Biomedical subjects

Joseph Bressler

Publications and source records attributed to Joseph Bressler.

10 recordsLinked to original sources

PubMed2005

Blood mercury levels and neurobehavioral function.

CONTEXT: Due to its cardiovascular benefits, fish consumption is widely encouraged among older Americans. However, this fast-growing population is at increased risk of cognitive impairment and may be particularly sensitive to methylmercury, a neurotoxicant found in fish. OBJECTIVE: To describe associations of blood mercury levels with neurobehavioral test scores in an urban adult population. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis to determine the effect of mercury levels on neurobehavior in 474 randomly selected participants in the Baltimore Memory Study, a longitudinal study of cognitive decline involving 1140 Baltimore residents aged 50 to 70 years. We measured total mercury in whole blood samples and used multiple linear regression to examine its associations with neurobehavioral test scores. First-visit data were obtained in 2001-2002. MAIN OUTCOME MEASURES: Twenty scores from 12 neurobehavioral tests. RESULTS: The median blood mercury level was 2.1 microg/L (range, 0-16 microg/L). After adjustment for covariates, increasing blood mercury was associated with worse performance on Rey complex figure delayed recall, a test of visual memory (beta, -0.224; 95% confidence interval, -0.402 to -0.047). However, increasing blood mercury levels were associated with better performance on finger tapping, a test of manual dexterity (beta for dominant hand, 0.351; 95% confidence interval, 0.017-0.686). CONCLUSION: Overall, the data do not provide strong evidence that blood mercury levels are associated with worse neurobehavioral performance in this population of older urban adults.

Adult↗

PubMed2005

Blood lead is a predictor of homocysteine levels in a population-based study of older adults.

Lead and homocysteine are both associated with cardiovascular disease and cognitive dysfunction. We evaluated the relations among blood lead, tibia lead, and homocysteine levels by cross-sectional analysis of data among subjects in the Baltimore Memory Study, a longitudinal study of 1,140 randomly selected residents in Baltimore, Maryland, who were 50-70 years of age. Tibia lead was measured by (superscript)109(/superscript)Cd K-shell X-ray fluorescence. The subject population had a mean +/- SD age of 59.3 +/- 5.9 years and was 66.0% female, 53.9% white, and 41.4% black or African American. Mean +/- SD blood lead, tibia lead, and homocysteine levels were 3.5 +/- 2.4 microg/dL, 18.9 +/- 12.5 microg/g, and 10.0 +/- 4.1 micromol/L, respectively. In unadjusted analysis, blood lead and homocysteine were moderately correlated (Pearson's r = 0.27, p < 0.01). After adjustment for age, sex, race/ethnicity, educational level, tobacco and alcohol consumption, and body mass index using multiple linear regression, results revealed that homocysteine levels increased 0.35 micromol/L per 1.0 microg/dL increase in blood lead (p < 0.01). The relations of blood lead with homocysteine levels did not differ in subgroups distinguished by age, sex, or race/ethnicity. Tibia lead was modestly correlated with blood lead (Pearson's r = 0.12, p < 0.01) but was not associated with homocysteine levels. To our knowledge, these are the first data to reveal an association between blood lead and homocysteine. These results suggest that homocysteine could be a mechanism that underlies the effects of lead on the cardiovascular and central nervous systems, possibly offering new targets for intervention to prevent the long-term consequences of lead exposure.

Aged↗

PubMed2004

Activity-dependent expression of Egr1 mRNA in somatosensory cortex of developing rats.

The rat barrel field in somatosensory cortex is a well-characterized model of neocortical development, with activity-dependent and activity-independent components. Egr1 encodes an inducible transcription factor that is required for certain forms activity-dependent plasticity. This study examines Egr1 mRNA expression in the developing barrel field under basal conditions and after short-term deprivation or stimulation of whiskers. Egr1 mRNA was measured with in situ hybridization at postnatal Day (P) 6, P9, P12, P15, and P21. For short-term deprivation, whiskers were trimmed close to the skin and Egr1 mRNA was examined 3 hr later. For controlled stimulation of a single whisker, surrounding whiskers were trimmed, a wire was glued to the designated whisker, and animals were placed in an AC magnetic field pulsed at 2 Hz, 10 mT rms for 15 min. Egr1 mRNA was examined 30 min later. At P6, basal Egr1 mRNA in the barrel field was very low and was increased only slightly by stimulation (P < 0.05). At each of the later ages, there was a large increase in Egr1 mRNA in stimulated versus deprived barrels (P < 0.001). Egr1 mRNA expression after whisker stimulation increased exponentially with age through P15 (P < 0.001) and then declined between P15 and P21. The onset of Egr1 responses to whisker stimulation at P9 and the striking increase in activity-dependent Egr1 mRNA expression in the second postnatal week suggest that this transcription factor may play a role in activity-dependent processes that occur in this developmental period, such as maturation of barrel cortex circuitry.

