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Biomedical subjects

R S Thomas

Publications and source records attributed to R S Thomas.

At least 19 recordsLinked to original sources
PubMed2003

Relative safety of traditional agricultural tractor power take-off (PTO) drivelines compared to fluid power--a review.

Nearly all tractor PTO arrangements used today consist of a rotating mechanical shaft with two or more universal joints and splined couplings. Although this method of power transfer has been the standard for decades, it continues to be a hazard to farm workers. Commonly, PTO accidents involve the snagging of clothes, resulting in the victim being rapidly and violently drawn into (and around) the rotating shaft. Entanglement injuries are both common and severe in the agricultural workforce, with poor shielding maintenance as a contributing factor. If PTO loads were driven with fluid power, this entanglement hazard would be eliminated. With high-pressure injection injury being the principal hazard, the fluid power alternative appears to pose a lower risk in terms of both frequency of occurrence and severity of injury.

Accidents, Occupational↗
PubMed2001

A clonal growth model: time-course simulations of liver foci growth following penta- or hexachlorobenzene treatment in a medium-term bioassay.

A combination of experimental and simulation approaches were used to analyze the clonal growth of preneoplastic, enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen. Male Fisher 344 rats, 8 weeks of age, were initiated with a single dose (200 mg/kg, i.p.) of diethylnitrosamine (DEN). Beginning 2 weeks later, animals were exposed to daily gavage consisting of 0.1 mmol/kg pentachlorobenzene (PECB) or hexachlorobenzene (HCB) in corn oil vehicle for 6 weeks. Partial hepatectomy was performed 3 weeks after initiation. Experimental data including liver weight, hepatocyte density (number of hepatocytes/unit volume), 5-bromo-2'-deoxyuridine-labeling index for analysis of cell division rate, and number and volume of glutathione-S-transferase pi-positive foci were collected 23, 26, 28, 47, or 56 days after initiation. Model parameters describing liver growth were obtained directly from the experimental data. The probability of mutation/division of normal cells and the growth rate of initiated cells were inferred by a comparison of model outcomes with the observed time courses of foci development. To describe the time-dependent increases in foci volume and the concomitant reduction of foci number observed in all treatment groups, the calibrated model for the DEN controls incorporated the hypothesis of two initiated cell populations (referred to as A and B cells) within the framework of the two-stage model. The B cells are initiated cells that have a selective growth advantage under conditions that inhibit the growth of A cells and normal hepatocytes. The parameter values defined in the DEN controls were used to evaluate experiments involving the administration of PECB or HCB. Both PECB and HCB caused a significant increase in foci volume compared with the DEN controls. HCB treatments resulted in increased proliferation of normal hepatocytes, which was not observed for PECB under the same treatment regimen. The best description of the data resulted from the model incorporating the hypothesis that PECB and HCB promoted the growth of foci via increased net growth rates of B cells. We present here a biologically based clonal growth simulation platform to describe the growth of preneoplastic foci under experimental manipulations of initiation-promotion studies. This simulation work is an example of quantitative approaches that could be useful for the analysis of other initiation-promotion studies.

Animals↗
PubMed2001

Identification of toxicologically predictive gene sets using cDNA microarrays.

We have developed an approach to classify toxicants based upon their influence on profiles of mRNA transcripts. Changes in liver gene expression were examined after exposure of mice to 24 model treatments that fall into five well-studied toxicological categories: peroxisome proliferators, aryl hydrocarbon receptor agonists, noncoplanar polychlorinated biphenyls, inflammatory agents, and hypoxia-inducing agents. Analysis of 1200 transcripts using both a correlation-based approach and a probabilistic approach resulted in a classification accuracy of between 50 and 70%. However, with the use of a forward parameter selection scheme, a diagnostic set of 12 transcripts was identified that provided an estimated 100% predictive accuracy based on leave-one-out cross-validation. Expansion of this approach to additional chemicals of regulatory concern could serve as an important screening step in a new era of toxicological testing.

