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Biomedical subjects

B Weiss

Publications and source records attributed to B Weiss.

At least 91 records · Page 5Linked to original sources
PubMed1997

Perinatal methanol exposure in the rat. II. Behavioral effects in neonates and adults.

The use of methanol as a component of automobile fuel will increase perinatal exposures in the general population. Few studies have addressed questions concerning neurotoxicity stemming from such exposures. In the current study, four cohorts of pregnant Long-Evans rats, each cohort consisting of an exposure and a control group, were exposed to 4500 ppm methanol vapor in Rochester-type inhalation chambers for 6 hr daily beginning on Gestation Day 6. Exposure continued for both dams and pups through Postnatal Day 21 (PND 21) to model gestational and neonatal toxicity in humans. Several behavioral procedures were used to assess exposure effects in the offspring. Male-female littermates were studied whenever possible to examine sex differences, with one pair from a litter for each procedure. Exposure to methanol did not affect suckling latency and nipple attachment on PND 5 or performance on an aversive olfactory conditioning procedure on PND 10. Exposure to methanol did alter performances in a motor activity procedure. Methanol-exposed neonates were less active on PND 18, but more active on PND 25 than the equivalent control group pups. Two operant conditioning procedures, not used previously in this context, assayed other littermates as adults. A fixed ratio schedule required the rat to rotate a running wheel a specified number of revolutions to obtain food-pellet reinforcers. When the fixed ratio requirement changed, number of responses (revolutions) per 1-hr session displayed a complex interaction with treatment. Changes in performance over the course of training differed between males and females depending on exposure to methanol. Compared to initial baseline performances, methanol-exposed males showed decreases, and methanol-exposed females increases, in the rate of running. A stochastic spatial discrimination procedure permitted subjects to respond on any three levers, with the probabilities of food-pellet delivery determined by the location of the preceding response. A reinforcement matrix defined the response sequence required to maximize reinforcements. When the matrix was changed, the methanol-exposed subjects responded less efficiently at asymptotic levels of performance than controls. Across procedures, developmental exposure to 4500 ppm methanol vapor was associated with subtle behavioral changes in both neonates and adults.

Administration, Inhalation↗
PubMed1997

Evidence that therapy works in clinically representative conditions.

This article reports a secondary analysis of past therapy outcome meta-analysis. Fifteen meta-analysis provided effect sizes from 56 studies in previous reviews that met 1 of 3 increasingly stringent levels of criteria for clinical representativeness. The effect sizes were synthesized and compared with results from the original meta-analyses. Effect sizes from more clinically representative studies are the same size at all 3 criteria levels as in past meta-analyses. Almost no studies exist that meet the most stringent level of criteria. Results are interpreted cautiously because of controversy about what criteria best capture the notion of clinical representativeness, because so few experiments have tested therapy in clinical conditions, and because other models for exploring the generalizability of therapy outcome research to clinical conditions might yield different results.

Humans↗
PubMed1997

Endocrine disruptors and sexually dimorphic behaviors: a question of heads and tails.

Early brain development seems destined to be the territory where questions about the neurotoxicity of endocrine disruptors will be contested, so we ought to clarify how we propose to invade it. Everything else we have learned tells us that the most sensitive indices are likely to be the most subtle, a term we often use to describe the phenomena and domain of neurobehavioral toxicology. It might mean an effect that is small in amplitude, or that requires sensitive measures to detect. One class of effects that might result from environmental exposure to endocrine disruptors reflects both kinds of subtlety. It consists of sexually dimorphic behaviors that seem biologically driven but that could easily masquerade as socially-defined or gender differences. Performances on neuropsychological tests fall into this category. Beyond debates about their origins, such differences tend to be relatively modest in size, especially by the routine criteria adopted by toxicologists. Overwhelmingly, they rely on differences in means accompanied by p values. Such criteria are inappropriate for assessing hypotheses or calculating risks based on the impact of what invariably will be quite low environmental levels. In this arena at least, the quantification of effects should proceed from examinations of distributions. Instead of conventional descriptions based on measures of central tendency, we should instead examine the shapes of distributions, especially the tails. Neuropsychological differences between males and females are amplified and emerge at the extremes, even when sex accounts for no more than a minuscule proportion of the variance. Lead taught a similar lesson about how to quantify population impacts. Furthermore, such differences at the extremes suggest both practical and theoretical implications that can too easily be ignored but that provide paths for fruitful exploration.

