broader base of optimal pH activity from 5.8 to 10.0, more resistance to proteolysis and less inhibition by various inhibitors. The uncoupled enzyme exhibited greater storage stability at 25 degrees after 24 hr and at 0 degrees after 18 days. Alteration of the microenvironment by introduction of sulfhydryl groups or of carriers having positive or negative charges had variable effects on the hydroxylase activity.
Animals↗
Methylmercury developmental neurotoxicity: a comparison of effects in humans and animals.
A qualitative and quantitative comparison of the neuropathological and neurobehavioral effects of early methylmercury (MeHg) exposure is presented. The focus of the qualitative comparison is the examination of how specific end-points (and categories of behavioral functions) compare across species. The focus of the quantitative comparison is the investigation of the relationship between MeHg exposure, target-organ dose and effects in humans and animals. The results of the comparisons are discussed in the context of the adequacy of the proposed EPA neurotoxicity battery to characterize the risk of MeHg to humans. The comparisons reveal several qualitative and quantitative similarities in the neuropathological effects of MeHg on humans and animals at high levels of exposure. Reports of neuropathological effects at lower levels are available for animals only, precluding any comparison. At high levels of exposure, specific neurobehavioral end-points affected across species are also similar. Effects at lower levels of exposure are similar if categories of neurobehavioral functioning are compared. Changes in the EPA test battery consistent with the results of the comparisons are discussed.
Animals↗
Neurobehavioral toxicity of methanol reflected by operant running.
Eleven Long-Evans male rats were trained to respond for food delivery by running in wheels under a Fixed Ratio = FR 20 schedule of reinforcement. Each 360 degrees rotation counted as a single response. Three food pellets were delivered for each reinforcement. The wheels, which provided transverse rods to be gripped by the rats, were specifically designed to reflect motor deficits produced by neurotoxicants. Each animal received two replicates of three different doses of methanol (50% in water): 1.0, 2.0, and 3.0 g/kg by gavage. The sequence for each animal was determined by a counterbalanced design. Gavage was followed by admitting the animal to the running wheel compartment 10 min later. Running wheel sessions lasted for 1 hour daily and were conducted 6 days/week. Statistical analyses showed insignificant differences between water and no-treatment control days, indicating no effect of the gavage procedure. However, a dose-effect relationship between methanol dose and responses per session proved statistically significant and linear (p < 0.0001) down to a dose equivalent to 10% of the LD50. In addition, detailed analyses of intervals between successive rotations (IRTs) indicated a displacement of the distribution toward longer intervals (decreased velocities) with increasing dose. The absence of a corresponding rise in the incidence of long pauses suggested that impaired coordination, reduced endurance, or their combination, rather than nonspecific variables, accounted for these results.
Animals↗
Modulation of adrenergic receptors during aging.
In aging there is not only a reduced density of adrenergic receptors but also a reduced capacity to adapt these receptors to a changing neuronal input or hormonal environment. A reduced density of receptors presumably would result in a decreased ability of aged individuals to respond to stimulation of these receptors, and a reduced ability to modulate these receptors would result in a decreased capacity to adapt their responses to a changing internal or external environment. Future studies should be directed at the genomic mechanisms that control receptor synthesis.
Adaptation, Physiological↗
Teratogenicity of methanol following a single oral dose in Long-Evans rats.
The teratogenicity of methanol was investigated following a single oral exposure preceded by an equal volume of mineral oil to guard against local gastric irritation. Four groups of pregnant Long-Evans rats were gavaged on day 10 of gestation with the following solutions: 0.0 (n = 13), 1.3 (n = 12), 2.6 (n = 11), and 5.2 (n = 10) mL MeOH/kg. Wilson sectioning (head only), gross necropsy, and Alizarin red skeletal examinations were performed on day 20 of gestation. At 5.2 mL/kg, the dams demonstrated > 20% decrease in weight gain in comparison to the control, which was the only clinical toxic manifestation or histopathologic change noted for the dams. Methanol at all doses failed to produce any significant change in standard reproductive indices (e.g., postimplantation loss). A significant decrease in fetal body weight (11 to 19.5%), however, was associated with prenatal oral ingestion of methanol. Both internal and external examination of the fetuses demonstrated a dose-dependent increase in anomalies [0 = 0.6%, 1.3 mL/kg = 3.7%, 2.6 mL/kg = 7%, 5.2 mL/kg = 16.5% (litter percents)]. The dose-related anomalies were undescended testes, exophthalmia, and anophthalmia. Thus, acute methanol given orally produces anomalies, even when there is no apparent maternal toxic response.