Animals↗
PubMed2000

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice.

A physiological examination of mice harboring a null allele at the aryl hydrocarbon (Ah) locus revealed that the encoded aryl hydrocarbon receptor plays a role in the resolution of fetal vascular structures during development. Although the aryl hydrocarbon receptor is more commonly studied for its role in regulating xenobiotic metabolism and dioxin toxicity, a developmental role of this protein is supported by the observation that Ah null mice display smaller livers, reduced fecundity, and decreased body weights. Upon investigating the liver phenotype, we found that the decrease in liver size is directly related to a reduction in hepatocyte size. We also found that smaller hepatocyte size is the result of massive portosystemic shunting in null animals. Colloidal carbon uptake and microsphere perfusion studies indicated that 56% of portal blood flow bypasses the liver sinusoids. Latex corrosion casts and angiography demonstrated that shunting is consistent with the existence of a patent ductus venosus in adult animals. Importantly, fetal vascular structures were also observed at other sites. Intravital microscopy demonstrated an immature sinusoidal architecture in the liver and persistent hyaloid arteries in the eyes of adult Ah null mice, whereas corrosion casting experiments described aberrations in kidney vascular patterns.

Animals↗
PubMed2000

A physiologically based pharmacodynamic analysis of hepatic foci within a medium-term liver bioassay using pentachlorobenzene as a promoter and diethylnitrosamine as an initiator.

A stochastic clonal growth model for describing quantitative changes in size and number of putative preneoplastic lesions was modified to analyze the time-course information of cell proliferation and glutathione S-transferase pi (GST-P) foci within a medium-term bioassay. The study used F344 rats and a single initiating event using diethylnitrosamine (200 mg/kg ip) at Week 0. After a 2-week recovery period, chemical treatment began by gavage administration of pentachlorobenzene (PeCB; 100 micromol/kg/day, 7 days/week) in a corn oil vehicle and continued for 6 weeks. One week after beginning gavage dosing, a two-thirds partial hepatectomy was performed and the animals were serially euthanized at 48, 120, 168, 624, and 840 h postsurgery, which corresponds to 216, 288, 336, 792, and 1008 h following the beginning of PeCB treatment, respectively. For analysis, two types of models were evaluated for describing the time-course changes in GST-P foci. First, a sequential model describing the transformation of normal cells into a homogenous initiated cell population (i.e., one-cell model). Second, a two-cell model that describes a heterogeneous foci population by splitting the initiated cell population into two distinct types. In our study, the one-cell model was unable to adequately represent the time-course data for changes in both size and number of foci. In contrast, the two-cell model, which was parameterized to describe a negative selection mechanism, produced adequate simulations of both the size and number of foci. This model-based analysis suggested that the differences between PeCB-treated and untreated animals were primarily in parameters involving the rates of cell death.

Administration, Oral↗
PubMed2000

Reflex facilitation during the stretch-shortening cycle.

Maximal torque during the concentric phase of a movement has been shown to be enhanced by prior eccentric muscle actions, a movement strategy referred to as the stretch-shortening cycle. Although the mechanical basis for this enhancement is well established, the neural component is not. We hypothesized that brief high-frequency bursts of spindle afferent discharge during the eccentric phase of the stretch-shortening cycle could be one mechanism for facilitating the volitional drive. To test this hypothesis, three sets of experiments were done. In the first (N=15), we demonstrated that both the peak and mean EMG of the soleus (S) and lateral gastrocnemius (LG) muscles were considerably greater during a reciprocal hopping (RHOP) task than for maximum isometric contractions (MIVCs). In the second experiment, we tested whether the dynamic nature of the RHOP or the eccentric phase of the RHOP contributed to the EMG potentiation. Peak and mean EMG produced with a concentric hop (CHOP), in which the lengthening phase of the hop was eliminated, were compared with that produced with the RHOP and MIVCs conditions (N=7). The RHOP produced greater peak EMG than either the CHOP or the MIVCs while the mean EMG for both hopping conditions was considerably more than the MIVCs. In the final experiment, we attempted to mimic the brief high-frequency burst of spindle afferent activity during the lengthening phase of the stretch-shortening cycle in the absence of muscle length changes. High-frequency (100 Hz) afferent stimulation (HFS) was delivered during MIVCs. At rest, the HFS produced negligible EMG activity but when superimposed over MIVCs produced a marked potentiation of the S EMG over values obtained during MIVCs alone. Evidence that HFS synchronizes the EMG associated with volitional activation is also provided. We conclude that a substantial but brief facilitation and possible synchronization of the neural drive is provided by the spindle afferents during the eccentric phase of the stretch-shortening cycle.

