Biomedical subjects
Publications and source records attributed to K W Brown.
HLA status was assessed in matched groups of schizophrenics, 20 with and 20 without tardive dyskinesia. The antigen frequencies were also compared with that in a control sample. The anticipated excess of HLA-B44 was not confirmed. Pooled data displayed a shortfall of HLA-Cw7 and an excess of HLA-B44 in schizophrenics relative to population controls.
The effect of drug-induced Parkinsonism and of the topography of the dyskinetic movements on the psychological consequences of tardive dyskinesia was assessed in 20 schizophrenic subjects and 20 non-dyskinetic schizophrenic controls matched for age, sex, the presence of anticholinergic medication, and the presence and severity of drug-induced Parkinsonism. Limb-truncal subscale scores but not orofacial scores had a significant correlation with cognitive impairment and with negative symptoms. Drug-induced Parkinsonism was found to be a powerful confounding variable.
The results of both the Salmonella/microsome mutagenicity assay and high-performance liquid chromatography (HPLC) analysis were used to evaluate the interactions of binary mixtures of benzo(a)pyrene (BAP) and several different polychlorinated aromatic hydrocarbons. Binary mixtures of either 2-nitro-3,7,8-trichlorodibenzo-p-dioxin (2NTCDD) or pentachlorophenol (PCP) with BAP produced synergism, whereas strictly additive effects were observed with mixtures of octa- or hepta-chlorodibenzo-p-dioxin and BAP. At a dose of 50 micrograms per plate, BAP induced 120 total revertants, whereas the binary mixture of BAP and PCP induced 303 total revertants. The binary mixture of BAP at 1 microgram per plate and 2NTCDD at 0.5 microgram per plate induced 261 net revertants, whereas BAP alone induced 42 net revertants. HPLC analysis of the mixtures indicated that preincubation of BAP with 2NTCDD increased the quantity of benzo(a)pyrene-7,8-dihydrodiol, and 9,10-dihydrodiol metabolites detected. The data suggest that nonmutagenic components of a complex mixture may alter the metabolism of promixate mutagens. Thus, in the present study, 2NTCDD appears to have inhibited the detoxication of BAP metabolites.
The mutagenic potential of two soils amended with a municipal sewage sludge at two application rates was monitored over a 2-year period using Salmonella/microsome mutagenicity assay. Samples were collected from undisturbed monolith lysimeters of Weswood sandy clay (Fluventic Ustochrept) and Padina sandy loam (Grossarenic Paleustalf) amended with dried sewage sludge at 50 and 100 Mg/ha. Soil samples were collected and sequentially extracted with methylene chloride and methanol. The residues from these extracts were tested for mutagenicity at five doses with and without metabolic activation in Salmonella strain TA98. In general, the mutagenic potential of the amended soils of both application rates for the first 8 weeks following sludge application increased and then slowly decreased. The maximum mutagenic response observed in the soil extracts was 222 revertants at a dose of 10 mg of residue. This response was induced by the methanol extract from the Weswood soil collected 56 days after the application of 50 Mg/ha sewage sludge as compared to the 100 Mg/ha application which induced 202 revertants/mg. The mutagenicity of all fractions extracted from the sludge-amended soil at both application rates collected 717 days after application were not appreciably different from extracts from the unamended soils. The data indicate that chemicals that were mutagenic in bacteria persist in the soil and that at the higher application rates, as much as 2 years may be required for the mutagenic potential of the soil to return to background levels.
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This work examines the basis for our earlier observation that certain monoclonal antibodies (MAbs) specific for the B-cell-associated C3d/Epstein-Barr virus (EBV) receptor molecule CD21 also react with the surface of some epithelial cells. Of 9 proven anti-CD21 MAbs now examined on frozen sections of human nasopharynx, tonsil and ecto-cervix, only 3 (HB5, anti-B2, AB1) showed staining of stratified epithelium; 2 of these (HB5, anti-B2) also reacted with the surface of epithelial cells freshly dispersed from these sites. The proportion of HB5- and anti-B2-reactive cells in primary epithelial cultures fell to a low but stable level within days of explantation, while almost all permanently established epithelial cell lines, whether SV40 virus-transformed or of malignant origin, were not reactive with either MAb. This contrasts with the pattern of expression of another surface marker also found selectively on cells of the lymphoid and epithelioid lineages, the CDw40 antigen. Staining with CDw40 MAbs on epithelial sections was usually restricted to the basal (proliferating) layer, but the proportion of CDw40-positive cells increased to a relatively high level in normal epithelial cultures; furthermore, most epithelial cell lines expressed this antigen. Immunoprecipitation from the surface of metabolically labelled epithelial cells with the anti-CD21 MAb HB5 yielded a protein of approximate MW 200 kDa, clearly different in size from the 145 kDa CD21 molecule on B cells. This 200 kDa protein was identified on fresh ecto-cervical epithelium, on primary cultures of a laryngeal carcinoma and on one unusual SV40-transformed epithelial cell line. We conclude that stratified human epithelial cells express a 200 kDa surface molecule which is antigenically related to, but not identical with, the CD21 antigen on B cells. It remains to be seen whether this epithelial cell protein can function as an EBV receptor.
