Biomedical subjects

L S Levy

Publications and source records attributed to L S Levy.

At least 37 records · Page 2Linked to original sources

PubMed1997

Establishing an occupational exposure limit for hexavalent chromium in the European Union.

A Criteria Document for hexavalent chromium [Cr(VI)], currently under preparation at the Institute of Occupational Health, University of Birmingham, is intended for use in setting an occupational exposure limit (OEL) for Cr(VI) in the European Union (EU). The requirement for establishing OELs, specifically known as indicative limit values, in the EU is set out in Council Directive 80/1107/EEC, amended by Council Directive 88/642/EEC. To facilitate this procedure the Commission has set up a Scientific Committee for Occupational Exposure Limits to Chemical Agents. The Committee, which is composed of independent scientific experts from member states, is responsible for reviewing available scientific data. A Criteria Document forms the basis of the scientific data considered during this process and contains an up-to-date, critical evaluation of available information which is relevant to setting an exposure limit. After consideration of the scientific data for a particular substance, the Committee advises the Commission on setting a health-based OEL. Consideration of other questions such as technical matters and socioeconomic issues occurs during later stages of the procedure, before an OEL is finally adopted. The procedure allows for consultation with interested parties. The Criteria Document for Cr(VI) contains sections on substance identification, chemical and physical properties, production and use data, recent data on occupational exposure, current methods for measurement and analysis, and toxicology. The toxicology section contains a critical evaluation of both human and animal data and forms a major part of the document. This section enables identification of critical health effects associated with exposure to Cr(VI) and consideration of dose-response relationships and provides the basis for any risk assessment and recommendation for an OEL.

Carcinogens↗

PubMed1997

The problems associated with pesticide use by irrigation workers in Ghana.

The use of pesticides in Ghanaian agriculture, though beneficial in reducing crop loss both before and after harvest, has been associated with threats to human health often due to the misapplication of the chemicals. This study was an initial attempt to explore the knowledge, attitudes and practices of 123 farm workers on three irrigation project areas in the Accra Plains, Ghana, regarding the safe handling and use of pesticides, to assess the prevalence of symptoms associated with organophosphorus pesticides (OPs) and carbamates and to determine the prevalence of pesticide-related symptoms, and blood cholinesterase. The study design was cross-sectional in type. Methods used were interviews and observation, and biological monitoring. The results revealed moderate levels of knowledge of the routes of absorption of pesticides and of potential symptoms following exposure. Knowledge of personal protective measures was poor to moderate. High risk practices included frequent handling of the chemicals, home storage of pesticides and short re-entry intervals. Despite knowledge of some health risks associated with pesticides, the use of personal protective equipment (PPE) was minimal due primarily to financial constraints. The prevalence of symptoms was higher and cholinesterase levels lower than in a control group of teachers. It is suggested that there is a need for more epidemiologic studies to investigate the problems associated with pesticide induced ill health as well as research into appropriate and affordable PPE. PPE needs to be subsidized. Training of agriculture and health workers in safety precautions, recognition, and management of pesticide-related ill health is a matter of urgency.

Adult↗

PubMed1997

The feline leukemia virus long terminal repeat contains a potent genetic determinant of T-cell lymphomagenicity.

Feline leukemia virus (FeLV) is an important pathogen of domestic cats. The most common type of malignancy associated with FeLV is T-cell lymphoma. SL3-3 (SL3) is a potent T-cell lymphomagenic murine leukemia virus. Transcriptional enhancer sequences within the long terminal repeats (LTRs) of SL3 and other murine retroviruses are crucial genetic determinants of the pathogenicities of these viruses. The LTR enhancer sequences of FeLV contain identical binding sites for some of the transcription factors that are known to affect the lymphomagenicity of SL3. To test whether the FeLV LTR contains a genetic determinant of lymphomagenicity, a recombinant virus that contained the U3 region of a naturally occurring FeLV isolate, LC-FeLV, linked to the remainder of the genome of SL3 was generated. When inoculated into mice, the recombinant virus induced T-cell lymphomas nearly as quickly as SL3. Moreover, the U3 sequences of LC-FeLV were found to have about half as much transcriptional activity in T lymphocytes as the corresponding sequences of SL3. This level of activity was severalfold higher than that of the LTR of weakly leukemogenic Akv virus. Thus, the FeLV LTR contains a potent genetic determinant of T-cell lymphomagenicity. Presumably, it is adapted to be recognized by transcription factors present in T cells of cats, and this yields a relatively high level of transcription that allows the enhancer to drive the requisite steps in the process of lymphomagenesis.