Animals↗
PubMed1996

D2 dopamine receptor antisense increases the activity and mRNA of tyrosine hydroxylase and aromatic L-amino acid decarboxylase in mouse brain.

A D2 dopamine receptor antisense oligodeoxynucleotide was administered intracerebrovetricularly to mice twice on the first day and then once daily for 2 days. The animals were killed 2 h after the last injection, and tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities assayed in the corpus striatum, olfactory tubercle and frontal cortex. Tyrosine hydroxylase activity increased in corpus striatum but not in the olfactory tubercle or in the frontal cortex, while the activity of aromatic L-amino acid decarboxylase increased in all three brain regions. The treatment with the antisense oligomer also elevated the mRNA levels for the two enzymes in the midbrain. In contrast, repeated injection of a vehicle or a random oligomer was without effect on enzyme activity or mRNA D2 antisense oligodeoxynucleotides appear to be selective tools to investigate the role of D2 dopamine receptors in brain.

Animals↗
PubMed1996

SoxR, a [2Fe-2S] transcription factor, is active only in its oxidized form.

SoxR protein is known to function both as a sensor and as a transcriptional activator for a superoxide response regulon in Escherichia coli. The activity of SoxR was tested by its ability to enable the transcription of its target gene, soxS, in vitro. The activity of the oxidized form was lost when its [2Fe-2S] clusters were reduced by dithionite under anaerobic conditions, and it was rapidly restored by autooxidation. This result is consistent with the hypothesis that induction of the regulon is effected by the univalent oxidation of the Fe-S centers of SoxR. In vivo, this oxidation may be caused by an alteration of the redox balance of electron chain intermediates that normally maintains soxR in an inactive, reduced state. Oxidized SoxR was about twice as effective as reduced SoxR in protecting the soxS operator from endonucleolytic cleavage. However, this difference could not account for a greater than 50-fold difference in their activities and therefore could not support a model in which oxidation activates SoxR by enabling it to bind to DNA. NADPH, ferredoxin, flavodoxin, or ferredoxin (flavodoxin):NADP+ reductase could not reduce SoxR directly in vitro at a measurable rate. The midpoint potential for SoxR was measured at -283 mV.

Amino Acid Sequence↗
PubMed1996

Perinatal methanol exposure in the rat. I. Blood methanol concentration and neural cell adhesion molecules.

Although the acute toxicity of methanol is well documented, few studies have addressed the consequences of perinatal exposures to the low concentrations that are expected to arise from its proposed use as a component of automobile fuel. This report describes the general research design of a series of studies, the effects of methanol exposures on blood concentrations in dams and neonates, and indices of brain development. Four cohorts of Long-Evans pregnant rats, each cohort consisting of an exposure (n = 12) and a control (n = 12) group, were exposed whole-body to 4500 ppm methanol vapor or air for 6 hr daily beginning on Gestation Day 6. Both dams and pups were then exposed through Postnatal Day 21 (PND 21). Blood methanol concentrations determined by gas chromatography from samples obtained immediately following a 6-hr exposure reached approximately 500-800 micrograms/ml in the dams during gestation and lactation. Average concentrations for pups attained levels about twice those of the dams. Selected offspring from Cohort 4 were exposed for one additional 6-hr session at ages that extended out to PND 52. Regression analyses showed that the blood methanol concentrations of the pups declined until about PND 48, at which time their levels approximated those of their dams. Such pharmacokinetic differences might increase the risks posed to developing organisms. Light-microscopic analysis showed no significant abnormalities in the brains of the methanol-treated animals. However, assays of neural cell adhesion molecules (NCAMs) in brains of pups sacrificed on PND 4 showed staining for both the 140 and the 180 kDa isoforms to be less intense in the cerebellum of exposed animals. NCAM differences were not apparent in animals sacrificed 15 months after their final exposure.

Animals↗
PubMed1996

Uptake and distribution of fluorescein-labeled D2 dopamine receptor antisense oligodeoxynucleotide in mouse brain.

