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PubMed1999

Glutathione S-transferase (GST) M1 and GST T1 genotypes and hematopoietic effects of benzene exposure.

This study investigated whether or not the genotypes glutathione S-transferase theta (GST T1) and mu (GST M1) correlated with low white blood cell (WBC) count found in benzene exposed workers. We found that individuals with genotypes positive for both GST T1 and GST M1 showed the highest prevalence of low WBC [odds ratio (OR) = 4.67, P = 0.046, 95% confidence interval (CI) = 1.02-24.15] when the benzene exposure was high. Multiple logistic regression showed that benzene exposure (OR = 2.81, P = 0.062, 95% CI = 0.96-8.30) was associated with increased OR on low WBC and interactions between the benzene exposure and the genotype of GST T1 were also observed. These observations suggest that GST T1 and GST M1 may play important roles in the biotransformation of benzene, the effect which leads to its hematotoxicity.

Benzene↗

PubMed2005

GBP1 overexpression is associated with a paclitaxel resistance phenotype.

In the search for novel genes involved in the paclitaxel resistance phenotype, prior studies of gene expression in paclitaxel-resistant cell lines and their paired drug-sensitive parental lines using high-density Affymetrix GeneChip arrays identified guanylate-binding protein 1 (GBP1) gene as an overexpressed transcript. The GBP1 gene encodes a large GTPase that is induced by interferon gamma (IFN-gamma) in a variety of eukaryotic cells. In this report we characterize GBP1 and demonstrate that GBP1 expression is consistently upregulated in 7 of 8 paclitaxel or doxorubicin-resistant human cancer cell lines as compared to its expression in the relevant drug-sensitive parental lines. Analysis of GBP1 expression using the Cancer Profiling Array showed that GBP1 is ubiquitously expressed with no significant difference in expression levels between normal and tumor tissue. Parallel analysis of the Cancer Cell Line Profiling Array determined that GBP1 expression in a majority of cell lines derived from human tumors of different tissue origin was induced to variable levels following exposure to multiple stress agents including paclitaxel and doxorubicin. Importantly, stable expression of a GBP1 transgene in the paclitaxel-sensitive ovarian cancer cell line OVCAR8 was sufficient to confer moderate paclitaxel resistance. Our data suggest that increased expression of the GBP1 gene may play an important role in the development of multi-drug resistance (MDR).

Antineoplastic Agents, Phytogenic↗

PubMed2004

Radiation-induced temporary hair loss as a radiation damage only occurring in patients who had the combination of MDCT and DSA.

As imaging technologies become increasingly advanced, it is possible to obtain detailed morphological information as well as functional imaging data. In some imaging technologies, the radiation dose increases with the ability to obtain better images or more detailed information. We encountered three cases of temporary bandage-shaped hair loss, which was caused by perfusion studies of the head by multi-detector row computed tomography (MDCT) for evaluation of cerebral blood flow in patients with vascular disorders. In all three patients with temporary hair loss, two angiographies of the head had been performed in the period of serial CT examinations. This suggested the possibility that radiation exposure from angiography performed in serial examinations, combined with the perfusion studies of the head with MDCT, played an important role in this temporary, bandage-shaped hair loss. Radiologists should be aware that a cumulative or multiplier effect of radiation exposure from multiple diagnostic techniques may result in hair loss and other types of radiation complications.

Adult↗

PubMed2004

A novel splice acceptor mutation in the DSPP gene causing dentinogenesis imperfecta type II.

The dentin sialophosphoprotein (DSPP) gene (4q21.3) encodes two major noncollagenous dentin matrix proteins: dentin sialoprotein (DSP) and dentin phosphoprotein (DPP). Defects in the human gene encoding DSPP cause inherited dentin defects, and these defects can be associated with bilateral progressive high-frequency sensorineural hearing loss. Clinically, five different patterns of inherited dentin defects are distinguished and are classified as dentinogenesis imperfecta (DGI) types I, II, and III, and dentin dysplasia types I and II. The genetic basis for this clinical heterogeneity is unknown. Among the 11 members recruited from the studied kindred, five were affected with autosomal dominant DGI type II. The mutation (g.1188C-->G, IVS2-3C-->G) lay in the third from the last nucleotide of intron 2 and changed its sequence from CAG to GAG. The mutation was correlated with the affection status and was absent in 104 unaffected individuals (208 alleles) with the same ethnic and geological background. The proband was in the primary dentition stage and presented with multiple pulp exposures. The occlusal surface of his dental enamel was generally abraded, and the dentin was heavily worn and uniformly shaded brown. The dental pulp chambers appeared originally to be within normal limits without any sign of obliteration, but over time (by age 4), the pulp chambers became partially or completely obliterated. The oldest affected member (age 59) showed mild hearing loss at high-frequency (8 kHz). Permanent dentition was severely affected in the adults, who had advanced dental attrition, premature loss of teeth, and extensive dental reconstruction.

