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The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology. [ABSTRACT FROM AUTHOR]

Objectives The Covid-19 pandemic necessitated a rapid global transition towards telemedicine; yet much remains unknown about telemedicine's acceptability and safety in rheumatology. To help address this gap and inform practice, this study investigated rheumatology patient and clinician experiences and views of telemedicine. Methods Sequential mixed methodology combined analysis of surveys and in-depth interviews. Between and within-group differences in views of telemedicine were examined for patients and clinicians using t-tests. Results Surveys (patients n  = 1340, clinicians n  = 111) and interviews (patients n  = 31, clinicians n  = 29) were completed between April 2021 and July 2021. The majority of patients were from the UK (96%) and had inflammatory arthritis (32%) or lupus (32%). Patients and clinicians rated telemedicine as worse than face-to-face consultations in almost all categories, although >60% found it more convenient. Building trusting medical relationships and assessment accuracy were great concerns (93% of clinicians and 86% of patients rated telemedicine as worse than face-to-face for assessment accuracy). Telemedicine was perceived to have increased misdiagnoses, inequalities and barriers to accessing care. Participants reported highly disparate telemedicine delivery and responsiveness from primary and secondary care. Although rheumatology clinicians highlighted the importance of a quick response to flaring patients, only 55% of patients were confident that their rheumatology department would respond within 48 hours. Conclusion Findings indicate a preference for face-to-face consultations. Some negative experiences may be due to the pandemic rather than telemedicine specifically, although the risk of greater diagnostic inaccuracies using telemedicine is unlikely to be fully resolved. Training, choice, careful patient selection, and further consultation with clinicians and patients is required to increase telemedicine's acceptability and safety. Trial registration This telemedicine study is part of a pre-registered longitudinal multi-stage trial, the LISTEN study (ISRCTN-14966097), with later Covid-related additions registered in March 2021, including a pre-registered statistical analysis plan. [ABSTRACT FROM AUTHOR]

Objectives We report the results of a pilot young patient survey that targeted patients with JSLE and JDM, exploring well-being, resilience and general concern about the coronavirus disease 2019 (COVID-19) pandemic as well as self-assessment of disease activity. Methods The survey was completed anonymously by patients who had been approached via the automatically generated hospital database between June and December 2020. In addition to disease characteristics, geographic location, education and employment level, we explored young patients' resilience, mood and feelings, mental well-being, self-assessed disease activity and general COVID-19 concerns using validated tools and visual analogue scales. Results This pilot study found that self-perceived disease activity was the strongest predictor of COVID-19 concern, irrespective of gender, employment and education status or well-being and resilience. Generalized concerns regarding the COVID-19 pandemic were significantly higher in females, although their self-reported DASs were comparable to male respondents. Conclusion Our findings highlight a gender bias in the generalized concern related to the COVID-19 pandemic, irrespective of the examined potential confounders. This suggests the need for further research around young patient self-reported outcomes outside hospital visits, especially in the context of gender differences and potential challenges of future pandemics. [ABSTRACT FROM AUTHOR]

The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5 × 10−5, 5 × 10−3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9–10 weeks age) via nose-only inhalation (INH) exposure for 1 h. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal injection (IP) and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated time points and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 h post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the TK and genotoxicity of NNK. [ABSTRACT FROM AUTHOR]

Objective The aim was to explore the impact of patient–physician interactions, pre- and post-diagnosis, on lupus and UCTD patients' psychological well-being, cognition and health-care-seeking behaviour. Methods Participants were purposively sampled from the 233 responses to a survey on patient experiences of medical support. Twenty-one semi-structured interviews were conducted and themes generated using thematic analysis. Results The study identified six principal themes: (i) the impact of the diagnostic journey; (ii) the influence of key physician(s) on patient trust and security, with most participants reporting at least one positive medical relationship; (iii) disparities in patient–physician priorities, with patients desiring more support with quality-of-life concerns; (iv) persisting insecurity and distrust, which was prevalent and largely influenced by previous and anticipated disproportionate (often perceived as dismissive) physician responses to symptoms and experiences of widespread inadequate physician knowledge of systemic autoimmune diseases; (v) changes to health-care-seeking behaviours, such as curtailing help-seeking or under-reporting symptoms; and (vi) empowerment, including shared medical decision-making and knowledge acquisition, which can mitigate insecurity and improve care. Conclusion Negative medical interactions pre- and post-diagnosis can cause a loss of self-confidence and a loss of confidence and trust in the medical profession. This insecurity can persist even in subsequent positive medical relationships and should be addressed. Key physicians implementing empowering and security-inducing strategies, including being available in times of health crises and validating patient-reported symptoms, might lead to more trusting medical relationships and positive health-care-seeking behaviour. [ABSTRACT FROM AUTHOR]