Adolescent↗
PubMed2000

Comparative hepatocarcinogenicity of hexachlorobenzene, pentachlorobenzene, 1,2,4,5-tetrachlorobenzene, and 1,4-dichlorobenzene: application of a medium-term liver focus bioassay and molecular and cellular indices.

Of the twelve different chlorobenzene isomers, a thorough evaluation of carcinogenicity has only been assessed on monochlorobenzene, 1,2-, and 1,4-dichlorobenzene, and hexachlorobenzene. In the studies presented here, we measured the ability of 1,4-dichlorobenzene (DCB), 1,2,4,5-tetrachlorobenzene (TeCB), pentachlorobenzene (PeCB), and hexachlorobenzene (HCB) to promote glutathione S-transferase pi (GSTP1-1) positive preneoplastic foci formation in rat liver, following diethylnitrosamine (DEN) initiation. The results from these studies show that TeCB, PeCB, and HCB all promote the formation of GSTP1-1 positive foci and that DCB does not. The numbers and area of foci were greatest following HCB promotion, and TeCB and PeCB were approximately equal in their promoting ability. Levels of hepatic CYP1A2, CYP2B1/2, non-focal GSTP1-1, and c-fos were measured in response to treatment with the 4 chlorobenzene isomers, as were reduced glutathione (GSH) and oxidized glutathione (GSSG) levels. Results from these studies show that induction of CYP1A2 and CYP2B1/2 have correlation with both the presence and degree of GSTP1-1 foci promotion by the 4 chlorobenzenes. Alterations in GSH and GSSG levels were similar in PeCB- and TeCB-treated animals in that GSSG levels were significantly decreased, whereas HCB and DCB did not have this effect, although HCB treatment led to a significant increase in GSH levels. We conclude that induction of CYP1A2 or CYP2B1/2 by chlorobenzene isomers may indicate promotional ability, and that this property might be exploited to predict the hepatocarcinogenicity of other chlorobenzene isomers.

Animals↗
PubMed1998

A novel transcription factor, ELF5, belongs to the ELF subfamily of ETS genes and maps to human chromosome 11p13-15, a region subject to LOH and rearrangement in human carcinoma cell lines.

The ETS transcription factors are a large family implicated in the control of cellular proliferation and tumorigenesis. In addition, chromosomal translocations involving ETS family members are associated with a range of different human cancers. Given the extensive involvement of ETS factors in tumorigenesis, it becomes important to identify any additional ETS genes that may also play oncogenic roles. We identify a novel gene, ELF5, that appears to belong to the ELF (E74-like-factor) subfamily of the ETS transcription factor family, based upon similarity within the 'ETS domain'. ELF5 displays a similar, but more restricted, expression pattern to that of the newly isolated epithelium-specific ETS gene, ELF3. Unlike most other ETS family members, ELF5 is not expressed in hematopoietic compartments, but is restricted to organs such as lung, stomach, kidney, prostate, bladder and mammary gland. ELF5 is localized to human chromosome 11p13-15, a region that frequently undergoes loss of heterozygosity (LOH) in several types of carcinoma, including those of breast, kidney and prostate. We find that ELF5 expression is not detectable in a number of carcinoma cell lines, some of which display loss or rearrangement of an ELF5 allele. Similar to other ETS family members, ELF5 displays specific binding to DNA sequences containing a GGAA-core. In addition, ELF5 is able to transactivate through these ETS sequences, present upstream from a minimal promoter. Our data suggest that ELF5 may play roles in mammary, lung, prostate and/or kidney function, and possibly also in tumorigenesis.