Abnormalities, Drug-Induced↗
Prenatal cocaine exposure produces gender-specific motor effects in aged rats.
This investigation employed a longitudinal analysis of a complex motor skill in rats that were exposed prenatally to cocaine. Offspring were derived from four maternal treatment groups: 50 mg/kg cocaine, their pair-fed controls, 25 mg/kg cocaine, and freely fed controls. Cocaine was administered via gavage from gestation day 6-20. A maternal fostering procedure was used. Pairs of male and female littermates began training when 9, 13, or 19 months old. The behavioral procedure involved fixed-ratio (FR) lever pressing to obtain brief periods of wheel running. The oldest males from the 50 mg/kg, 25 mg/kg, and pair-fed groups performed significantly fewer wheel revolutions per opportunity than females or freely fed males. In general, animals earned fewer opportunities to run as the FR requirement was increased over sessions. However, within each age-by-gender group, subjects from the four treatment groups performed equivalent amounts of lever pressing. The specific effect on the motor aspect of the procedure may have resulted from a reduction of motor coordination, balance, or strength, or a diminished capacity of wheel running to serve as a reinforcing stimulus in a cocaine-sensitive subgroup.
Animals↗
Effects of age and gender but not prenatal cocaine on random ratio and delayed spatial alternation responding in rats.
This investigation employed a longitudinal analysis of rat operant behavior under two different schedules of reinforcement following prenatal exposure to cocaine. Offspring were derived from four maternal exposure groups: 50 mg/kg cocaine, their pair-fed controls, 25 mg/kg cocaine, and freely fed controls. Cocaine was administered via gavage from gestation day 6-20. A maternal fostering procedure was used. Pairs of male and female littermates were assigned to a 7-, 14-, or 21-month cohort and at the appropriate age were trained to respond on one lever in a two-lever operant chamber. Reinforcement was delivered with a series of random ratio (RR) schedules where the RR value was increased across sessions. After RR training, animals were examined with a delayed spatial alternation (DSA) procedure in the same chambers. Male offspring responded at higher rates than females during high-probability RR schedules, whereas advancing age was associated with lower response rates during low-probability RR schedules in both males and females. Prenatal cocaine exposure exerted only limited effects on RR responding during transition and did not affect DSA behavior. The results of this longitudinal analysis suggest that prenatal cocaine does not exert global or far-reaching learning deficits in prenatally exposed rats.
Aging↗
In situ hybridization histochemistry as a tool to study gene expression and its regulation in the central nervous system.
The recent application of in situ hybridization histochemistry to neuroanatomy, neuroendocrinology, and neuropharmacology has permitted explorations into the regulation of gene expression in the central nervous system (CNS) at the level of single neurons. Although cDNAs were the first probes to be used in hybridization studies, cRNAs and synthetic oligonucleotides have been recently employed because of the many advantages these single-stranded probes offer compared to the cDNAs. Using synthetic oligonucleotides, we described the distribution of the calmodulin mRNA and the regulation of proenkephalin mRNA in the rat brain. The results reported show the specificity of the hybridization and that the levels of calmodulin mRNA are more abundant in the cerebral cortex than in the striatum. Furthermore, we demonstrated that the administration of 6-hydroxydopamine in early postnatal life induces an increase in the expression of striatal proenkephalin mRNA measured at postnatal day 32.
Amino Acid Sequence↗
An analytical system for identifying the volatile pyrolysis products of plastics.
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Chlorides↗
Analysis of the volatile combustion products of polyphenylene oxide plastics.
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Acetaldehyde↗
Congenital leukemia: successful treatment of a newborn with t(5;11)(q31;q23).