Objectives The aim was to explore patient experiences and views of their symptoms, delays in diagnosis, misdiagnoses and medical support, to identify common experiences, preferences and unmet needs. Methods Following a review of LUPUS UK's online forum, a questionnaire was posted online during December 2018. This was an exploratory mixed methods study, with qualitative data analysed thematically and combined with descriptive and statistically analysed quantitative data. Results There were 233 eligible respondents. The mean time to diagnosis from first experiencing symptoms was 6 years 11 months. Seventy-six per cent reported at least one misdiagnosis for symptoms subsequently attributed to their systemic autoimmune rheumatic disease. Mental health/non-organic misdiagnoses constituted 47% of reported misdiagnoses and were indicated to have reduced trust in physicians and to have changed future health-care-seeking behaviour. Perceptions of physician knowledge and listening skills were highly correlated with patient ratings of trust. The symptom burden was high. Fatigue had the greatest impact on activities of daily living, yet the majority reported receiving no support or poor support in managing it. Assessing and treating patients holistically and with empathy was strongly felt to increase diagnostic accuracy and improve medical relationships. Conclusion Patient responses indicated that timely diagnosis could be facilitated if physicians had greater knowledge of lupus/related systemic autoimmune diseases and were more amenable to listening to and believing patient reports of their symptoms. Patient priorities included physicians viewing them holistically, with more emotional support and assistance in improving quality of life, especially in relation to fatigue. [ABSTRACT FROM AUTHOR]

The use of botanicals and dietary supplements derived from natural substances as an adjunct to an improved quality of life or for their purported medical benefits has become increasingly common in the United States. This review addresses the safety assessment and regulation of food products containing these substances by the U.S. Food and Drug Administration (FDA). The issue of safety is particularly critical given how little information is available on the toxicity of some of these products. The first section uses case studies for stevia and green tea extracts as examples of how FDA evaluates the safety of botanical and herbal products submitted for consideration as Generally Recognized as Safe under the Federal Food, Drug, and Cosmetics Act. The 1994 Dietary Supplement Health Education Act (DSHEA) created a regulatory framework for dietary supplements. The article also discusses the regulation of this class of dietary supplements under DSHEA and addresses the FDA experience in analyzing the safety of natural ingredients described in pre-market safety submissions. Lastly, we discuss an ongoing interagency collaboration to conduct safety testing of nominated dietary supplements. [ABSTRACT FROM AUTHOR]

Titanium dioxide (TiO2) is included in some sunscreen formulations to physically block ultraviolet radiation. A dermal penetration study was conducted in minipigs with three TiO2 particles (uncoated submicron sized, uncoated nano-sized, and dimethicone/methicone copolymer-coated nanosized) applied 5% by weight in a sunscreen. These and control formulations were topically applied to minipigs at 2 mg cream/cm2 skin (4 applications/day, 5 days/week, 4 weeks). Skin (multiple sites), lymph nodes, liver, spleen, and kidneys were removed, and the TiO2 content was determined (as titanium) using inductively coupled plasma mass spectroscopy. Titanium levels in lymph nodes and liver from treated animals were not increased over the values in control animals. The epidermis from minipigs treated with sunscreens containing TiO2 showed elevated titanium. Increased titanium was detected in abdominal and neck dermis of minipigs treated with uncoated and coated nanoscale TiO2. Using electron microscopy-energy dispersive x-ray analysis, all three types of TiO2 particles were found in the stratum corneum and upper follicular lumens in all treated skin samples (more particles visible with coated nanoscale TiO2). Isolated titanium particles were also present at various locations in the dermis of animals treated with all three types of TiO2-containing sunscreens; however, there was no pattern of distribution or pathology suggesting the particles could be the result of contamination. At most, the few isolated particles represent a tiny fraction of the total amount of applied TiO2. These findings indicate that there is no significant penetration of TiO2 nanoparticles through the intact normal epidermis. [ABSTRACT FROM PUBLISHER]