Amino Acid Sequence↗
PubMed1998

The role of Ets-1 in mast cell granulocyte-macrophage colony-stimulating factor expression and activation.

Ets-1 is a transcription factor with restricted expression in lymphocytes, and it has been implicated in the regulation of T cell genes such as TCR alpha, TCR beta, CD4, IL-2, and TNF-alpha. We show in this study that Ets-1 is also expressed in some mast cells constitutively and can be induced in primary mast cells with stimuli that activate mast cells. We also show that Ets-1 plays a role in the regulation of granulocyte-macrophage CSF (GM-CSF), a cytokine expressed by activated mast cells. We have characterized a murine growth factor-independent mast cell line, FMP6-, derived from a factor-dependent cell line, FMP1.6. FMP6- has acquired a distinct connective tissue mast cell-like phenotype, as characterized by the expression of mast cell proteases MMCP-4 and MMCP-6, expression of IL-12, and the down-regulation of IL-4. The parental FMP1.6 cell line displays a mucosal mast cell-like phenotype. FMP6- cells have increased Ets-1 expression and achieve growth-factor independence by the autocrine production of GM-CSF and IL-3. Transient transfection of an Ets-1 expression construct in FMP6- cells results in transactivation of a GM-CSF reporter, while a point mutation in the consensus Ets binding site in the conserved lymphokine element, CLE0, abolishes Ets-1 transactivation. Importantly, antisense Ets-1 demonstrates an ability to repress the activity of the GM-CSF reporter. These data suggest a role for Ets-1 in mast cell growth regulation and activation, and because of the central role of mast cells in inflammatory processes, such as asthma and rheumatoid arthritis, they identify Ets-1 as potentially contributing to the pathophysiology of such diseases.

Animals↗
PubMed1998

Use of a medium-term liver focus bioassay to assess the hepatocarcinogenicity of 1,2,4,5-tetrachlorobenzene and 1,4-dichlorobenzene.

1,2,4,5-Tetrachlorobenzene (TeCB) and 1,4-dichlorobenzene (DCB) are important environmental contaminants that have been used extensively for a variety of industrial applications. Limited data are available in the literature regarding the carcinogenicity of TeCB. DCB has been shown to cause renal adenocarcinomas in rats and hepatic adenomas and carcinomas in mice at high doses in a 2-year study. In the studies presented here, we report that TeCB can promote the formation of preneoplastic foci and DCB cannot in a medium-term initiation/promotion assay. These results suggest that TeCB is a liver tumor promoter and that DCB is not at fairly low doses (0.1 and 0.4 mmol/kg per day).

Animals↗
PubMed1998

Enhanced regional expression of glutathione S-transferase P1-1 with colocalized AP-1 and CYP 1A2 induction in chlorobenzene-induced porphyria.