A male neonate presented with a high white cell count, an 11q23 translocation, and M5b leukemia. He was treated at 3 days of age with intensive combination chemotherapy after progressing despite exchange transfusions. The patient achieved complete remission at 28 days of age. Therapy was completed at the age of 6 months. At the time of this report, the patient is 17 months old and remains in remission. Twenty-nine patients with congenital acute myeloid leukemia were also reviewed. Twenty of these patients received varying therapies. Ten of the treated patients achieved complete remission; two died of toxicity; and eight died of progressive disease. Two patients had a translocation affecting 11q23. Congenital leukemia is a rare and usually fatal condition in patients without Down syndrome. The patient reported here shows that survival may be achieved with very intensive chemotherapy plus supportive care, despite extremely high white blood cell counts and unfavorable translocation.
Adult↗
A risk assessment perspective on the neurobehavioral toxicity of endocrine disruptors.
Agents that alter the functional properties of endocrine systems pervade the environment. Their full implications for public health and ecological integrity, however, may not be captured by labels such as "disruptor" because their actions ramify in so many directions. The process by which we describe and evaluate such actions, risk assessment, is also the means by which society judges their significance. It determines the allocation of resources to their investigation and, potentially, control. A full, formal, risk assessment endeavor, in the detail applied to cancer evaluation, still awaits application to endocrine disruptors, however. It will not be as transparent a process because, unlike the conventional risk model based on carcinogens, identification of a chemical as an endocrine disruptor, as is true of neurobehavioral toxicants in general, will not trigger a virtually automatic sequence of policy steps. The primary distinction between cancer and endocrine disruptors and neurotoxicants is the plethora of possible endpoints by which toxicity can be expressed. Cancer is a unitary index. Adverse consequences flowing from exposure to endocrine disruptors can take an almost infinite variety of forms, including neurobehavioral outcomes. In their most troubling manifestations, these emerge as disorders of early development. They can range from deviant patterns of male copulatory behavior to impaired cognitive function. Each of these indices, in turn, exhibits multiple dimensions. Moreover, some aftermaths, as with cancer, might emerge only after long latencies. Different stages of the life cycle following developmental exposure will manifest different outcomes as a consequence. Some adverse effects may arise for the first time in advanced age because it is a period of declining compensatory margins. These multiple facets of neurobehavioral toxicity, and, by extension, their coupling to endocrine disruptors, imply a risk assessment process that corresponds, in many ways, to the global views adopted by ecotoxicologists.
Aging↗
Association of particulate air pollution and acute mortality: involvement of ultrafine particles?
Recent epidemiological studies show an association between particulate air pollution and acute mortality and morbidity down to ambient particle concentrations below 100 micrograms/m3. Whether this association also implies a causality between acute health effects and particle exposure at these low levels is unclear at this time; no mechanism is known that would explain such dramatic effects of low ambient particle concentrations. Based on results of our past and most recent inhalation studies with ultrafine particles in rats, we propose that such particles, that is, particles below approximately 50 nm in diameter, may contribute to the observed increased mortality and morbidity In the past we demonstrated that inhalation of highly insoluble particles of low intrinsic toxicity, such as TiO2, results in significantly increased pulmonary inflammatory responses when their size is in the ultrafine particle range, approximately 20 nm in diameter. However, these effects were not of an acute nature and occurred only after prolonged inhalation exposure of the aggregated ultrafine particles at concentrations in the milligrams per cubic meter range. In contrast, in the course of our most recent studies with thermodegradation products of polytetrafluoroethylene (PTFE) we found that freshly generated PTFE fumes containing singlet ultrafine particles (median diameter 26 nm) were highly toxic to rats at inhaled concentrations of 0.7-1.0 x 10(6) particles/cm3, resulting in acute hemorrhagic pulmonary inflammation and death after 10-30 min of exposure. We also found that work performance of the rats in a running wheel was severely affected by PTFE fume exposure. These results confirm reports from other laboratories of the highly toxic nature of PTFE fumes, which cannot be attributed to gas-phase components of these fumes such as HF, carbonylfluoride, or perfluoroisobutylene, or to reactive radicals. The calculated mass concentration of the inhaled ultrafine PTFE particles in our studies was less than 60 micrograms/m3, a very low value to cause mortality in healthy rats. Aging of the fumes with concomitant aggregation of the ultrafine particles significantly decreases their toxicity. Since ultrafine particles are always present in the urban atmosphere, we suggest that they play a role in causing acute lung injury in sensitive parts of the population.