Many cosmetics, sunscreens, and other consumer products are reported to contain nanoscale materials. The possible transdermal absorption of nanoscale materials and the long-term consequences of the absorption have not been determined. We used polyethylene glycol coated cadmium selenide (CdSe) core quantum dots (QD; 37 nm diameter) to evaluate the penetration of nanoscale material into intact, tape stripped, acetone treated, or dermabraded mouse skin. QD were suspended in an oil-in-water emulsion (approximately 9μM) and the emulsion was applied at 2 mg/cm2 to mouse dorsal skin pretreated as follows: intact; tape stripped to remove the stratum corneum; acetone pretreated; dermabraded to remove stratum corneum and epidermis. QD penetration into the skin was monitored in sentinel organs (liver and regional draining lymph nodes) using inductively coupled plasma mass spectrometry analysis of cadmium (from the CdSe QD). No consistent cadmium elevation was detected in the sentinel organs of mice with intact, acetone pretreated, or tape-stripped skin at 24- and 48-h post-QD application; however, in dermabraded mice, cadmium elevations were detected in the lymph nodes and liver. QD accumulation (as cadmium) in the liver was approximately 2.0% of the applied dose. The passing of QD through the dermabraded skin was confirmed using confocal fluorescence microscopy. These results suggest that transdermal absorption of nanoscale materials depends on skin barrier quality, and that the lack of an epidermis provided access to QD penetration. Future dermal risk assessments of nanoscale materials should consider key barrier aspects of skin and its overall physiologic integrity. [ABSTRACT FROM PUBLISHER]

Nanoparticles are small-scale substances (<100 nm) with unique properties and, thus, complex exposure and health risk implications. This symposium review summarizes recent findings in exposure and toxicity of nanoparticles and their application for assessing human health risks. Characterization of airborne particles indicates that exposures will depend on particle behavior (e.g., disperse or aggregate) and that accurate, portable, and cost-effective measurement techniques are essential for understanding exposure. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods, and the effect of skin condition on penetration. Carbon nanotubes apparently have greater pulmonary toxicity (inflammation, granuloma) in mice than fine-scale carbon graphite, and their metal content may affect toxicity. Studies on TiO2 and quartz illustrate the complex relationship between toxicity and particle characteristics, including surface coatings, which make generalizations (e.g., smaller particles are always more toxic) incorrect for some substances. These recent toxicity and exposure data, combined with therapeutic and other related literature, are beginning to shape risk assessments that will be used to regulate the use of nanomaterials in consumer products. [ABSTRACT FROM AUTHOR]

The rates of cell proliferation and cell loss in conjunction with the differentiation status of a tissue are among the many factors contributing to carcinogenesis. Nongenotoxic (non-DNA reactive) chemicals may affect this balance by increasing proliferation through direct mitogenesis or through a regenerative response following loss of cells through cytotoxic (oncotic) or apoptotic necrosis. In a recent NTP study in Fischer rats and B6C3F1 mice, the mycotoxin fumonisin B1 caused renal carcinomas in male rats and liver cancer in female mice. In an earlier study in male BD-IX rats, fumonisin B1 caused hepatic toxicity and hepatocellular carcinomas. An early effect of fumonisin B1 exposure in these target organs is apoptosis. However, there is also some evidence of oncotic necrosis following fumonisin B1 administration, especially in the liver. Induction of apoptosis may be a consequence of ceramide synthase inhibition and disruption of sphingolipid metabolism by fumonisin B1. Fumonisin B1 is not genotoxic in bacterial mutagenesis screens or in the rat liver unscheduled DNA-synthesis assay. Fumonisin B1 may be the first example of an apparently nongenotoxic (non-DNA reactive) agent producing tumors through a mode of action involving apoptotic necrosis, atrophy, and consequent regeneration. [ABSTRACT FROM PUBLISHER]