A distinct, nonfocal expression pattern was observed for glutathione S-transferase P1-1 (rGSTP1-1) in rats exposed to either hexachloro-(HCB) or pentachlorobenzene (PeCB). The nonfocal expression was localized to the centrilobular region with the most intense staining nearest the central vein. A Western blot analysis revealed a 5- and 15-fold induction of rGSTP1-1 with PeCB and HCB treatment on an equal molar basis, respectively. Evaluation of porphyrin fluorescence also revealed a centrilobular accumulation with average porphyrin measurements of 0.319, 0.590, and 0.206 micrograms/g tissue for PeCB, HCB, and corn-oil controls, respectively. Due to the role of Activator Protein-1 (AP-1) in rGSTP1-1 expression and CYP 1A2 in the pathogenesis of porphyria cutanea tarda, immunohistochemical localization of c-jun, c-fos, and CYP 1A2 was also performed. Increased expression and colocalization within the liver lobule was observed for c-jun, c-fos, CYP 1A2, rGSTP1-1, and areas of porphyrin accumulation. These observations are consistent with studies that have associated the induction of GST-P with jun- and fos-related gene products.

Animals↗
PubMed1998

Evidence for hepatocarcinogenic activity of pentachlorobenzene with intralobular variation in foci incidence.

Pentachlorobenzene (PeCB) is an important environmental contaminant derived primarily from the by-product contamination of the popular fungicides hexachlorobenzene and pentachloronitrobenzene. Its tumor-promoting activity was studied in a medium-term initiation/promotion assay in male F344 rats. Animals were given a single i.p. injection of diethylnitrosamine (200 mg/kg body weight) and 2 weeks later were administered 0.1 or 0.4 mmol/kg per day PeCB by gavage in a corn oil vehicle, 7 days/week. At the end of week 3, rats were subjected to a partial hepatectomy. Results showed that PeCB, at both doses, significantly increased both the number and area of glutathione S-transferase pi (GST-P) foci (>0.2 mm diameter) (P < 0.05). This trend was dose-dependent. In addition to increases in preneoplastic foci, liver glutathione concentrations and glutathione-associated enzymes showed significant changes in animals treated with PeCB. Glutathione reductase (GR) and gamma-glutamylcysteine synthetase (gamma-GCS) were both significantly induced in the centrilobular region. Changes in oxidized glutathione concentrations corresponded with the increase in GR activity with decreases of 40 and 30% in the low and high dose groups, respectively. No significant changes were detected in reduced glutathione concentrations. Together with changes in GR and gamma-GCS expression, a decrease in GST-P foci around the central veins was significant (P = 0.004) at the high dose. In these animals, 26% of the foci were classified as centrilobular whereas 37 and 39% of the foci were centrilobular in the low dose and control groups, respectively. Because of the co-localized nature of the changes in glutathione-associated enzymes and the decreased incidence of centrilobular foci, our results suggest that the reduced cellular environment may ultimately play a role in negatively selecting for foci growth.

Animals↗
PubMed1998

Approaches to developing alternative and predictive toxicology based on PBPK/PD and QSAR modeling.

Systematic toxicity testing, using conventional toxicology methodologies, of single chemicals and chemical mixtures is highly impractical because of the immense numbers of chemicals and chemical mixtures involved and the limited scientific resources. Therefore, the development of unconventional, efficient, and predictive toxicology methods is imperative. Using carcinogenicity as an end point, we present approaches for developing predictive tools for toxicologic evaluation of chemicals and chemical mixtures relevant to environmental contamination. Central to the approaches presented is the integration of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) and quantitative structure--activity relationship (QSAR) modeling with focused mechanistically based experimental toxicology. In this development, molecular and cellular biomarkers critical to the carcinogenesis process are evaluated quantitatively between different chemicals and/or chemical mixtures. Examples presented include the integration of PBPK/PD and QSAR modeling with a time-course medium-term liver foci assay, molecular biology and cell proliferation studies. Fourier transform infrared spectroscopic analyses of DNA changes, and cancer modeling to assess and attempt to predict the carcinogenicity of the series of 12 chlorobenzene isomers. Also presented is an ongoing effort to develop and apply a similar approach to chemical mixtures using in vitro cell culture (Syrian hamster embryo cell transformation assay and human keratinocytes) methodologies and in vivo studies. The promise and pitfalls of these developments are elaborated. When successfully applied, these approaches may greatly reduce animal usage, personnel, resources, and time required to evaluate the carcinogenicity of chemicals and chemical mixtures.