Aerosols↗
Manganese in the context of an integrated risk and decision process.
Current approaches to risk assessment regard it as a process that should embody both health and ecological risks, societal values, and cost-benefit analysis, that should seek the views of affected parties, and that should examine available options more holistically than in the past. Even with a single agent, manganese, the process requires a great breadth of information and keen attention to how all of its different components fit together. An evaluation of exposure variables alone needs to consider contributions from multiple media, their physical forms and pathways such as inhaled fumes and particles, and ingestion of water, food, soil, and dust (especially by children). Endpoints need also to be broadened, especially to include susceptibility across the life cycle and the impact of low-level neurotoxicity on rate of aging. Finally, the pursuit of risk reduction options for manganese should be embedded in a process that clarifies all), the consequences of a particular option, including the raising or lowering of other risks and the full economic consequences.
Age Factors↗
Vulnerability to pesticide neurotoxicity is a lifetime issue.
Early development is not the only life stage during which which we see intensified responses to the adverse effects of chemicals. Vulnerability to toxic processes rises again late in life, and in many ways recapitulates the imperfect defenses deployed by the immature organism. One feature common to both early and late phases is a reduced capacity to compensate for impairment. In the first case, the functional mechanisms have yet to evolve. In the second, they have passed into what might be called a post-mature decline. Traced across the life cycle, this progression might be depicted as an inverted U. The developing brain, however, is equipped with immense plastic potential; the aging brain has lost much of its plasticity. The altered function of the aging brain, however, is not simply an outcome of how long the organism has lived. "Aging" is not a mechanistic explanation. Events occurring during life must account for the changes. Older brains are already high-maintenance properties, so that exposure to substances with neurotoxic properties, such as pesticides, may accelerate the process, or exploit its dwindling capacities to resist their effects. From this vantage point, toxicants can act in three ways to depress function during advanced age: they may interfere with brain development, leaving a legacy of diminished redundancy not apparent until it is further compromised during aging; they may hasten the progressive erosion of function observed with certain abilities; they may exert greater effects in the aging brain because the aging nervous system has already undergone a reduction in its ability to withstand toxic challenges.
Aged↗
[Sodium caseinate induces differentiation of 32D pluripotential hematopoietic cells].
AIM: To determine the role of sodium caseinate (CasNa) in the modulation of hemopoiesis. MATERIALS AND METHODS: 32D cells, a murine hemopoietic multipotential cell line dependent on interleukin-3 (IL-3) for proliferation and survival, were used. These cells were cultured with 0.5 ng/mL of IL-3, together with different concentrations of CasNa. We evaluated: proliferation (direct counting under the microscope and use of thymidine 3H), morphological differentiation (giemsa staining), cytochemistry (specific staining for monocytes and granulocytes), and function (presence of Fc receptors and reduction of nitro-blue tetrazolium). In addition, we determined cell viability through trypan blue exclusion and apoptosis using the TUNEL assay in situ. RESULTS: We showed that CasNa induced a decrease in cell proliferation, which is dose dependent, and is neither a result of a diminished cell viability, nor due to an increase in cell death through apoptosis. In addition, CasNa induces cell differentiation towards the monocytic lineage. CONCLUSIONS: CasNa has the capacity to differentiate 32D cells towards the monocytic lineage, and, importantly, has a potent differentiating activity on 32D cells being able to promote differentiation in a shorter time than the well known factors G-CSF and GM-CSF.
Apoptosis↗
Orthotopic heart transplantation: an efficient treatment in a young boy with doxorubicin-induced cardiomyopathy.
We present the case of a boy who underwent orthotopic heart transplantation at the age of 14 years because of doxorubicin-induced cardiomyopathy 9 years after treatment of a Wilms tumor of the left kidney. Three years after heart transplantation the patient enjoys a normal daily life. Invasive studies show normal cardiac hemodynamic results and in spite of previous nephrectomy and long-term cyclosporine treatment, renal function is only slightly impaired. So far no secondary neoplasia has occurred under chronic immunosuppression.
Adolescent↗