Canine osteosarcoma is a spontaneous malignancy in dogs, characterized by micrometastasis to pulmonary and extrapulmonary tissues at the time of diagnosis. Standard treatment involves amputation of the affected leg, but median survival time is 3–4 months with death due to metastasis. A randomized double-blind trial was conducted to evaluate liposome-encapsulated muramyl tripeptide-phosphatidylethanolamine (liposome/MTP-PE) as a treatment for metastasis in dogs undergoing amputation for osteosarcoma. Fourteen dogs were treated with liposome/MTP-PE, and 13 were treated with empty liposomes. Median survival time was 222 days for dogs treated with liposome/MTP-PE, compared to 77 days for dogs treated with empty liposomes (<.002). In the liposome< MTP-PE-treated group there were still four dogs alive and free of metastasis at >1 year post surgery. Treatment was well tolerated; no significant toxic effects were noted except for mild elevations in body temperature (1–2 °C) for 2–6 hours post injection. [J Natl Cancer Inst 81:935-938, 1989] [ABSTRACT FROM PUBLISHER]

Treatment of normal human diploid fibroblasts with 0.3 — 22 μM 1-nitrosopyrene resulted in a dose-dependent decrease in relative cloning efficiency and an increase in anchorage-independent growth in soft agar. When compared to previous experiments, 1-nitrosopyrene was 10- to 20-fold more cytotoxic and 5- to 10-fold more potent at inducing morphological transformation than 1-nitropyrene. Incubation of the fibroblasts with 8 μM 1-nitropyrene in the presence of xanthine oxidase, a mammalian nitroreductase, resulted in the formation of one major DNA adduct, N-(deoxyguanosin-8-yI)-1-aminopyrene, at a level of 1.1 adducts per 10 nucleo-tides. Fibroblasts treated with 1-nitrosopyrene formed the same DNA adduct; however, only a 0.3 μM concentration was required to give 0.7 adducts per 10 nucleotides in the fibro-blast DNA. These data indicate that a limiting step in the cellular toxicity and transformation of normal human diploid fibroblasts by 1-nitropyrene is the initial reduction to 1-nitrosopyrene. [ABSTRACT FROM PUBLISHER]

1-Nitropyrene is an environmental mutagen and carcinogen which undergoes both oxidative and reductive metabolism. We have previously shown that nitroreduction to N-hydroxy-1-aminopyrene leads to the formation of arylamine-DNA adducts. In the present study, we have investigated the oxidative metabolism of 1-nitropyrene and the subsequent binding of ring-oxidized metabolites to DNA. In vitro incubations were conducted using hepatic microsomes from uninduced rats or from rats pretreated with phenobar-bital, Aroclor 1254, 3-methykholanthrene, or 3-methyl-cholanthrene and trans-stilbene oxide. H.p.l.c. analysis of the incubation mixtures indicated the presence of the previously reported metabolites, 1-aminopyrene, 3-, 6-, and 8-hydroxy-1-nitropyrene, and 1-nitropyrene trans-4, 5-dihydrodiol. In addition, 1-nitropyrene 4, 5-oxide, 1-nitropyrene 9, 10-oxide, 1-nitropyrene ira/is-9, 10-dihydrodiol and 1-pyrenol were identified. The formation of both K-region dihydrodiols could be increased by transstHbene oxide induction of microsomal epoxide hydrase. Formation of the K-region epoxides was greatest using phenobarbital- and Aroclor-induced microsomes and increased with increasing oxygen tension, while 1-pyrenol formation was highest in 3-methylcholanthrene-induced microsomal incubations and was not affected by the oxygen tension. When calf thymus DNA was added to the microsomal incubations, similar levels of DNA-binding occurred in incubations conducted under oxygen, air, argon or anaerobic conditions. H.p.l.c. analysis of the enzymatically hydrolyzed DNA indicated the presence of multiple DNA adducts with the major product coeluting with AKdeoxy-guanosin-8-yl)-l-aminopyrene. The K-region oxides bound directly to DNA to give adducts similar to the minor products detected in the microsomal incubations. Incubation of the K-region oxides with the nitroreductase, xanthine oxidase, increased the DNA-binding and resulted in an additional ad-duct which coeluted with AKdeoxyguanosin-8-yl)-l-amino pyrene. 3-Hydroxy-l-nitropyrene bound extensively to DNA upon nitroreduction by rat liver cytosol or xanthine oxidase, while 6- and 8-hydroxy-l-nitropyrene bound only slightly. None of these oxidized metabolites was activated to DNA-binding species by cytosolic nitroreduction followed by AcCoA-dependent acetylation. The fact that oxidizedmetabolites of 1-nitropyrene are reduced to DNA-binding derivatives more easily than 1-nitropyrene itself may be important in vivo where 1-nitropyrene has been shown to be readily oxidized. [ABSTRACT FROM PUBLISHER]