To determine the uptake and distribution of oligodeoxynucleotides in brain, a 20-mer phosphorothioated oligodeoxynucleotide complementary to a portion of the D2 dopamine receptor mRNA was fluorescently labeled with fluorescein isothiocyanate (FITC) and injected into the lateral cerebral ventricles of mice. At various survival times after the injection, the brains were removed, fixed, sectioned, and viewed under a fluorescent microscope. The results showed that the oligodeoxynucleotide was rapidly taken up into the brain. Initially the label was relatively diffusely spread throughout the interstitial spaces of the brain, then became redistributed to the cellular compartments. The signal extended from those forebrain nuclei located immediately in contact with the ventricles, such as the corpus striatum, septum, and hippocampus, to areas further removed from the ventricles, such as the cerebral cortex, nucleus accumbens, and substantia nigra. When the FITC-labeled D2 antisense oligodeoxynucleotide was given once daily for 4 d, the signal intensity seen 24 h after the last injection appeared to be of greater intensity overall compared to that seen after a single injection. At early time-points the oligodeoxynucleotide signals appeared to be punctuated and were found in cell bodies as well as in proximal dendritic processes. However, not all cells were equally labeled, suggesting an uneven uptake and accumulation of the D2 antisense into the various cell types. At later time-points the fluorescent signal appeared granular; at these times the injected material was largely degraded. These studies show that a D2 dopamine receptor antisense oligodeoxynucleotide is rapidly taken up from cerebral ventricles into brain, becomes widely distributed throughout the brain tissue to areas far removed from direct contact with the ventricles, and appears to accumulate to a different extent in the various brain areas and cell types.

Animals↗
PubMed1996

Assessment of the composition of bone marrow prior to and following autologous BMT and PBSCT by magnetic resonance.

Lumbar bone marrow was assessed by means of magnetic resonance (MR) in 23 examinations of eight patients who underwent autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT). Various imaging and spectroscopic techniques were applied for measurements carried out prior to conditioning for ABMT/PBSCT and in the course of reconstitution and correlated with clinical and blood chemistry data in these patients. The signal intensity from lumbar bone marrow was determined in T1-weighted and water- and fat-selective MR images. The distribution of the magnetic field was demonstrated by a field-mapping method. Localized proton spectroscopy was performed from volume elements of 2 ml located in the central region of vertebral bodies in order to evaluate the fraction of the water signals, the transverse relaxation times T2 of the signals from water and lipids, and the line widths of the spectral signals. Regions of bone marrow after inflammatory conditions or intensive irradiation are shown to be not involved in marrow reconstitution. Additional information about marrow composition was obtained by the magnetic field mapping and by the line widths in the spectra. Considerable alterations of the amount of paramagnetic hemosiderin were revealed following transplantation. Patients with low water signal and strong local inhomogeneities of the magnetic field in the marrow prior to transplantation had a delayed hematopoietic reconstitution compared with the patients lacking these MR features.

Adult↗
PubMed1996

Reduced level of calmodulin in PC12 cells induced by stable expression of calmodulin antisense RNA inhibits cell proliferation and induces neurite outgrowth.

The role calmodulin plays in the growth and differentiation of nerve cells was assessed by altering the levels of calmodulin in the PC12 rat pheochromocytoma cell line and determining the effects of altering these levels on cellular proliferation and differentiation. Calmodulin levels in the PC12 cells were increased or decreased by transfecting the cells with a mammalian expression vector into which the rat calmodulin gene I had been cloned in the sense or antisense orientation, respectively. The cells transfected with the calmodulin sense gene showed increased levels of calmodulin immunoreactivity and increased levels of calmodulin messenger RNA as ascertained by immunocytochemistry and slot-blot analysis, respectively. Cells transfected with the calmodulin antisense construct showed reduced levels of calmodulin immunoreactivity. Reducing the levels of calmodulin by expression of antisense calmodulin messenger RNA resulted in a marked inhibition of cell growth, whereas increasing the levels of calmodulin by overexpressing calmodulin messenger RNA resulted in an acceleration of cell growth. Transfected PC12 cells having reduced levels of calmodulin immunoreactivity exhibited spontaneous outgrowth of long, stable and highly branched neuritic processes. PC12 cells in which calmodulin was overexpressed showed no apparent changes in cell morphology, but did show an altered response to the addition of nerve growth factor. While nerve growth factor slowed cellular proliferation and induced extensive neurite outgrowth, in parental PC12 cells nerve growth factor induced little or no neurite outgrowth and little inhibition of cell proliferation in transfected cells overexpressing calmodulin. These results indicate that calmodulin is essential for the proliferation of nerve cells and for the morphological changes that nerve cells undergo during differentiation. The study also suggests the possibility that a calmodulin antisense approach may be used to inhibit the proliferation of neuronal tumors.