Animals↗

PubMed2004

Different mechanisms mediate uptake of lead in a rat astroglial cell line.

The mechanism by which lead (Pb) enters astrocytes was examined in a rat astroglial cell line in order to characterize specific pathways for transport. Pb uptake was saturable at pH 5.5 and 7.4, although quantitative differences existed in the Michaelis-Menten constants. At pH 7.4, the Vmax and Km were 2700 fmoles/mg protein/min and 13.4 microM, respectively, whereas the Vmax and Km were 329 fmoles/mg and 8.2 microM in the buffer at pH 5.5, respectively. The presence of extracellular iron inhibited uptake in a buffer at pH 5.5 but not at pH 7.4. Cells treated with the iron chelator deferoxamine displayed higher levels of the iron transporter divalent metal transporter 1 (DMT1) mRNA and protein, and consistent with increased DMT1 expression, the treated cells displayed greater uptake of Pb in the buffer at pH 5.5 but not at pH 7.4. Alternatively, at pH 7.4, the transport of Pb was blocked by the anion transporter inhibitor 4,4'-diisothiocyanatodihydrostilbene-2,2'-disulfonic acid (DIDS), which bound to cell surface proteins at concentrations that were similar to those that blocked Pb uptake. DIDS did not inhibit uptake of Pb in the buffer at pH 5.5. Greater uptake of Pb was observed in a buffer containing sodium bicarbonate, which was abrogated in the presence of DIDS. In summary, the astroglial cell line displays two distinct pH-sensitive transport mechanisms for Pb.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed2004

Disparities in cognitive functioning by race/ethnicity in the Baltimore Memory Study.

The Baltimore Memory Study is a cohort study of the multilevel determinants of cognitive decline in 50-70-year-old randomly selected residents of specific city neighborhoods. Prior studies have demonstrated that cognitive function differs by race/ethnicity, with lower scores in minorities than in whites, but the underlying basis for these differences is not understood. Studies have differed in the rigor with which they evaluated and controlled for such important confounding variables as socioeconomic status (SES), health-related behaviors, comorbid illnesses, and factors in the physical environment. The goal of this study was to describe differences in neurobehavioral test scores by race/ethnicity, before and after control for a four-dimensional measure of SES and health-related behaviors and health conditions, in a cross-sectional analysis of first visit data. Random samples of households in the study area were selected until enrollment goals were reached. Among the 2,351 persons on whom eligibility was determined, 60.8% were scheduled for an enrollment visit; of these, 1,140 (81.3%) were enrolled and tested. These study participants were 34.3% male and 65.7% female and were from 65 Baltimore, Maryland, neighborhoods. After adjustment for age, sex, and testing technician, there were large and statistically significant differences in neurobehavioral test scores by race/ethnicity, with African-American scores lower than those for whites, for both men and women. After adjustment for individual SES (educational status, household income, household assets, and occupational status), the average difference declined by 25.8%. After additional adjustment for SES, health-related behaviors and health conditions, and blood lead, the average difference declined another 10%, but large differences persisted; African Americans had test scores that averaged 0.43 standard deviation lower than those for whites across all neurobehavioral tests. These differences were present in all cognitive domains, including tests that would not be characterized as susceptible to differential item functioning by race/ethnicity, suggesting that the results are not due to race/ethnicity-associated measurement error.

Black or African American↗

PubMed2003

The involvement of lipid activators of protein kinase C in the induction of ZIF268 in PC12 cells exposed to lead.