Adolescent↗

PubMed2006

Parent and teacher identification of children at risk of developing internalizing or externalizing mental health problems: a comparison of screening methods.

The accuracy of screening methods for predicting children's internalizing, externalizing, or total behavior problems by 1-year follow-up were compared. Parents and teachers completed two screening measures each: a measure of exposure to multiple family risk factors (the Family Risk Factor Checklist: FRFC) and a simple nomination question of child risk status, which involved informants answering one question concerning whether they believed a child was at higher risk than average of developing a mental health problem in the future. Both parents and teachers were more accurate at identifying children at risk of externalizing than internalizing disorders. For parents, the FRFC showed similar sensitivity to simple nomination as a screen for predicting later total behavior problems, lower sensitivity for internalizing problems, and there was a nonsignificant trend for the FRFC to have higher sensitivity for externalizing problems than simple nomination. The specificity of simple nomination was somewhat higher than that of the FRFC for all three mental health outcomes. For teachers, simple nomination showed higher sensitivity than the FRFC for predicting internalizing, externalizing, and total behavior problems, but the difference was nonsignificant for internalizing problems. The specificity for both teacher screens was similar across mental health outcomes. For a population base rate of externalizing problems of 13%, teacher nominations for children at risk of externalizing problems had a sensitivity of 69%, specificity of 78%, positive predictive value (PPV) of 32%, and negative predictive value (NPV) of 94%. Teacher nominations of at-risk children had greater predictive accuracy than parent nominations. The simple nomination method shows promise as a cost-efficient screen. When screening children who did not yet have behavioral symptoms, both parent and teacher measures resulted in substantial misclassification errors. However, the use of these screening measures at a population level could benefit large numbers of children who subsequently receive selective preventive interventions.

Child↗

PubMed2026

Bisphenols and their role in female infertility and hormone-related cancer.

Various types of external chemicals can disrupt the endocrine system, interfering with normal hormone function and causing a broad spectrum of negative health effects. Endocrine-disrupting chemicals (EDCs) are a diverse group of natural and synthetic chemicals that are known to contaminate the environment. It is postulated that these agents can contribute to the development of many diseases, including infertility and cancer, because of their ability to interfere with estrogen receptors (ERs). Bisphenols (BPs) are a group of compounds that belong to EDCs, the most common of which is bisphenol A (BPA). Due to restrictions on the use of BPA in industry, analogues such as bisphenol S (BPS) and bisphenol F (BPF) have been introduced. However, some reports indicate that BPA analogues also have negative effects on the endocrine system in both humans and animals because of their structural similarity. This review summarises current knowledge related to BPA, its analogues and their role in female infertility and hormone-related cancers. Furthermore, this review also points to the problem of exposure to more than one estrogenic agent and highlights the importance of considering exposure to multiple chemicals when assessing health effects and setting daily limits.

Humans↗

PubMed1987

Effects of inhalation of ethylene dichloride on pulmonary defenses of mice and rats.

The effects of single or multiple inhalation exposures to ethylene dichloride (DCE) on the pulmonary defense systems of mice and rats were evaluated. Single exposures of mice to the threshold limit value of DCE (10 ppm) resulted in decreased pulmonary bactericidal activity to inhaled Klebsiella pneumoniae and increased mortality from Streptococcus zooepidemicus respiratory infection. A single exposure to 5 ppm DCE caused increased mortality from streptococcal pneumonia although bactericidal activity was not affected. Neither of these two parameters changed following single or five consecutive daily exposures to 2.5 ppm DCE. Single exposures to 10 or 100 ppm DCE did not affect mouse alveolar macrophage (AM) inhibition of the proliferation of a tumor target cell in vitro or AM in vitro phagocytosis of red blood cells. In rats, no effects were observed on pulmonary bactericidal activity. AM in vitro phagocytosis, AM cytostasis and cytolysis of tumor target cells, AM ectoenzymes, or blastogenesis of mitogen-stimulated rat T- and B-lymphocytes from lung-associated, mesenteric, and popliteal lymph nodes following single exposure to 100 or 200 ppm DCE or after twelve 5-hr exposures to 10, 20, 50, or 100 ppm DCE.

Administration, Inhalation↗

PubMed1992

Effect of cocaine, ethanol or nicotine on ornithine decarboxylase activity in early chick embryo brain.