3T3 Cells↗

PubMed1997

Importance of a c-Myb binding site for lymphomagenesis by the retrovirus SL3-3.

All murine leukemia viruses (MuLVs) and related type C retroviruses contain a highly conserved binding site for the Ets family of transcription factors within the enhancer sequences in the viral long terminal repeats (LTRs). The T-cell lymphomagenic MuLV SL3-3 (SL3-3) also contains a c-Myb binding site adjacent to the Ets site. The presence of this Myb site distinguishes SL3 from most other MuLVs. We tested the importance of these two sites for the lymphomagenicity of SL3-3. Mutation of the Ets site had little effect on viral pathogenicity, as it only slightly extended the latency period to disease onset. In contrast, mutation of the Myb site strongly inhibited pathogenicity, as only a minority of the inoculated mice developed tumors in the two mouse strains that were tested. All tumors that were induced by either mutant appeared to be lymphomas, and no evidence for reversion of either mutation was detected. The effects of the Ets and Myb site mutations on transcriptional activity of the SL3 LTR were tested by inserting the viral enhancer sequences into a plasmid containing the promoter region of the c-myc gene linked to a reporter gene. Mutation the Myb site almost eliminated enhancer activity in T lymphocytes, while mutation of the Ets site had smaller effects. Thus, the effects of the enhancer mutations on transcriptional activity in T cells paralleled their effects on viral lymphomagenicity. The absence of the c-Myb site in the LTR enhancer of the weakly lymphomagenic MuLV, Akv, likely contributes to the low pathogenicity of this virus relative to SL3-3. However, Moloney MuLV also lacks the Myb site in its LTR, although it induces T-cell lymphomas with a potency similar to that of SL3-3. Thus, it appears that SL3-3 and Moloney MuLV evolved genetic determinants of T-cell lymphomagenicity that are, at least in part, distinct.

Animals↗

PubMed1997

Cooperating events in lymphomagenesis mediated by feline leukemia virus.

Feline leukemia virus (FeLV)-mediated lymphomagenesis in the domestic cat has been examined as a model of lymphoid malignancy in a naturally outbreeding population. The pathogenesis of two distinct, naturally occurring types of FeLV-induced tumors has been investigated: (1) a thymic lymphoma of T-cell origin, typical of FeLV-induced lymphoma, and (2) an extrathymic, extranodal lymphoma of non-B non-T-cell origin. The genetic features of these tumors are clearly distinguishable, and include determinants encoded both by the virus and the host. Virally encoded determinants of pathogenesis include the long terminal repeat (LTR) and the envelope SU protein. Cellular determinants include the involvement of a set of proto-oncogenes, and other factors characteristic of the specific cell type of origin of the tumor. Functional studies are aimed at evaluating the action and interaction of these genetic determinants in the pathogenesis of lymphoma in an animal model system.

Animals↗

PubMed1996

Primary sequence and evolutionary conservation of ribosomal protein genes from the domestic cat.

Ribosomal proteins complex with ribosomal RNA to form the subunits of the ribosome, and as such, serve essential functions in protein synthesis. Accumulating evidence suggests that ribosomal proteins are bifunctional molecules with roles in diverse cellular processes in addition to protein synthesis. Previous studies have demonstrated that expression of four ribosomal proteins. L41, S3a, S4, and S17, is elevated in malignant lymphomas of the domestic cat. Reported here is the nucleotide sequence of cDNA clones encoding feline ribosomal proteins L41, S3a, S4, and S17.

Amino Acid Sequence↗

PubMed1996

Abnormalities on neurological examination among sheep farmers exposed to organophosphorous pesticides.