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Cell cultures have been produced from five Wilms' tumours. All cultures had a finite lifespan and a pattern of antigen expression which indicated that the cells were derived from the differentiated components of the tumours. No cells showed any of the expected characteristics of the putative Wilms' tumour stem cell. Nevertheless, in both cases where the original tumours showed a loss of heterozygosity at chromosome 11p alleles, the cultured cells also demonstrated a loss of heterozygosity. Thus these cell cultures definitely originated from Wilms' tumour tissue. The results demonstrate that cell cultures can be produced from the differentiated tissues present in Wilms' tumours and that these non-immortal cells show no 'transformed' phenotype, even though they possess the genetic changes present in the original tumour.
Simian virus 40 (SV40) transformation has been used in a variety of mammalian cells and has been shown to extend their life span. We therefore decided to apply these results to normal kidney and tumoral cells derived from Wilms' patients. Wilms' tumour, a nephroblastoma which presents in early childhood, has been linked to deletions and rearrangements in chromosome 11. Analysis of gene structure in the 11p13 locus involved in the development of the tumour has been restricted by the very short life-span of the tumoral cells in vitro. We transfected normal kidney WT/NK, tumoral WT/T cells and human foetal kidney HFK cells with 2 SV40-derived plasmids SV3neo (pBR322-SV40-containing neomycin bacterial gene) and SVori- (pMK-origin mutated SV40). We isolated a high number of SV40-transfected cell lines. The efficiency of transfection appeared to be extremely low in WT/T cells compared with HFK and even WT/NK. The life span of the cell lines was increased in relation to their untransfected homologues. However, in all of the cell lines except 3, senescence occurred, after crisis step or not. We looked at different markers associated with SV40 transformation of mammalian cells and specifically with the presence of SV40 T antigen in the cells and its consequences: AIG, tumorigenicity, expression and insertion in genomic DNA of SV40 T antigen. Genetic studies involving karyotypic and restriction fragment length polymorphism (RFLP) analysis demonstrated that, despite a frequent pseudo-diploidy, the cell lines derived have conserved the 11p13 locus.
The mutagenic potential of binary mixtures of nitro-polychlorinated dibenzo-p-dioxins and other environmentally related compounds was determined using Salmonella typhimurium strain TA98 in the standard plate incorporation assay. Samples tested included binary mixtures of 4-nitro-4'-chlorobiphenyl with 6-nitro-4,2',3',4',5'-pentachlorobiphenyl, 4-nitrobenzo-p-dioxin with 4-nitro-2,3,8-trichlorodibenzo-p-dioxin, and benzo[a]pyrene with either nitropentachlorobiphenyl or nitrotrichlorodibenzo-p-dioxin. Inhibition was the primary interaction observed for the mixtures of polyhalogenated dioxins or biphenyls with the direct-acting mutagens nitrodibenzo-p-dioxin or nitrochlorobiphenyl. At the highest dose tested, nitrotrichlorodibenzo-p-dioxin inhibited the bacterial mutagenicity of nitrodibenzo-p-dioxin by almost 50%, while pentachlorobiphenyl inhibited the mutagenicity of nitrobiphenyl by 34%. Conversely, synergism was the primary interaction observed for mixtures of halogenated aromatics with the promutagen benzo[a]pyrene. The addition of nitrotrichlorodioxin to benzo[a]pyrene enhanced the mutagenicity of the latter compound by as much as 70%, while the mutagenic potential of a mixture of benzo[a]pyrene and nitropentachlorobiphenyl was approximately 50% greater than the mutagenicity of benzo[a]pyrene alone. In summary, mixtures of nonmutagenic nitropolyhalogenated biphenyls or dibenzo-p-dioxins appear to inhibit the mutagenicity of direct-acting mutagens, while these same compounds seem to enhance the mutagenic potential of the promutagen benzo[a]pyrene.