Fetal drug exposure causes multiple deficits in the developing child. For both humans and animal models, the single most common drug-related problem is fetal growth suppression. This defect is associated with significant perinatal morbidity and mortality and may also be related to significant behavioral problems appearing later in life. Studies focussed on the molecular mechanism of fetal drug effects in placental models are complicated by multiple interactions of the drug with mother, placenta and fetus. Using early (76-168 h) chick embryos as a non-placental model, and three common drugs of abuse (nicotine, ethanol and cocaine) it was found that each drug suppressed the peak in fetal brain ornithine decarboxylase (ODC) activity that normally occurs at 120 h of development. For each drug, the decrease in ODC activity at 120 h was followed by a small but significant increase in ODC. Thus, although the drug-treated embryos were smaller in size, they appeared to be undergoing compensatory growth and, in fact, became equal in weight to the vehicle-treated animals, if allowed to hatch.

Animals↗

PubMed1987

Evaluation of the interaction of three genotoxic agents in eliciting sister-chromatid exchanges using response surface methodology.

Chinese hamster cells (V79) were treated with ethylnitrosourea (ENU), bischloroethylnitrosourea (BCNU), and cis-diamminedichloroplatinum(II) (DDP) alone and in combination. Sister chromatid exchanges (SCEs) were quantitated as measures of genotoxicity of the three agents. The combination experiment employed a factorial design in which cells were treated, in various concentration combinations, with all agents simultaneously. Response surface methodology using a polynomial model in treatment variables to approximate the mean the distribution of SCE events was employed for analysis of the interactions of the three genotoxic agents. Due to unequal variances of the number of SCEs in the various treatment groups, a weighted least-squares analysis was used to estimate the parameters of the dose-response relationship. The single-agent results suggest that the DDP concentration-response curve has a much steeper slope than the ENU and BCNU curves, and is concave downward as compared to the relatively linear concentration-response curves of ENU and BCNU. The combination results suggest that ENU and DDP are involved in a negative interaction. The BCNU/DDP interaction, the ENU/BCNU interaction, and the three-factor interaction are not statistically significant. The analysis of these data demonstrates the usefulness of a statistical procedure for evaluating the biological effects resulting from exposure to multiple cytotoxic agents. The methodology can be used with many other types of endpoints and is not limited by the number of treatment agents.

Animals↗

PubMed1982

Induction of benzo[a]pyrene hydroxylase in skin and liver by cutaneous application of jute batching oil.

Skin painting with 30 microliter of jute batching oil (JBO) for 8 days resulted in increased gross liver weight, microsomal protein content and benzo[alpha]pyrene hydroxylase activity of liver. Skin benzo[alpha]pyrene hydroxylase activity at the treated site increased by 10-fold. An investigation of cytochrome pigment status in liver and skin of treated animals showed a specific increase in P-448 level in both tissues. Single skin applications of JBO elevated the level of skin and liver benzo[alpha]pyrene hydroxylase activity to its maximum after 1 day and 2 days, respectively, which, in absence of further treatment with mineral oil, declined gradually to normal levels in due course. The results suggest that single or multiple cutaneous exposure(s) with JBO can increase carcinogen metabolising status of skin and liver which may be one of the causative factors for the tumorigenic effects of JBO in skin.

Administration, Topical↗

PubMed1981

Co-mutagenic effects of 2-aminoanthracene and cigarette smoke condensate on smoker's urine in the Ames Salmonella assay system.

Cigarette smoke condensate (CSC) and cigarette smoker's urine (concentrated) (UC) were tested alone and in combination with direct and indirect mutagens for histidine reversion in the Ames Salmonella assay system. While both CSC and smoker's urine showed some mutagenic activity upon metabolic activation with S9-mix, each of them in combination with the aromatic amine 2-aminoanthracene (2AA) exhibited a synergistic effect on mutagenicity. Such a synergistic effect was not found when these agents were combined with the direct mutagens, ethylmethane sulfonate (EMS) and methylmethane sulfonate (MMS), or the indirect mutagens, benzo[a]pyrene (BP) and 9,10-dimethyl-1,2-benzanthracene (DMBA), tested in this study, nor was the synergistic effect observed when 2AA was tested with urine from a non-smoker. The results, thus, reflected a specificity of the co-mutagenic action of factor(s) in cigarette smoke or smoker's urine and 2AA. The significance of co-mutagens in carcinogenesis has been discussed and the importance of investigating co-mutagenesis particularly in the case of suspected human exposure to multiple environmental agents has been emphasized.

Anthracenes↗

PubMed1992

The spinal pharmacology of acutely and chronically administered opioids.