OBJECTIVES: Organophosphates are effective pesticides which are frequently used in several agricultural settings. Although their acute effects are well characterised, it remains unclear whether long term exposure can damage the human nervous system. This study sought to investigate their long term effects by comparing abnormalities on neurological examination between groups of workers exposed to organophosphates and an unexposed group. METHODS: 146 exposed sheep farmers and 143 unexposed quarry workers were recruited into a cross sectional study of symptoms and neuropsychological effects of long term exposure to organophosphates in sheep dip. From a symptom questionnaire given immediately after dipping the 10 most symptomatic and 10 least symptomatic farmers were selected. Several months later each of these, along with 10 of the unexposed quarry workers, underwent a standardised neurological examination similar to that which might be used in clinical practice, at at time as remote as possible from recent exposure to organophosphates so as to exclude any acute effects. RESULTS: All 30 selected subjects agreed to participate. The components of the examination which showed a significant difference were two point discrimination on the dorsum of the hand (symptomatic farmers 22 mm; asymptomatic farmers 13 mm; quarry workers 8 mm) and the dorsum of the foot (symptomatic farmers 34 mm; asymptomatic farmers 10 mm; quarry workers 11 mm), and mean calf circumference (symptomatic farmers 35.0 cm; asymptomatic farmers 36.3 cm; quarry workers 38.6 cm). Overall the prevalence of neurological abnormalities was low. CONCLUSIONS: The differences in neurological examination detected between groups were subtle and their clinical significance was unclear. However, they do suggest evidence of an adverse neurological effect from exposure to organophosphates. Further, larger scale studies will be required before it is possible to confirm or refute the differences detected.

Adult↗

PubMed1996

Mechanisms that contribute to the development of lymphoid malignancies: roles for genetic alterations and cytokine production.

Recent studies have defined genetic alterations commonly associated with transformed lymphocytes. This review suggests roles for these alterations in the development of lymphoid neoplasms. Damage to the genes encoding proteins that function in intracellular signaling, transcription, or regulation of the cell cycle has been identified and linked at varying degrees to the progression of certain lymphoid malignancies. An understanding of the mechanistic consequences following such genetic alterations is essential to an understanding of the development of these lymphoid neoplasms. In contrast, it is also becoming clear that the dysregulated expression of proteins that are not genetically altered can also contribute to the progression of lymphoid malignancies. One such example is the excessive expression of "normal" lymphokines of cytokines which accompanies many lymphoproliferative diseases. The dysregulated expression of cytokines during malignancy can result in the augmentation of growth of transformed lymphocytes, as well as an alteration of the anti-tumor immune response. The latter mechanism is especially important because evasion of the impending immune response is a prerequisite for the progression of lymphoproliferative diseases. Taken together, this review supports the notion that the development of lymphoid malignancies is multifactorial, involving genetic alterations as well as dysregulated cytokine expression.

Animals↗

PubMed1995

Genetic determinants of feline leukemia virus-induced multicentric lymphomas.

Three discrete forms of feline leukemia virus (FeLV)-associated lymphoma have been described clinically: (1) thymic, (2) alimentary, and (3) multicentric. The most common and best-characterized lymphomas are of T-cell origin, generally occurring in the thymus. These tumors typically contain mature T-cells, involve the activation of a distinctive set of proto-oncogenes, and contain FeLV proviruses whose long terminal repeat (LTR) sequences contain tandemly repeated enhancers. Previous studies of a small group of extrathymic, multicentric lymphomas implicated a different set of genetic determinants. The present study expands those observations by examining the lineage of origin, the involvement of proto-oncogenes, and the structure of LTR and env gene sequences in a set of 11 natural, extrathymic lymphomas of the multicentric type. A pattern of genetic events associated with FeLV-positive multicentric lymphomas emerges from this analysis that is clearly distinct from the pattern associated with thymic lymphomas. The tumors do not contain T-cells or B-cells, as evidenced by the germ line organization of TCR beta and IgH loci. Proto-oncogenes strongly implicated in T-cell lymphomagenesis are not involved in these tumors. Rather, a distinct set of proto-oncogenes may be involved. Most striking is the repeated occurrence of an FeLV isolate whose LTR and env gene bear unique sequence elements.