1,6-Dinitropyrene and 1,8-dinitropyrene are environmental contaminants which are mutagenic in bacteria and cultured mammalian cells. Since nitroreduction, and possibly O-acetylation, have been implicated in the metabolic activation of these compounds, the reduced intermediates, 1-nitro-6-nitroso-pyrene and 1-nitro-8-nitrosopyrene, were synthesized and their mutagenicity examined in and Chinese hamster ovary (CHO) cells. Nitration of 1-acetyl-aminopyrene yielded a mixture of 1-acetylamino-6-nitropy-rene and 1-acetylamino-8-nitropyrene, which was separated by flash chromatography. Following deacetylation, the amino-nitropyrenes were oxidized to the desired nitronitrosopyrenes with -chloroperoxybenzoic acid. Both nitronitrosopyrenes showed similar levels of mutagenicity in strain TA98 and a nitroreductase-deficient analogue, TA98NR, but much lower activity in the esterificase-deficient strain, TA98/1, 8-DNP, which suggested that reduced metabolites require further activation by O-acetylation. In contrast, the analogous compound, 1-nitrosopyrene, was equally mutagenic in all three strains while its parent compound, 1-nitropyrene, demonstrated a much reduced mutagenicity in strain TA98NR. In CHO cells, 1-nitropyrene was not mutagenic and the dinitropyrenes were only weakly active, while all three nitroso-pyrene derivatives were highly mutagenic. These data support the hypothesis that nitrated pyrenes are metabolized to muta-gens through nitroreduction. In the limiting step in the metabolic activation of 1-nitropyrene appears to be the initial reduction to 1-nitrosopyrene, while with the dinitropy-renes subsequent esterification of the reduced intermediates seems critical. With CHO cells, the initial reduction to nitroso derivatives is the limiting step for all nitropyrenes, and esterification does not appear to occur in the activation sequence. [ABSTRACT FROM PUBLISHER]

[4, 5, 9, 10–H]1-nitropyrene was incubated with NADH- or NADPH-fortified rat liver microsomes under an argon atmosphere. Residual substrate and metabolites were extracted with ethyl acetate and analyzed by high pressure liquid chromatography. Both reduced and oxidized products were formed: namely, 1-aminopyrene, -4, 5-dihydroxy-4, 5-dihydro-1-nitropyrene, and 3-, 6- and 8-hydroxy-1-nitropyrene. When incubations were conducted with rat liver cytosol, only the reduced products 1-nitrosopyrene and 1-aminopyrene were detected. In parallel experiments, [4, 5, 9, 10–H]1-nitropyrene was administered to rats by intravenous injection or gavage and the bile was collected. After 4 h, approximately one-third of the intravenously-administered compound appeared in the bile as O-glucuronides of 3-, 6- and 8-hydroxy-1-nitropyrene, the O-glucuronide of -4, 5-dihydroxy-4, 5-dihydro-1-nitropyrene, and unidentified glutathione conjugates. The same metabolites were found in rats treated with 1-nitropyrene by gavage; however, only 10% of the dose appeared in the bile within 12 h. These studies indicate that both nitroreduction and ring oxidation are involved in the hepatic metabolism of 1-nitropyrene. The importance of these pathways in the etiology of 1-nitropyrene tumorigenesis is discussed. [ABSTRACT FROM PUBLISHER]