26 patients were studied to assess the association between iron deficiency and akathisia. 13 akathisic patients were matched with 13 non-akathisic controls. Serum iron and percentage saturation were significantly decreased in the akathisic group, whereas total iron-binding capacity was significantly increased. A negative correlation between serum iron and akathisia rating (rs = -0.42) was also found.
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Prokaryotic bioassays, capable of detecting point mutations and lethal damage to DNA, and a GC/MS/Data System analysis were employed to evaluate the genotoxic characteristics of wood-preserving bottom sediment. Organic compounds in the waste were initially extracted with dichloromethane and then fractionated by liquid-liquid extraction into acid, base and neutral fractions. The crude extract and each of 3 subfractions were tested in 4 strains of S. typhimurium to detect point mutations and 6 strains of B subtilis to detect lethal damage to DNA. The assay using S. typhimurium responded to indirect-acting mutagens in the crude extract and all 3 primary fractions, with the maximum mutagenic response of 181 net revertants induced by the base fraction at a dose of 500 micrograms/plate. In the DNA-repair assay, the survival ratio for the repair-deficient strain recE4 when compared to the repair-proficient strain 168 wt was 0.17 and 0.09 in the acid and base fractions, respectively, at a dose of 100 micrograms/plate. Potentially genotoxic compounds identified in the waste fractions by GG/MS/DS analysis include acenaphthylene, pentachlorophenol, methyl phenanthrene, fluoranthene and pyrene. However, it appears that these identified chemicals did not contribute significantly to the observed mutagenic activity of the sample extracts.
The eukaryotic haploid and diploid forms of Aspergillus nidulans were used to detect gene mutations and various types of chromosome damage, respectively, in the acid, base and neutral fractions of a wood-preserving bottom sediment. The corresponding response to prokaryotic mutagenicity assays and major chemical constituents of the 3 waste fractions were described by Donnelly et al. (1987). The haploid methionine system detected genotoxic compounds in all 3 primary waste fractions without metabolic activation. With metabolic activation, the maximum response observed in the gene mutation assay was induced by the base fraction. In the diploid assay without metabolic activation, the acid fraction induced the maximum number of major chromosome abnormalities, while the base fraction induced the maximum number of minor deletions or insertions. These results appear to reflect the different composition of the waste fractions since each fraction induced a different type of genetic damage in the two bioassays employed. Alternately, because exposure in the diploid assay was during a growth stage, the results may reflect a varying response at different points of the cell division cycle. The results obtained using eukaryotic bioassays indicate that the wood preserving waste contains compound(s) capable of inducing point mutations, chromosome damage, recombination, and compound(s) acting as spindle poisons.
Over a 10-year period, 65 of 196 patients (33%) with ovarian epithelial malignancy, previously treated with chemotherapy, had a second-look operation if the disease was clinically absent. All procedures were done by one of three gynecologic oncologists, and 48% of the patients had a positive second-look procedure. Of patients with original stage I, II disease, 25% had a positive second-look operation, contrasting with 61% of patients with stage III, IV. Significant perioperative morbidity occurred: one patient had intraoperative vascular collapse; 15% had prolonged ileus; 17% had small bowel resections at the time of the second-look operation or in the postoperative period. Of all patients with negative second-look operations, 24% have had recurrent disease from 5 to 23 months after the procedure. These recurrences were in the liver or distant sites in 63% of the patients. Second-look operations, if still indicated by negative noninvasive techniques, should be performed in tertiary care centers under study situations in a standard fashion.
Human foetal keratinocytes were transfected with a recombinant plasmid (pSV6-1) which contained an origin defective SV40 genome. The resulting transformed cell line had many properties in common with previously described SV40-transformed keratinocytes, including expression of simple epithelial-type keratins. It was non-tumourigenic in nude mice at early passages, forming small benign cysts, however, after approximately 46 in vitro passages, these transformed keratinocytes formed invasive squamous cell carcinomas in athymic nude mice. Several in vitro changes were associated with this acquisition of tumourigenicity (a) an alteration in cellular morphology, (b) development of a cytogenetically marked clone and (c) loss of cell surface fibronectin. The loss of fibronectin was also observed in vivo; cysts formed by SV6-1 Bam/HFK produced human fibronectin whereas tumours did not, although both tumours and cysts were laminin- and keratin-positive. These results indicate that the spontaneous development of secondary events in immortalised human cells may lead to the acquisition of a malignant phenotype.
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