Amino Acid Sequence↗

PubMed1995

Identification of differentially expressed genes in T-lymphoid malignancies in an animal model system.

The molecular events characterizing lymphoid malignancy have been examined in an animal model system, specifically, the retroviral induction of leukemia and lymphoma in the domestic cat following infection with feline leukemia virus (FeLV). Genes differentially expressed in FeLV-induced lymphomas were isolated using a strategy of differential hybridization. Six genes were identified which demonstrate a higher level of expression in an FeLV-induced feline thymic tumor as compared with normal thymus. The differentially expressed genes encode the feline homologues of ribosomal proteins S3a, S4, S17, and L41, elongation factor-1 alpha, and cytochrome oxidase sub-unit I. Northern-blot analysis and quantification by phosphorimaging demonstrates that these genes are expressed at levels from 1.5- to 3.1-fold higher in J5-1 thymic tumor as compared with normal thymus. Expression of the selected ribosomal protein mRNA was further examined in a series of human and feline tissues, including normal tissues, malignant tumors and cell lines. Our data reveal that elevation of the selected ribosomal protein mRNA is associated with all FeLV-induced thymic lymphomas examined. The differentially expressed ribosomal protein mRNA accumulates in a balanced manner in thymic lymphomas. By contrast, the elevation in ribosomal protein mRNA levels is not associated uniformly with hematopoietic malignancy. T-lymphoid malignancy, solid tumors or actively proliferating cells. Rather, the elevation appears to be a uniform and distinctive feature of T-cell malignancy of this particular type. The elevated expression of these genes may be causally related to the neoplastic process.

Adult↗

PubMed1995

Neuropsychological effects of long-term exposure to organophosphates in sheep dip.

Organophosphate-based pesticides are widely used throughout the world. The acute effects of over-exposure to such compounds are well known. Concern has also been expressed that long-term exposure may result in damage to the nervous system. In a cross-sectional study, we compared neuropsychological performance in 146 sheep farmers who were exposed to organophosphates in the course of sheep dipping with 143 non-exposed quarry workers (controls). The farmers performed significantly worse than controls in tests to assess sustained attention and speed of information processing. These effects remained after adjustment for covariates. The farmers also showed greater vulnerability to psychiatric disorder than did the controls as measured by the General Health Questionnaire. There were no observed effects on short-term memory and learning. Repeated exposure to organophosphate-based pesticides appears to be associated with subtle changes in the nervous system. Measures should be taken to reduce exposure to organophosphates as far as possible during agricultural operations.

Adolescent↗

PubMed1995

Function of a unique sequence motif in the long terminal repeat of feline leukemia virus isolated from an unusual set of naturally occurring tumors.

Feline leukemia virus (FeLV) proviruses have been characterized from naturally occurring non-B-cell, non-T-cell tumors occurring in the spleens of infected cats. These proviruses exhibit a unique sequence motif in the long terminal repeat (LTR), namely, a 21-bp tandem triplication beginning 25 bp downstream of the enhancer. The repeated finding of the triplication-containing LTR in non-B-cell, non-T-cell lymphomas of the spleen suggests that the unique LTR is an essential participant in the development of tumors of this particular phenotype. The nucleotide sequence of the triplication-containing LTR most closely resembles that of FeLV subgroup C. Studies performed to measure the ability of the triplication-containing LTR to modulate gene expression indicate that the 21-bp triplication provides transcriptional enhancer function to the LTR that contains it and that it substitutes at least in part for the duplication of the enhancer. The 21-bp triplication confers a bona fide enhancer function upon LTR-directed reporter gene expression; however, the possibility of a spacer function was not eliminated. The studies demonstrate further that the triplication-containing LTR acts preferentially in a cell-type-specific manner, i.e., it is 12-fold more active in K-562 cells than is an LTR lacking the triplication. A recombinant, infectious FeLV bearing the 21-bp triplication in U3 was constructed. Cells infected with the recombinant were shown to accumulate higher levels of viral RNA transcripts and virus particles in culture supernatants than did cells infected with the parental type. The triplication-containing LTR is implicated in the induction of tumors of a particular phenotype, perhaps through transcriptional regulation of the virus and/or adjacent cellular genes, in the appropriate target cell.