Animals↗
PubMed1996

Intrastriatal administration of an oligodeoxynucleotide antisense to the D2 dopamine receptor mRNA inhibits D2 dopamine receptor-mediated behavior and D2 dopamine receptors in normal mice and in mice lesioned with 6-hydroxydopamine.

Previous studies have shown that the intracerebroventricular injection of antisense oligodeoxynucleotides targeted to the mRNAs encoding the different subtypes of dopamine receptors inhibited behaviors mediated by these receptors. The present studies were designed to determine whether such antisense oligodeoxynucleotides could produce similar effects when injected into a discrete brain area. A D2 dopamine receptor antisense oligodeoxynucleotide (D2 antisense) was repeatedly injected into one corpus striatum of either normal mice or mice with unilateral lesions of the striatum induced by 6-hydroxydopamine. In the latter, intrastriatal injection of D2 antisense blocked the contralateral rotational behavior induced by the parenteral administration of the D2 dopamine receptor agonist quinpirole. The inhibitory effect of D2 antisense was dose- and time-related and was reversed upon cessation of D2 antisense treatment. This inhibitory effect was also selective in that D2 antisense treatment inhibited the rotational behavior induced by quinpirole but not that induced by the D1 dopamine receptor agonist SKF 38393 or by the muscarinic cholinergic agonist oxotremorine. Following repeated intrastriatal injections of D2 antisense into normal mice, parenteral administration of quinpirole caused rotational behavior ipsilateral to the side in which the D2 antisense was injected. No such rotational behavior was seen when similarly treated mice were challenged with SKF 38393 or oxotremorine. The quinpirole-induced rotational behavior in mice given intrastriatal injections of D2 antisense disappeared upon cessation of D2 antisense treatment. Repeated intrastriatal administration of D2 antisense also caused a significant reduction in the levels of D2, but not D1, dopamine receptors in striatum, as determined by receptor autoradiography. The levels of D2 dopamine receptors returned to normal upon cessation of D2 antisense treatment. Intrastriatal administration of an oligodeoxynucleotide with randomly placed nucleotides failed to alter the rotational response to quinpirole in either 6-hydroxydopamine-lesioned or normal mice and failed to alter the levels of D2 dopamine receptors in striatum. These results show that selective inhibition of behavioral responses mediated by D2 dopamine receptors can be achieved by the direct injection of a D2 antisense oligodeoxynucleotide into a discrete brain area.

Animals↗
PubMed1996

The intersection of risk assessment and neurobehavioral toxicity.

Neurobehavioral toxicology is now established as a core discipline of the environmental health sciences. Despite its recognized scientific prowess, stemming from its deep roots in psychology and neuroscience and its acknowledged successes, it faces additional demands and challenges. The latter, in fact, are a product of its achievements because success at one level leads to new and higher expectations. Now the discipline is counted upon to provide more definitive and extensive risk assessments than in the past. These new demands are the basis for the appraisals presented in the SGOMSEC 11 workshop. They extend beyond what would be offered in a primer of methodology. Instead, these appraisals are framed as issues into which what are usually construed as methodologies have been embedded.

Animals↗
PubMed1996

Impact of on-site social work services on the documentation of client and family-centered information: the experience of Ryan White CARE Act (Title IV) pediatric program sites in Maryland.