Systematic studies on the pharmacology of the antinociceptive activity of spinally administered agents have emphasized the action in animal models of mu and delta opioid receptors. Importantly, aside from receptor selectivity, the opioid agonists differ in the property of efficacy. Agents with high efficacy (large receptor reserves) show smaller rightward shifts in their dose-response curves in the face of a given degree of opioid tolerance or when the stimulus intensity is elevated. With regard to loss of drug effect with long-term exposure (tolerance), multiple mechanisms may be considered, including changes in stimulus intensity, change in afferent processing, or changes in receptor number/coupling. Basic studies are providing insights into these several mechanisms.

Drug Tolerance↗

PubMed1990

Mutually dependent response elements in the cis-regulatory region of the neurotensin/neuromedin N gene integrate environmental stimuli in PC12 cells.

The expression of the gene encoding the neuroendocrine peptides neurotensin (NT) and neuromedin N is strictly dependent on simultaneous exposure to multiple inducers in PC12 pheochromocytoma cells. NT peptide and NT/N mRNA levels are synergistically induced by combinations of NGF, dexamethasone, activators of adenylate cyclase, and lithium ion. We have used transient transfection assays to delineate the rat NT/N gene sequences necessary for this complex regulation. Progressive deletions of the 5' flanking region revealed that sequences between -216 and +56 are sufficient to confer the full spectrum of responses exhibited by the endogenous gene to a reporter gene. Detailed mutational analysis of this region indicates that it is composed of an array of inducible cis-regulatory sequences, including AP-1, cAMP response, and glucocorticoid response elements. Specific mutation of either the AP-1 site or each of two cAMP response elements indicates that they are functionally interdependent. This array of response elements serves to integrate multiple environmental stimuli into a unified transcriptional response.

Adrenal Gland Neoplasms↗

PubMed2006

Perceived physical and social causality in animated motions: spontaneous reports and ratings.

Michotte argued that we perceive cause-and-effect, without contributions from reasoning or learning, even in displays of two-dimensional moving shapes. Two studies extend this line of work from perception of mechanical to social causality. We compared verbal reports with structured ratings of causality to gain a better understanding of the extent to which perceptual causality occurs spontaneously or depends on instruction or context. A total of 120 adult observers (72 in the main experiment, 48 in an initial experiment) saw 12 (or 8) different computer animations of shape A moving up to B, which in turn moved away. Animations factorially varied the temporal and spatial relations of the shapes, and whether they moved rigidly or in a non-rigid, animal-like manner. Impressions of social as well as physical causality appeared in both free reports and ratings. Perception of physical causality was stronger than perception of social causality, particularly in free reports. No differences of this nature appear in infants and children, so the asymmetry may reflect learnt knowledge. Physical causality was relatively unspecific initially, but discrimination of causal and delayed control events improved with exposure to multiple events. Experience seems to affect the causal illusion even over a short timeframe; the idea of 'one-trial causality' may be somewhat misleading. Regardless of such effects on the absolute level of responses, the different measures showed similar patterns of variation with the spatio-temporal configuration and type of motion. The good fit of ratings and reports validates much recent work in this area.

Adolescent↗

PubMed2006

Accuracy of digital and analogue cephalometric measurements assessed with the sandwich technique.

INTRODUCTION: The purpose of the study was to evaluate the accuracy of cephalometric measurements obtained with digital tracing software compared with equivalent hand-traced measurements. In the sandwich technique, a storage phosphor plate and a conventional radiographic film are placed in the same cassette and exposed simultaneously. The method eliminates positioning errors and potential differences associated with multiple radiographic exposures that affected previous studies. It was used to ensure the equivalence of the digital images to the hard copy radiographs. Cephalometric measurements instead of landmarks were the focus of this investigation in order to acquire data with direct clinical applications. METHODS: The sample consisted of digital and analog radiographic images from 47 patients after orthodontic treatment. Nine cephalometric landmarks were identified and 13 measurements calculated by 1 operator, both manually and with digital tracing software. Measurement error was assessed for each method by duplicating measurements of 25 randomly selected radiographs and by using Pearson's correlation coefficient. A paired t test was used to detect differences between the manual and digital methods. RESULTS: An overall greater variability in the digital cephalometric measurements was found. Differences between the 2 methods for SNA, ANB, S-Go:N-Me, U1/L1, L1-GoGn, and N-ANS:ANS-Me were statistically significant (P < .05). However, only the U1/L1 and S-Go:N-Me measurements showed differences greater than 2 SE (P < .0001). CONCLUSIONS: The 2 tracing methods provide similar clinical results; therefore, efficient digital cephalometric software can be reliably chosen as a routine diagnostic tool. The user-friendly sandwich technique was effective as an option for interoffice communications.