Lead (Pb) induces the expression of immediate early genes (IEG) in PC12 cells by a mechanism that involves protein kinase C (PKC). To define the mechanisms, the involvement of two commonly observed lipid activators of PKC, diacylglycerols, and phosphatidylinositols, were examined. A dose-dependent increase in the expression of the IEG zif268 was observed in PC12 cells exposed to Pb. The PKC inhibitor Ro-31-8220 blocked the induction. An increase in levels of diacylglycerols was observed in PC12 cells exposed to Pb, but the increase was inhibited by Ro-31-8220. The phosphatidylinositol 3-kinase inhibitor Wortmannin, but not the inhibitor LY 294002, blocked the induction zif268 in Pb-exposed cells. Small increases in phosphatidylinositol 3-kinase activity were observed after exposure to Pb. In summary, diacylglycerols are elevated in PC12 cells exposed to Pb by a mechanism that requires PKC. It is possible that diacylglycerols contribute to the induction of zif268 by Pb by sustaining PKC activation.

Androstadienes↗

PubMed2002

Exposure to lead elevates induction of zif268 and Arc mRNA in rats after electroconvulsive shock: the involvement of protein kinase C.

Exposure to lead is well known to impair cognitive function in young children. Because of the importance of gene regulation for neurodevelopment, we examined the effect of lead on the induction of the mRNA of the immediate early genes zif268 and Arc. The time course for the induction of zif268 mRNA and Arc mRNA by electroconvulsant shock (ECS) was altered in the area of the dentate gyrus of the hippocampus in rats exposed to lead from postnatal days (PND) 1 to 28. Other areas of the hippocampus were not affected by lead. The effects on the induction of zif268 mRNA were observed at blood lead levels as low as 12 microg/dl. No change in the induction of zif268 mRNA was observed in the hippocampus of rats exposed to lead from PND 28 to PND 56. Because of the possible involvement of protein kinase C (PKC) in the effect of lead, activation of different isoforms of PKC was investigated. An increase in the amount of PKC epsilon and PKC gamma was observed at 60 min after ECS in the membrane fraction from hippocampus, indicating activation of these isoforms. The amount of PKC epsilon in membranes was higher in rats exposed to lead than in rats not exposed to lead after ECS. Taken together, the data suggest that lead may disturb regulation of specific immediate early genes by activating PKC epsilon.

Animals↗

PubMed2002

Neither forced running nor forced swimming affect acute pyridostigmine toxicity or brain-regional cholinesterase inhibition in rats.

Stress-induced change in the distribution of the drug pyridostigmine (PYR) has been proposed as a contributing factor to unexplained illnesses in Persian Gulf War veterans. We evaluated the effects of two stress models, forced running and forced swimming, on acute PYR (30 mg/kg, p.o.) toxicity and cholinesterase (ChE) inhibition in the blood and selected brain regions of young adult male Sprague-Dawley rats (6 weeks of age). Plasma corticosterone levels were measured at 0, 1 and 3 h after termination of forced swimming or forced running to confirm the induction of stress. PYR was given either immediately before stress (15 min swimming; 20 min running) or immediately after stress (15 min swimming; 90 min running) and cholinergic toxicity and ChE inhibition were evaluated at 1, 2 or 4 h after PYR exposure. Additionally, rats were subjected to either swimming (15 min) or running (90 min) stress, anesthetized, injected with horseradish peroxidase (HRP, 100 mg/kg, transcardial) and brain-regional HRP activity measured as an indicator of altered blood-brain barrier integrity. Both forced swimming and forced running resulted in significant elevations of plasma corticosterone levels. PYR caused cholinergic toxicity at all time-points evaluated. Swimming and running stress had little influence on expression of PYR-induced toxicity, however. Blood ChE activity was generally inhibited 77-91% at 1-4 h after PYR, but rats pretreated with PYR prior to forced swimming showed lesser inhibition (64%) 1 h after dosing, possibly because of swimming-induced hypothermia and delayed absorption of the drug. Minimal changes in ChE activity were noted in frontal cortex, cerebellum and hippocampus following PYR exposure (maximal inhibition 28%), and neither swimming nor running stress affected the degree of inhibition. Neither stress model increased HRP accumulation in any brain region. The results suggest that stress associated with forced running or forced swimming has little effect on acute PYR toxicity, entry of PYR into the brain or PYR-induced brain-regional ChE inhibition.