BACKGROUND: The purpose of this study is to (1) describe client and maternal demographic, social, and medical characteristics of pediatric clients receiving medical and social services at Ryan White (Title IV) program sites, and (2) determine the impact of on-site social work services in documenting client and family-related information used to assess the psychosocial needs of the families affected by human immunodeficiency syndrome and acquired immunodeficiency syndrome (HIV/AIDS). METHODS: We studied infants born to known HIV-infected women who received HIV-related medical services at a federally funded Title IV Ryan White CARE Act provider site in Maryland. Eligibility criteria included < 24 months of age at time of initial clinic visit, a history of birth to a known HIV-infected woman, and a minimum of one comprehensive clinical visit for medical evaluation at a selected Title IV provider site. Study populations were categorized into three independent clinic cohorts. A pre- and postintervention study design was used to assess the impact of the intervention (i.e., on-site social work activities) on variables of interest. Clinic cohorts were (a) preintervention group (N = 181), from January 1, 1986 to December 31, 1989; (b) initial postintervention group (N = 216), from January 1, 1991 to December 31, 1992; and, (c) long-term postintervention group (N = 197), from January 1, 1993 to March 1, 1994. Client and maternal demographic, social, and medical information were recorded and statistical comparisons between pre- and postintervention clinic cohorts were completed with the use of standard statistical methods. RESULTS: Pediatric clients were predominantly African American (94%), lived in low-income family units reflected by the prevalence of public assistance programs (i.e., Medicaid), had a high likelihood of Medicaid enrollment (> 80%), and reported a high frequency of social disruption (e.g., protective services interventions and housing difficulties). Greater than half of all medical records documented the "mother" as the client's primary caregiver in the three cohorts (a,b,c, above) pre- and postintervention cohorts, 51%, 65%, and 66.5%, respectively. Over two-thirds of the mothers among all cohorts were reported to have a current or past history of illicit drug use or alcohol abuse, 69%, 62%, and 67.5%, respectively. Postintervention groups, both initial and long term, were significantly more likely than the preintervention group to have documented medical record information relevant to a history of protective services, housing problems, and maternal demographic, social, and clinical information. Maternal HIV-related clinical status and select social factors (e.g., drug use, housing) remained underreported in both postintervention groups. CONCLUSIONS: Title IV pediatric clinical sites deliver services to a predominantly urban, poor, minority community-the population at greatest risk for pediatric HIV-infection in Maryland. Alternative family members as the primary caregiver for infants and children was common and increased over time. These findings demonstrate that Title IV funded programs have been successful in the documentation of valuable client and maternal information necessary for the development of family-centered clinical and support services to a highly vulnerable population of HIV at-risk or infected infants and children in Maryland.

Adult↗
PubMed1996

Developmental neurotoxicity of methanol exposure by inhalation in rats.

The possibility of widespread methanol exposure via inhalation stemming from its adoption as an automotive fuel or fuel component arouses concerns about the potential vulnerability of the fetal brain. This project was designed to help address such concerns by studying the behavior of neonate and adult rats following perinatal exposure to methanol vapor. Four cohorts of pregnant Long-Evans hooded rats, each cohort consisting of an exposure and a control group, were exposed to 0 parts per million (ppm) (control) or 4,500 ppm methanol vapor for six hours daily beginning on gestation day (GD) 6 with dams and pups then being exposed postnatal day (PND) 21. Exposures took place in 2-m3 Rochester-type inhalation chambers while the animals remained in their plastic breeder cages. Prenatal and postnatal blood methanol concentrations were determined by gas chromatography. Blood methanol concentrations of the dams, measured immediately following a six-hour exposure, were approximately 500 to 800 micrograms/mL throughout gestation and lactation. Average blood methanol concentrations of the pups were about twice those of the dams. Because such results appeared consistently across the other cohorts, we decided to obtain additional data with Cohort 4. Once it had undergone the standard exposure protocol, we selected sets of extra pups from those that had not been assigned previously to the adult phase of behavioral testing. Each set was exposed once, at ages that extended out to PND 52, for one additional six-hour session of exposure to 4,500 ppm methanol. The blood methanol concentrations of these pups declined until about PND 48, at which time they approximated those of the dams. These findings might be accounted for by a process of metabolic maturation in the pups that remains to be identified.

Animals↗
PubMed1996

Long ago and far away: a retrospective on the implications of Minamata.