Algorithms↗
PubMed1997

A novel epithelial-expressed ETS gene, ELF3: human and murine cDNA sequences, murine genomic organization, human mapping to 1q32.2 and expression in tissues and cancer.

The ETS family of genes are implicated in cancers such as Ewings sarcoma, acute myeloid leukemia and chronic myelomonocytic leukemia. Further, they have important functions in embryonic development. Hence, identification and characterization of members of this family are important. We identify a novel ETS family member, ELF3, and report its human and murine cDNA sequences. The mouse cDNA has an alternatively spliced transcript with an extra 60 bp inserted. Hence we present the organization of the murine Elf3 gene together with its exon/intron structure. This gene consists of 9 exons and 8 introns spanning 4.8 kb. ELF3 binds and transactivates ETS sequences and interestingly also shows the ability to bind a GGAT-like purine core, a preferential ETS1/ETS2 type binding site. The expression of ELF3, unlike most other ETS family members, is absent in hematopoietic cells and hematopoietic organs in humans and mice. Intriguingly, the gene is specifically expressed in cell lines of epithelial origin and in organs such as lung, stomach, intestine, kidney that have specialized epithelial cells. We localize the human gene to 1q32.2, a region that is amplified in epithelial tumors of the breast, lung and prostate. Finally, we show that ELF3 expression is increased in a lung carcinoma and adenocarcinoma, as compared to normal tissue. ELF3 is also expressed in cell lines derived from lung cancers. These results suggest that this novel ETS gene may be involved in lung tumorigenesis.

Amino Acid Sequence↗
PubMed1997

The discrimination between overt and non-overt self-inflicted lesions.

Injuries following autoaggressive behaviour are found in patients examined in forensic medicine as well as in psychiatric clinics. Self-mutilation often is combined with a borderline personality disorder in psychiatric patients. Our investigation compares injuries and wounds in psychiatric patients and those in persons examined in the Institute for Forensic Medicine after referral by the police. Our intention was to show evident differences and/or conformities in both of these groups. Additionally we describe a 'third group' of patients which has not yet been mentioned. These women showed, at the same time, characteristics of patients with overt self-injuries and of those with non-overt self-injuries. In this 'third group' we can often find a mixture of reality and fantasy/imagination.

Adolescent↗
PubMed1997

ETS1, NFkappaB and AP1 synergistically transactivate the human GM-CSF promoter.

Activation of helper T cells results in coordinate expression of a number of cytokines involved in differentiation, proliferation and activation of the haematopoietic system. Granulocyte-macrophage colony stimulating factor (GM-CSF) is one such cytokine, whose increased expression results mostly from increases in transcription. Cis-acting elements with NFkappaB, AP1 and ETS-like binding motifs have been identified in the promoter region of the GM-CSF gene, and are important or essential for transcriptional activity following T cell activation. ETS1 is a transcription factor of the ETS family that is expressed in T cells. We have previously shown that ETS1 can transactivate GM-CSF in Jurkat T cells, but only after the cells have been stimulated by treatment with PMA and ionomycin, agents that mimic T cell activation. Thus we proposed that ETS1, which is expressed constitutively in Jurkat cells, may act in concert with PMA/ionomycin inducible factors. Here we show that ETS1 can transactivate a GM-CSF reporter construct in unstimulated Jurkat cells, providing that either NFkappaB or AP1 transcription factors are supplied by co-transfection. We confirm that binding of endogenous NFkappaB and AP1 is induced following PMA/ionomycin treatment of T cells. Transactivation by ETS1, NFkappaB and AP1 is synergistic, and mutation of the individual binding sites reveals that the transcriptional activities of these factors are interdependent. Our results suggest that constitutive ETS1, and inducible NFkappaB and AP1, cooperate as part of a higher order transcriptional complex in activated T cells.

Animals↗