Administration, Oral↗

PubMed2002

Mobilization of intracellular calcium in kidney epithelial cells is inhibited by lead.

The effect of lead (Pb) on intracellular calcium (Cai) after stimulation with agonists was studied in Madin-Darby canine kidney (MDCK) cells. In response to the agonist ADP, the levels of Cai increased by approximately threefold in MDCK cells bathed in a buffer with calcium (Ca) or in a buffer with nominal Ca. Pb inhibited the response to ADP in MDCK cells bathed in either buffer. The inhibition by Pb was observed after a 5 and 20-min exposure to Pb, but not after 2-min. Very high concentrations of ADP did not reverse the effects of Pb. Concentrations of Pb of 1 microM or more inhibited the response to ADP. Similarly, the response to bradykinin was also inhibited by Pb. Protein kinase C did not play a role since the protein kinase C inhibitor GF 109203X did not reverse the effects of Pb. Interestingly, MDCK cells treated with Pb at concentrations above 1 microM, for periods of 5-20 min, displayed elevated levels of inositol 1,4,5-trisphosphate. In conclusion, Pb inhibits mobilization of Cai after agonist stimulation by a mechanism that is unrelated to the type of agonist used. Evidence is presented suggesting that the inhibition is due to increases in levels of inositol 1,4,5-trisphosphate, which possibly decreases the amount of Cai available for mobilization.

Adenosine Diphosphate↗

PubMed2002

Acute and repeated restraint stress have little effect on pyridostigmine toxicity or brain regional cholinesterase inhibition in rats.

Pyridostigmine, a carbamate cholinesterase (ChE) inhibitor, has been used for decades in the treatment of the autoimmune disorder myasthenia gravis and was used prophylactically to protect soldiers from possible organophosphorus nerve agent exposures during the Persian Gulf War. Pyridostigmine is a charged, quaternary compound and thus would not be expected to easily pass the blood-brain barrier. Some studies have suggested, however, that stress may alter blood-brain barrier integrity and allow pyridostigmine to enter the brain. We evaluated the effects of acute and repeated restraint stress on functional signs of cholinergic toxicity (i.e., autonomic dysfunction and involuntary movements) and brain regional cholinesterase inhibition following either acute or repeated pyridostigmine exposures. The acute, oral maximum-tolerated dosage (MTD) of pyridostigmine was estimated at 30 mg/kg. Peak ChE inhibition in whole blood occurred from 0.5 to 4 h after MTD exposure, whereas minimal (<20%) brain ChE inhibition was noted. For acute restraint studies, rats were either (1) restrained for 90 min and then given pyridostigmine (30 mg/kg, po), (2) given pyridostigmine and immediately restrained for 60 min, or (3) restrained for 3 h, given pyridostigmine, and restrained for an additional 60 min. In all cases, rats were evaluated for cholinergic toxicity (SLUD signs and involuntary movements) and sacrificed 1 h after pyridostigmine treatment. Plasma corticosterone was significantly elevated immediately after a single 60-min session of acute restraint stress, but returned to control levels by 1 and 3 h later. Pyridostigmine-induced toxicity was not enhanced nor was brain ChE inhibition altered by acute restraint stress. Blood-brain barrier permeability, assessed by accumulation of horseradish peroxidase in brain regions following intracardiac injection, was not increased by restraint stress. For repeated restraint studies, rats were given pyridostigmine (0, 3, or 10 mg/kg/day) immediately prior to daily restraint (60 min) for 14 consecutive days. Plasma corticosterone was elevated at 1 and 7 days but not at 14 days. Pyridostigmine-treated rats in both dosage groups exhibited slight signs of toxicity for the first 3-5 days, after which cholinergic signs dissipated. Repeated restraint had little effect on functional signs of pyridostigmine toxicity, however. Whole blood and diaphragm ChE were markedly reduced 1 h after the last treatment, but stress had no influence on ChE inhibition in either peripheral or central tissues. The results suggest that acute and repeated restraint stress have little effect on pyridostigmine neurotoxicity or apparent entry of pyridostigmine into the brain.

Acute Disease↗