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PubMedDate not supplied

The effect of aluminum on conditioned avoidance response (CAR) in mice.

Aluminum is used in medical products and some parenteral products (Vaccines) contain aluminum. In a study of neurotoxicity of aluminum in mice, four groups of CD1 mice (5 males and 5 females per dose level) were treated as follows: group one drank 1.0% of aluminum (as AlCl3) during the weaning period from day 1 to 8 weeks of age; group two drank AlCl3 from 1 month to 4 months of age; group three mice (1 month old) were injected i.p. with 10, 30 and 100 mg of aluminum/kg/day for two days; group four mice (1 month old) were injected s.c. with 3, 10, and 30 mg of aluminum/kg/day for 2 days. Controls received the vehicle only. All mice were trained for CAR five times at 2 months of age. The CAR of mice that ingested AlCl3 during the weaning period to 8 weeks of age was lowered by 26% compared to the control group, which achieved 46% of CAR after five training sessions. Also, the retention of CAR was reduced to 30% whereas that of the control group remained at the same level after 1 month. CAR values of group two did not differ from those of its control. CAR of group three (at 30 mg/kg i.p.) was 36% lower than controls. CAR of s.c. group four (3, 10, and 30 mg/kg) was lowered to 16%-28% of the control; CAR retention was reduced to 18%. Therefore, the oral ingestion of aluminum induced neurotoxicity in mice which may be seen only at an early age, but injection of aluminum can cause neurotoxicity at any age.

Aluminum↗
PubMed2002

Epidermal expression of the full-length extracellular calcium-sensing receptor is required for normal keratinocyte differentiation.

The importance of the extracellular calcium-sensing receptor (CaR) in the stringent control of extracellular Ca(2+) concentration is well established. However, the presence of CaR in tissues not directly involved in regulating mineral ion homeostasis such as the epidermis suggests a role for CaR in other cellular functions. Although extracellular Ca(2+) regulates the differentiation of epidermal keratinocytes, the role of CaR in this process in the epidermis is not fully understood. In this study we showed using in situ hybridization and immunohistochemistry that CaR is expressed in suprabasal keratinocytes of the mammalian epidermis. We then evaluated the changes in epidermal keratinocyte morphology and differentiation in Casr(-/-) mice lacking the full-length CaR. These mice show increased expression of an alternatively spliced form of CaR which lacks acute Ca(2+)-signaling properties. The absence of the full-length CaR in the epidermis resulted in ultrastructural changes (abnormal keratohyalin granule formation and precocious lamellar body secretion) in the terminally differentiated granular keratinocytes. Furthermore, the expression of both mRNA and protein for the calcium inducible keratinocyte differentiation markers, filaggrin and loricrin, were down-regulated in the epidermis of Casr(-/-) mice, whereas the number of proliferating cells were increased even though the calcium gradient within the epidermis was enhanced. Our results demonstrate that the epidermal expression of the full-length CaR is required for the normal terminal differentiation of keratinocytes.

Animals↗
PubMed1996

Chromosomal aberrations in lymphocytes from car painters.

In the present paper we report the results of biological monitoring of a group of 25 car painters working in different automobile shops in Brasília. There was a significantly higher frequency of aneuplodies and chromosome deletions in the peripheral lymphocytes of car painters than in control subjects. We also detected a significant correlation between the time worked as a car painter and the frequency of aneuploidy. Smoking habits do not represent a significant factor in terms of production of the various types of chromosome aberrations among car painters. These results permitted us to conclude that the individuals studied represent a risk group and should be medically followed up with judicious periodic examinations.

Adult↗
PubMed2006

Calcium receptor stimulates chemotaxis and secretion of MCP-1 in GnRH neurons in vitro: potential impact on reduced GnRH neuron population in CaR-null mice.