Adolescent↗

PubMed2004

Arterial stiffness is greater in African Americans than in whites: evidence from the Forsyth County, North Carolina, ARIC cohort.

BACKGROUND: Impairment of arterial dilation is thought to occur earlier than arterial wall thickening in the atherosclerotic process. In comparison with whites, African Americans reportedly have a generalized attenuation of their vasodilation mechanisms. We set out to evaluate arterial stiffness and its correlates by ethnicity, hypothesizing that African Americans would have stiffer common carotid arteries (ie, lower arterial distension for a given systolic pressure) than their white counterparts. METHODS: The study population included 268 African Americans and 2459 whites, who were aged 45 to 64 years at baseline examination in 1986 to 1989, free of coronary heart disease and stroke/transient ischemic attack, from Forsyth County, North Carolina. The beta stiffness index and pulsatile arterial diameter change were derived from brachial blood pressure and from echo-tracked systolic and diastolic carotid arterial diameters. RESULTS: African Americans had stiffer carotid arteries than their white counterparts, with a right shift of the beta stiffness index distribution. After adjustment for selected cardiovascular risk factors, the mean beta stiffness index was 9% higher for African Americans (mean +/- SEM: 11.3 +/- 0.3) than for whites (mean +/- SEM: 10.3 +/- 0.1) among participants not taking antihypertensive medication. Socioeconomic status and comorbidities were differentially associated with arterial stiffness by ethnicity. Specifically, the association between these correlates and beta stiffness index was stronger in African Americans than in whites. CONCLUSIONS: This report on arterial mechanics in African Americans suggests that large artery stiffening either occurs earlier, or is more accelerated in African Americans than in whites in our sample, perhaps as a result of earlier exposure to multiple risk factors. This finding may have implications for hypertension prevention, as arterial stiffness is associated with the development of hypertension.

Black or African American↗

PubMedDate not supplied

SiMCAL 1 algorithm for analysis of gene expression data related to the phosphatidylserine receptor.

OBJECTIVE: SiMCAL 1 (simple multilevel clustering and linking, version 1) is a novel clustering algorithm for time-series microarray data, presented here with an application to a specific data set. The purpose of the algorithm is to present a complete feature set not found in either Jarvis-Patrick clustering, from which it is derived, or in other popular clustering methods such as hierarchical and k-means. The data concern the activity of the phosphatidylserine receptor (PSR) which is believed to be a crucial molecular switch in the mediation of inflammatory response in apoptosis and lysis. By analyzing the behavior of PSR-related genes in mouse macrophages, we hope to elucidate the mechanisms involved in this important biological process. METHODS AND MATERIALS: SiMCAL 1 is implemented in the Python programming language using the Numerical Python extensions, and the data are stored using the MySQL database management system. The data are derived from exposures of multiple Affymetrix mouse gene microarray chips to elevated levels of PSR antibody and control conditions. Code and data are available at (accessed: 17 January 2005). RESULTS: The algorithm meets its objectives: it is simple, in that it is computationally inexpensive; it is multilevel, in that it provides a small number of clearly defined hierarchical levels of clusters; and it offers linking between clusters at the same level in each hierarchy. Clustering and linking results indicate previously unknown co-regulation for genes expressing PGH synthase (COX2) and PGE2, appear to confirm increased production of proteins for clearance of apoptotic cells in the presence of PSR antibody, and correspond to other findings regarding the temporal relationship between PGE2 production and B cell proliferation and differentiation. These results are promising but should be taken as highly preliminary. CONCLUSION: Both the algorithm and its application to this problem show great potential for future development. We plan to improve and extend the SiMCAL family of algorithms, and to obtain new data so that the algorithm(s) may be further applied to this and other problems of interest.

Algorithms↗

PubMed2006

Effect of pesticide residues on health and different enzyme levels in the blood of farm workers from Gadap (rural area) Karachi-Pakistan.

Persons from 14 different fruit and vegetable farm stations from Gadap (rural area), Karachi-Pakistan were examined for the presence of pesticide (cypermethrin, deltamethrin, polytrin-C, diazinon, monocrotophos, DDT and DDE) residues in their blood samples. The present study is concerned with effects of residue on the enzyme levels (GPT, GOT and ALP) as well as the health hazards of pesticide exposed persons. There is a significant increased in the enzyme levels at different stations. Exposed persons complained about liver and kidney dysfunctions and RTI. It may be concluded that exposure of multiple pesticides for prolonged period has affected the normal functioning of different organ systems and possibly produced characteristics clinical effects such as hepatitis, dyspnea and burning sensation in urine.

Agriculture↗