Animals↗

PubMed1994

Calcium chelator Quin-2 prevents crocidolite-induced DNA strand breakage in human white blood cells.

Exposure of human white blood cells to UICC crocidolite asbestos in vitro resulted in the formation of DNA strand breakage in a dose-dependent manner up to a fibre concentration of 100 micrograms/ml. Subsequent incubations with the iron chelator desferrioxamine or the intracellular Ca2+ chelator Quin-2 prevented DNA strand break formation above control incubations. Addition of aurintricarboxylic acid, an endonuclease inhibitor, similarly abolished crocidolite-induced DNA strand breaks in these cells. These results suggest that crocidolite-derived hydroxyl radicals do not directly induce DNA strand breakage in mammalian white blood cells. In order to assess Ca2+ mobilisation from intracellular stores in control and crocidolite-treated cells, the fullness of these stores was measured by treating with thapsigargin, a specific inhibitor of the endoplasmic reticulum Ca(2+)-ATPase. On addition of thapsigargin to fura-2AM-loaded cells treated with crocidolite we demonstrated that the endoplasmic reticulum stores had been depleted as no further Ca2+ was released, unlike control cells. We suggest that strand breakage is caused by a complex set of events involving oxygen free radicals that may disturb intracellular Ca2+ homoeostasis and the breaks are produced by secondary reactions, involving Ca(2+)-mediated enzymes.

Aminoquinolines↗

PubMed1994

Iron-dependent formation of 8-hydroxydeoxyguanosine in isolated DNA and mutagenicity in Salmonella typhimurium TA102 induced by crocidolite.

Treatment of isolated DNA with crocidolite asbestos significantly increased the concentration of 8-hydroxydeoxyguanosine (8-OHdG) above background. Furthermore, incubating DNA with H2O2 and crocidolite potentiated the formation of 8-OHdG above levels observed with crocidolite alone. In the presence of desferrioxamine, desferrioxamine and ferrozine, dimethylsulphoxide (DMSO) or o-phenanthroline, crocidolite-induced DNA oxidation was reduced by 36, 73, 74 and 70% respectively. Crocidolite, but not chrysotile asbestos, enhanced background revertants in Salmonella typhimurium TA102, at sub-cytotoxic concentrations in a dose-dependent manner. The mutagenic effects of crocidolite were quite small and this indicates that crocidolite was a weak mutagen in this study. The number of revertants was reduced to the spontaneous rate for this strain after the fibres had been pretreated with desferrioxamine before assaying for genotoxicity in this oxygen radical-sensitive strain. These results help to explain a mechanistic role for iron in crocidolite-induced DNA oxidation and mutagenicity in TA102.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1994

Use of molecular epidemiological techniques in a pilot study on workers exposed to chromium.

OBJECTIVES: Molecular epidemiological techniques, capable of detecting damage to DNA, were used to see if such damage occurred in the lymphocytes of a group of workers exposed to chromium. The two aims of this pilot study were to see if these new techniques might make useful biological monitoring tools for workers exposed to chromium and also, to help assess whether the current occupational exposure limit for chromium (VI) was sufficiently protective in this specific working situation. METHODS: Volunteer groups of 10 workers exposed to chromium and 10 non-exposed workers provided urine and blood samples towards the end of the working week. Chromium concentrations were measured in whole blood, plasma, lymphocytes, and urine. Lymphocytes were used to examine two forms of DNA damage in the two groups; these were the level of DNA strand breakage and, the production of 8-hydroxydeoxyguanosine. RESULTS: Chromium concentration in whole blood, plasma, and urine of workers exposed to chromium was significantly raised (P < 0.01) compared with non-exposed controls, but in isolated lymphocytes, there was only a modest but significant (P < 0.05) increase in chromium in the group exposed to chromium. There was no difference in the levels of DNA strand breaks or 8-hydroxydeoxyguanosine between the groups. Air monitoring for chromium was not undertaken but current levels for the group exposed to chromium were reported to be around 0.01 mg/m3, which is 20% of the current United Kingdom occupational exposure limit. CONCLUSIONS: We were unable to detect any damage in lymphocytic DNA due to exposure to chromium. This may have been due to the low chromium exposure (< 20% of the United Kingdom occupational exposure limit), the ability of plasma to detoxify chromium (VI) to chromium (III) before it reached the lymphocytes, or perhaps the insensitivity of the molecular techniques used. It is now important to test these and other such techniques on groups exposed to levels closer to the United Kingdom occupational exposure limit.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1994