The factors controlling the migration of mammalian gonadotropin-releasing hormone (GnRH) neurons from the nasal placode to the hypothalamus are not well understood. We studied whether the extracellular calcium-sensing receptor (CaR) promotes migration/chemotaxis of GnRH neurons. We demonstrated expression of CaR in GnRH neurons in the murine basal forebrain and in two GnRH neuronal cell lines: GT1-7 (hypothalamus derived) and GN11 (olfactory bulb derived). Elevated extracellular Ca(2+) concentrations promoted chemotaxis of both cell types, with a greater effect in GN11 cells. This effect was CaR mediated, as, in both cell types, overexpression of a dominant-negative CaR attenuated high Ca(2+)-stimulated chemotaxis. We also demonstrated expression of a beta-chemokine, monocyte chemoattractant protein-1 (MCP-1), and its receptor, CC motif receptor-2 (CCR2), in the hypothalamic GnRH neurons as well as in GT1-7 and GN11 cells. Exogenous MCP-1 stimulated chemotaxis of both cell lines in a dose-dependent fashion; the effect was greater in GN11 than in GT1-7 cells, consistent with the higher CCR2 mRNA levels in GN11 cells. Activating the CaR stimulated MCP-1 secretion in GT1-7 but not in GN11 cells. MCP-1 secreted in response to CaR stimulation is biologically active, as conditioned medium from GT1-7 cells treated with high Ca(2+) promoted chemotaxis of GN11 cells, and this effect was partially attenuated by a neutralizing antibody to MCP-1. Finally, in the preoptic area of anterior hypothalamus, the number of GnRH neurons was approximately 27% lower in CaR-null mice than in mice expressing the CaR gene. We conclude that the CaR may be a novel regulator of GnRH neuronal migration likely involving, in part, MCP-1.

Animals↗
PubMed2002

An exploratory study of the relationship between road rage and crash experience in a representative sample of US drivers.

The phenomenon of road rage has been frequently discussed but infrequently examined. Using a representative sample of 1382 US adult drivers, who were interviewed in a 1998 telephone survey, exploratory analyses examined the relationship between self-reported measures of road rage, generally hazardous driving behaviors, and crash experience. Regarding specific road rage behaviors, most respondents reported having engaged in verbal expressions of annoyance; however only 2.45% reported ever having been involved in direct confrontation with another car or driver. After controlling for gender, age. driving frequency, annual miles driven and verbal expression, an angry/threatening driving subscale of road rage was significantly associated with hazardous driving behaviors that included frequency of driving over the legal blood alcohol limit, receipt of tickets in the past year. and habitually exceeding the speed limit as well as crash experience. However, the verbal/frustration expression subscale was not associated with crash experience or hazardous driving indicators, except for number of tickets, after controlling for other crash-related factors such as gender and age. Direct confrontation by deliberately hitting another car or leaving the car to argue with and/or injure another driver was rarely reported. Results suggest that angry/threatening driving is related to crash involvement; however, after controlling for exposure and angry/threatening and hazardous driving the relationship of milder expressions of frustration while driving and crash involvement was not significant.

Accidents, Traffic↗
PubMed1999

Broadband performance of an active headrest.

This paper presents a study of the attenuation of broadband random acoustic disturbances, when using a feedback active headrest system, as originally suggested by Olson and May. Previous studies showed that a practical active headrest can be designed for tonal disturbances using feedforward controllers. However, many applications, such as jet aircraft and cars, require feedback systems to control random disturbances over a wide frequency bandwidth. In this work, robust feedback controllers are designed to control broadband random disturbances in the low-frequency range based on measured data from a laboratory headrest system. The results show that a practically useful performance can be achieved, but only if the controller is designed to minimize the pressure at a "virtual microphone" close to the listener's ears, and that the performance is maintained reasonably well with movements of the listener's head. The paper emphasizes the importance of both the acoustics and the control in the design of broadband active headrest systems.

Acoustics↗
PubMed1988

Fitness to drive a car after recovery from severe head injury.

Driving skills in relation to residual psychologic impairments were studied in a sample of patients who had survived severe head injuries several years earlier. Daytime driving was studied in an instrumented car that recorded lateral position control on a highway track and during rides in the subjects' own cars with a professional observer. In comparison with a control group matched by age and driving experience, the patients performed worse on both driving tasks. In addition, the patient group showed clear impairments on a neuropsychologic test battery, despite the long intervals since their injuries. However, the only relationships found between test performance and driving involved visuomotor ability and lateral position control. No relationship was found between neurologic status and driving skill. The results are discussed in terms of patients' compensatory potential.

Acute Disease↗
PubMed2002

Turning gap acceptance decision-making: the impact of driver distraction.