Minamata claimed entry into the lexicon of toxicology 40 years ago as a definition of methylmercury poisoning, but deposited a legacy of unsolved puzzles that still endures. In fact, they scatter ramifications across the entire domain of neurotoxicology. One puzzle is how the earliest clinical index of adult toxicity, paresthesia, can remain stable, even with continued exposure. Does damage, like body burden, reach a plateau? A second enigma is the question of silent damage to nerve cell populations even more vulnerable than those whose loss of function results in minimal symptoms such as paresthesia. Is there a population of unidentified humans exposed to methylmercury whose deficits might be uncloaked by neurobehavioral test methods that have succeeded in revealing silent toxicity in populations exposed to lead, manganese, and elemental mercury? A third puzzle arises in the context of aging. Attrition of nerve cells occurs naturally as the brain ages, but is also accompanied by dendritic sprouting in those that remain. Damage incurred earlier in life, as in mild polio infections that seemed to fade, may emerge late in life in the form of the post-polio syndrome. Most explanations ascribe the syndrome to compensatory dendritic sprouting by surviving neurons and the consequent metabolic overload imposed on them. Could parallel processes be induced by neurotoxicants such as methylmercury? Or, alternatively, might the compensatory sprouting accompanying aging be inhibited by neurotoxic agents? All such questions have a bearing on how the risks of low-level exposures are evaluated.

Adult↗
PubMed1996

Proliferating and differentiating Schwann cell cultures from embryonic chick sciatic nerve maintained for months in vitro without antimitotics or growth factors.

In general, the available methods for culturing Schwann cells require specific antibodies and/or the addition of antimitotics to suppress fibroblasts, plus various factors to support their growth. Moreover, the maximal culture period of Schwann cells normally is limited to a few weeks. Here, three easy novel methods to culture Schwann cells from embryonic chick sciatic nerve are presented, that require no growth factors or agents elevating intracellular cAMP. In contrast to the conventional antimitotic treatment with cytosine arabinoside, we use D-valine to suppress fibroblasts. Our modified medium C leads within a few days to highly enriched Schwann cell cultures (culture I). Passage into a serum-reduced medium D allows for differentiating longterm cultures (culture II). In cultures I and II, the rate of cell division is low. However, after passage into serum-containing SC-medium, proliferation increases within one week to high levels (culture III). Cultures II and III can be grown for several months, during which time spontaneous immortalization can occur. The high purity of the cultures of about 95% is assessed using glia-specific antibodies for S-100 antigen, HNK-1 epitope, glia fibrillary acidic protein (GFAP), galactocerebroside (Gal C) and 3A7. These culture procedures are easy to perform and are suitable for differentiation, proliferation and coculturing experiments.

Animals↗
PubMed1996

Human performance during exposure to toluene.

PURPOSE: The purpose of this research was to examine the effects of inhalation of toluene on respiratory function and neuropsychological performance of humans. METHODS: We exposed six healthy adults to 100 ppm toluene or air (control) for 6 h, in a double-blind, randomized fashion, with exposures separated by at least 14 d and including 30 min of exercise at a level that quadrupled minute ventilation. Blood and exhaled air toluene levels were measured before, during, immediately, and 1 and 2 h post-exposure. Lung function was measured before and immediately after exposure. Three repetitions of two computerized neuropsychological tests were performed, including a brief standard neuropsychological battery (ANAM) and a 1-h complex performance test (SYNWORK). Statistical analysis of the psychological data was conducted as a repeated measures ANOVA. FINDINGS: Following exercise, the mean blood and exhaled air toluene levels averaged 1.5 micrograms and 28 ppm, respectively. Lung function was unchanged post-exposure. On the SYNWORK test, the Composite score obtained over time during toluene exposure was lower than that during room air (F = 29.20, p = 0.005), with the score from the final hour reduced by 10%. On standard neuropsychological tests, latency but not accuracy proved the sensitive measure for five of the seven subtests presented. CONCLUSIONS: Performance of complex tests and response time to simple brief tests can be disrupted by toluene inhalation at 100 ppm. Differences in performance between air and toluene conditions were greatest after exercise, indicating that physical activity may enhance the response to volatile organic solvents.

Adult↗