Retroviral determinants of leukemogenesis.

The slowly transforming, leukemogenic retroviruses of humans and other mammals induce malignant disease after prolonged latency but lack an oncogene to which their malignant potential can be attributed directly. The leukemogenic activity of these retroviruses can be attributed to at least three factors, including (1) transcriptional regulatory sequences in the long terminal repeat: (2) the insertional mutagenesis of cellular protooncogenes, thus activating their malignant potential; and (3) the actions of structural and regulatory proteins encoded by viral genes. The goal of this review is to summarize recent findings regarding the roles of these factors in retroviral leukemogenesis. The focus of the review is on the slowly transforming, leukemogenic retroviruses of mammals, including humans and experimental animals.

Animals↗

PubMed1994

Control of IL-6 expression and response in fibroblasts from patients with systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune connective tissue disease of unknown etiology in which aberrant fibroblast function results in fibrosis of the skin and internal organs. A distinguishing feature of dermal fibroblasts cultured from SSc lesions is that they produce constitutively, i.e., without exogenous stimulation, as much as 30-fold more interleukin-6 (IL-6) than do normal fibroblasts. The present study indicates that the mechanism of constitutive IL-6 secretion involves the accumulation of IL-6 mRNA in affected SSc fibroblasts, mediated by the constitutive binding of nuclear factors to the IL-6 promoter. DNA-protein complexes formed using nuclear extracts of constitutively expressing cells are distinct from those using extracts of normal cells, with or without exogenous stimulation of IL-6; thus, the mechanisms which regulate constitutive and inducible IL-6 gene expression are apparently distinct. The data also demonstrate that dermal fibroblasts respond very rapidly to IL-6 by increasing expression of the IL-6 gene, thus suggesting a mechanism for the establishment and/or persistence of constitutive expression. The constitutive secretion of IL-6 may play an important role in the perpetuation of the local immune dysregulation and fibroblast activation in the SSc lesion.

Adult↗

PubMed1993

Hexavalent chromium produces DNA strand breakage but not unscheduled DNA synthesis at sub-cytotoxic concentrations in hepatocytes.

Rat hepatocytes were used to investigate the possible induction of unscheduled DNA synthesis (UDS) and the extent of DNA strand breaks induced by sodium dichromate (a representative chromium(VI) compound) and chromium acetate hydroxide (chromium(III)) in vitro. Cytotoxicity, measured using tetrazolium salt (MTT) reduction assay, was found at a much higher dose of chromium(III), (> 50 microM), compared to that of chromium(VI), (> 2.5 microM), in cultured hepatocytes over 20 h treatment at 37 degrees C. Chromium(VI), but not chromium(III), stimulated minimal UDS in hepatocytes at sub-cytotoxic concentrations. A positive UDS response was only observed at cytotoxic concentration. DNA strand breaks in hepatocytes were induced by chromium(VI) following incubation at 37 degrees C for 1 h at doses of 10, 20 and 40 microM sodium dichromate. The subsequent ligation of such strand breaks in hepatocytes treated with 40 microM chromium(VI) for 1 h at 37 degrees C was demonstrated. The majority of strand breaks was repaired within 30 min following removal of the chromate. In conclusion, chromate-induced DNA strand breakage, possibly involving the formation of oxygen radicals and lack of significant UDS have some analogy to those produced by ionizing radiation.

Animals↗