PROBLEM: A number of studies have found that use of in-car phones by drivers can interfere with the cognitive processing necessary for making appropriate and timely vehicle control decisions. However, the specific linkage between communication-based distraction and unsafe decision-making has not been sufficiently explored. METHOD: In a closed-course driving experiment, 39 subjects were exposed to approximately 100 gaps each in a circulating traffic stream of eight vehicles on an instrumented test track that was wet about half the time. The subjects were at the controls of an instrumented car, which was oriented in a typical left-turn configuration (traffic-crossing situation in North America) and with parking brake on and the transmission in neutral. The subjects were instructed to press on the accelerator pedal when they felt that a gap was safe to accept. Their performances were monitored and incentives were provided for balancing safe decision-making with expeditious completion of the task. For half of the gap exposures (randomly assigned), each subject was required to listen and respond to a complex verbal message. RESULTS: When not distracted, the subjects' gap acceptance judgment was found to be significantly influenced by their age, the gap size, the speed of the trailing vehicle, the level of "indecision," and the condition of the track surface. However, when distracted, the subjects did not factor pavement surface condition into the decision process. On wet pavement, the subjects were judged to have initiated twice the level of potential collisions when distracted by the messages that they did when not distracted. DISCUSSION: Listening/responding to verbal messages may reduce the capacity of drivers to process adequately all the important information necessary for safe decision-making. The effects of the messages in our study seemed to cause the subjects to misjudge gap size and speed information when operating under the additional disadvantage of adverse pavement condition. SUMMARY: Attention to complex messages while making decisions about turning through gaps in an on-coming vehicle stream was associated with significantly increased unsafe decision making by subjects in our experiment when the additional complexity of wet surface condition was introduced. IMPACT ON INDUSTRY: While the results reflected a somewhat artificial situation where the measure was signaled intention to act rather than the act itself, nevertheless, they do strongly suggest a scenario in which mental distraction could contribute to crash risk. With the rapid proliferation of telematics in the vehicle market, even with the laudable objectives represented by the Intelligent Transportation Systems initiative, there is a danger of the primary task of the driver being subordinated to a perceived need to enhance information flow to/from the external "world." Industry and governments need to work together to ensure that apparently desirable in-vehicle communication improvements do not compromise safety.

Accidents, Traffic↗
PubMed1995

Detection of primary DNA damage: applicability to biomonitoring of genotoxic occupational exposure and in clinical therapy.

The biological effect of putative genotoxic chemicals in the work place environment was monitored in peripheral mononuclear blood cells of exposed workers. DNA strand breaks, alkali-labile sites of DNA and DNA cross-links were measured using the alkaline filter elution method. A dose dependent increase in DNA damage was found in sterilization workers exposed to ethylene oxide and metal workers with exposure towards N-nitrosodiethanolamine. Two subpopulations with different response to the external exposure were found in nonsmoking sterilization workers. Nurses handling antineo-plastic agents without adequate safety provisions showed a statistically significantly higher rate of DNA strand breaks compared to other nurses handling cytostatic drugs with recommended safety equipment and also compared to not exposed controls. Also in several other occupational groups such as fire fighters possibly exposed to several genotoxic chemicals after an accident in a chemical plant, roofers and petrol pump attendants a significantly higher amount of DNA damage was found compared to controls. No statistically significant differences in the amount of DNA strand breaks were found in cabinet makers and car mechanics compared to controls. In peripheral mononuclear blood cells of ovarial carcinoma patients as well as of patients with Morbus Hodgkin an increased DNA strand break rate was found after application of cytostatic drugs. The individual patients showed a very different response after drug intake. The increase in DNA damage after drug application is possibly related to the success of the chemotherapy.

Animals↗
PubMed2002

Is microvascular protection by cariporide and ischemic preconditioning causally linked to myocardial salvage?

Two independent cardioprotective interventions, Na(+)/H(+) exchange inhibition and ischemic preconditioning (PC), were investigated with respect to differential effects on microvascular and myocardial salvage in anesthetized rabbits (30 min of ischemia, 180 min of reperfusion). Cariporide (Car, 300 microg/kg) administered before occlusion and PC reduced infarct size (IS) as measured by triphenyltetrazolium staining [control, 46.0 +/- 4.2% of risk area (RA); Car, 17.6 +/- 3.7% (P < 0.01); PC, 27.5 +/- 4.1% (P < 0.01)] and concomitantly decreased the area of anatomic no reflow (ANR) as measured by thioflavin S staining [control, 40.4 +/- 3.7%; Car, 19.0 +/- 2.9% (P < 0.01); PC, 26.9 +/- 3.4% (P < 0.05)]. Regional myocardial blood flow (RMBF, measured by radioactive microspheres) in the RA, which deteriorated between 30 and 180 min of reperfusion (control, from 79 +/- 6 to 26 +/- 2% of nonischemic flow), was shifted to higher values with both treatments [Car, from 110 +/- 12 to 49 +/- 7% (P < 0.05); PC, from 109 +/- 8 to 38 +/- 6% (P < 0.05)]. However, neither intervention uncoupled the close relationship between IS and ANR (r = 0.92-0.95) or RMBF. Car given at reperfusion did not alter IS, ANR, RMBF, or the close interrelationships. Because size and spatial distribution of no reflow and myocardial necrosis remained closely coupled with independent cardioprotective interventions, a potential causal connection between microvascular and myocardial salvage is discussed.

Animals↗
PubMed1997

Cloning and characterization of argR, a gene that participates in regulation of arginine biosynthesis and catabolism in Pseudomonas aeruginosa PAO1.

Gel retardation experiments indicated the presence in Pseudomonas aeruginosa cell extracts of an arginine-inducible DNA-binding protein that interacts with the control regions for the car and argF operons, encoding carbamoylphosphate synthetase and anabolic ornithine carbamoyltransferase, respectively. Both enzymes are required for arginine biosynthesis. The use of a combination of transposon mutagenesis and arginine hydroxamate selection led to the isolation of a regulatory mutant that was impaired in the formation of the DNA-binding protein and in which the expression of an argF::lacZ fusion was not controlled by arginine. Experiments with various subclones led to the conclusion that the insertion affected the expression of an arginine regulatory gene, argR, that encodes a polypeptide with significant homology to the AraC/XylS family of regulatory proteins. Determination of the nucleotide sequence of the flanking regions showed that argR is the sixth and terminal gene of an operon for transport of arginine. The argR gene was inactivated by gene replacement, using a gentamicin cassette. Inactivation of argR abolished arginine control of the biosynthetic enzymes encoded by the car and argF operons. Furthermore, argR inactivation abolished the induction of several enzymes of the arginine succinyltransferase pathway, which is considered the major route for arginine catabolism under aerobic conditions. Consistent with this finding and unlike the parent strain, the argR::Gm derivative was unable to utilize arginine or ornithine as the sole carbon source. The combined data indicate a major role for ArgR in the control of arginine biosynthesis and aerobic catabolism.

Acyltransferases↗
PubMed1992

A computerized tomographic study in patients with delusional and non-delusional depression.

This is a description of a computerized tomographic study of 45 non-delusional depressed, 29 delusional depressed patients and 77 neurotic control subjects. The cerebral atrophy ratio (CAR) on the three different slices and the ventricular ratio (VBR) of the anterior horn and the body of the lateral ventricles were calculated, analyzed and compared using Student's t test. Compared to the control subjects, the non-delusional depressive patients had greater CAR values than the controls but there were no significant differences of VBR values between the two groups. The patients with delusional depression had significantly larger CAR and VBR values than the non-delusional depressives and control subjects. The delusional depressives had greater brain atrophy than the non-delusionals and it was suggested that organic cerebral factors may have etiological significance in the depressions, especially the delusional depressives.

Adult↗
PubMed2004

A novel role for the coxsackie adenovirus receptor in mediating tumor formation by lung cancer cells.

The Coxsackie Adenovirus Receptor (CAR) has primarily been studied in its role as the initial cell surface attachment receptor for Coxsackie and group C adenoviruses. Recent reports suggest that CAR mediates homotypic intercellular adhesion as part of the tight and/or adherens junction. Thus, CAR is well positioned to participate in intercellular interactions and signaling. Using an antisense (AS)-CAR plasmid vector, we silenced surface CAR expression in lung cancer cells that possessed a high basal expression of this molecule and monitored the resultant tumorigenesis. AS-CAR transfectants exhibit a profound loss in the ability to generate xenografts in scid/scid mice. The emergence of delayed-onset tumors in animals that received injection with AS-CAR transfectants correlates with the resurfacing of CAR expression, suggesting that such expression and tumor emergence are temporally related. To study the mechanism underlying the differences in tumorigenicity, control and AS-CAR cells were compared in terms of their in vitro growth potential. Whereas only subtle differences in the proliferative capacity of the two populations were evident when assayed with growth on plastic, significant differences became apparent when one compared the relative ability of these populations to form colonies in soft agar. These data indicate that silencing surface CAR expression abrogates xenograft tumorigenesis in vivo and colony formation in vitro and invoke the novel possibility that CAR expression is needed for the efficient formation of tumors by a subset of lung cancer cells.

Adenoviridae↗
PubMed2003

Comparative effects of carvedilol and losartan alone and in combination for preventing left ventricular remodeling after acute myocardial infarction in rats.

It has been verified that losartan has beneficial effects on ventricular remodeling (VRM) after acute myocardial infarction (AMI), but the effects of carvedilol alone or in combination with losartan on this condition have not been defined. The present study used rats to compare the effects of carvedilol and losartan alone and in combination for preventing VRM after AMI. After ligation of the left coronary artery, 100 surviving female Sprague-Dawley rats were randomly assigned to 1 of 4 groups: (1) AMI control (n=25), (2) carvedilol (Car, 1 mg x kg(-1) x day(-1)) (n=25), (3) losartan (Los, 3 mg x kg(-1) x day (-1)) (n=25), and (4) Car (1 mg x kg (-1). day(-1)) + Los (3 mg x kg(-1) x day (-1)) (n=25). A sham-operated group (n=17) was also randomly selected. Drugs were administered by gastric gavage for 4 weeks. After hemodynamic studies, the hearts were fixed and analyzed pathologically. Exclusive of the rats that had died or had an infarct size <35% or >55%, complete data were obtained for 65 rats, comprising AMI control (n=13), Car (n=12), Los (n=13), combination (n=14), and sham (n=13) groups. There were no significant differences in the size of infarct among the 4 AMI groups (45.8 approximately 46.7%, all p>0.05). Compared with the sham group, left ventricular (LV) end-diastolic pressure (LVEDP), volume (LVV), weight (LVW) and septal thickness (STh) were all significantly increased (all p<0.001), whereas +/-dp/dt was significantly decreased (both p<0.001) in the AMI group. In comparison with the AMI group, LVEDP, LVV, LVW and STh were all significantly decreased (LVEDP: 12.7+/-2.3, 9.7+/-2.8, and 8.6+/-3.5 mmHg vs 20.6+/-2.7 mmHg, all p<0.001; LVV: 0.74+/-0.07, 0.76+/-0.07, and 0.70+/-0.09 ml vs 0.86+/-0.05 ml, all p<0.05; LVW: 668.4+/-52.0, 702.6+/-45.4, and 683.9+/-67.7 mg vs 787.3+/-76.7 mg, p<0.05 approximately 0.001; STh: 1.57+/-0.05, 1.48+/-0.07, and 1.46+/-0.07 mm vs 1.71+/-0.04 mm, all p<0.05), whereas +/-dp/dt was significantly increased (all p<0.05) in the Car, Los, and combination groups, with LVEDP decreasing more in both Los and the combination groups than in the Car group alone (p<0.05) and STh decreasing more in the combination group than in the Car group alone (p<0.05). Carvedilol and losartan alone and in combination all prevent VRM after AMI in rats, with almost equivalent effect.

Animals↗
PubMed2000

Extracellular Ca(2+)-sensing receptor is a promiscuous divalent cation sensor that responds to lead.

The extracellular Ca(2+)-sensing receptor (CaR) responds to polycations, including Ca(2+) and neomycin. This receptor is a physiological regulator of systemic Ca(2+) metabolism and may also mediate the toxic effects of hypercalcemia. A number of divalent cations, including Pb(2+), Co(2+), Cd(2+), and Fe(2+), are toxic to the kidney, brain, and other tissues where the CaR is expressed. To determine which divalent cations can activate the CaR, we expressed the human CaR in HEK-293 cells and measured activation of phospholipase A(2) (PLA(2)) and the mitogen-activated protein kinase p42ERK in response to potential agonists for the receptor. HEK-293 cells expressing the nonfunctional mutant CaR R796W served as controls. Extracellular Ca(2+), Ba(2+), Cd(2+), Co(2+), Fe(2+), Gd(3+), Ni(2+), Pb(2+), and neomycin activated the CaR, but Hg(2+) and Fe(3+) did not. We analyzed the kinetics of activation of p42ERK and PLA(2) by the CaR in response to Ca(2+), Co(2+), and Pb(2+). The EC(50) values ranged from approximately 0.1 mM for Pb(2+) to approximately 4.0 mM for Ca(2+). The Hill coefficients were >3, indicating multiple cooperative ligand binding sites or subunits. Submaximal concentrations of Ca(2+) and Pb(2+) were additive for activation of the CaR. The EC(50) for Ca(2+) or Pb(2+) was reduced four- to fivefold by the presence of the other ion. These divalent cations also activated PLA(2) via the CaR in Madin-Darby canine kidney cells that stably express the CaR. We conclude that many divalent cations activate the CaR and that their effects are additive. The facts that the CaR is a promiscuous polycation sensor and that the effects of these ions are additive to activate it suggest that the CaR may contribute to the toxicity of some heavy metals such as Pb(2+), Cd(2+), Co(2+), and Fe(2+) for the kidney and other tissues where it is expressed.

Animals↗