The microbial metabolism of the mutagenic and carcinogenic polycyclic nitroaromatic hydrocarbon, 1-nitropyrene, has been studied. Under anaerobic conditions, bacterial suspensions from rat intestinal contents converted 1-nitropyrene to one major and two minor metabolites. The rate of metabolism by rat intestinal microflora (10 bacteria/ml) was rapid with > 90% conversion occurring within 1 h. The major metabolite was identified as 1-aminopyrene through high pressure liquid chromatographic and mass spectral comparisons with an authentic standard. The suspected metabolites, N-acetyl-1-aminopyrene, 1-nitrosopyrene, N-hydroxy-1-aminopyrene, and 3-, 6-, and 8-hydroxy-1- nitropyrene were synthesized, but these derivatives were not detected in culture extracts from rat intestinal contents in cubated anaerobically with 1-nitropyrene. Nine genera of anaerobic and facultative bacteria normally associated with the intestine also converted 1-nitropyrene to 1-aminopyrene. These data indicate that a wide range of intestinal bacteria are able to reduce 1-nitropyrene. The results are discussed in rela tion to the metabolism of this polycyclic nitroaromatic hydrocarbon. [ABSTRACT FROM PUBLISHER]

Fumonisin B1 is associated with various animal and human carcinomas and toxicoses, including leukoencelphalomalacia, hepatocarcinoma, pulmonary edema and esophageal carcinoma. We have examined the cellular effects of fumonisin B1 in vitro using cellular model systems relevant to potential human target tissues. Although fumonisin B1 has been described as a mitogen in Swiss 3T3 cells based on stimulation of [3H]thymidine incorporation, in the current work it was found that fumonisin B1 inhibited incorporation of [3H]thymidine by cultured neonatal human keratinocytes and HepG2 human hepatocarcinoma cells at 10−7 and 10−4 M respectively. Fumonisin B1 also inhibited clonal expansion of normal human keratinocytes and HET-1A human esophageal epithelial cells at 10−5 M and growth in mass culture of normal human fibroblasts at 10−7 M. The clonogenicity of normal human keratinocytes decreased to 45.5% of controls afterexposure to 10−4 M fumonisin B1 for 2 days. However, no differences in the cell cycle distribution of cultured keratinocytes was noted after exposure to 10−5 M fumonisin B1 for 40 h. Theviability of normal human keratinocytes and HET-1A cells decreased as a result of fumonisin B1 treatment, as determined by a fluorescein diacetate/propidium iodide flow cytometric cell viability assay. Fumonisin B1-treated keratinocytes released nucleosomal DNA fragments into the medium 2–3 days after exposure to 10−4 M fumonisin B1 and increased DNA strand breaks were detected in attached keratinocytes exposed to 0–10−4 M fumonisin B1 using a terminal deoxy-nucleotidyl transferase-based immunochemical assay system. Furthermore, fumonisin B1-treated keratinocytes and HET-1A cells developed morphological features consistent with apoptosis, as determined by phase contrast microscopy, fluorescent microscopy of acridine orange stained cells and electron microscopy. These results are consistent with the occurrence of fumonisin B1-mediated apoptosis in vitro. [ABSTRACT FROM PUBLISHER]

Cigarette smoking has been established as a risk factor for the development of cervical cancer. Polycydlic aromatic hydrocarbons such as benzo (B[]P) which are present in cigarette smoke, might account for this increased risk. The effects of B[]P on cell growth, aryl hydrocarbon hydroxylase, DNA adducts and p53 levels was measured in cervical cells. Since 90% of cervical preneoplastic lesions are positive for the human papillomavirus (HPV) we compared the effects of these chemicals in normal ectocervical epithelial cells (ECE) and human papillomavirus 16 (HPV16) immortalized ectocervical epithelial cells (ECE16-1). Exposure of normal ECE and HPV immortalized ECE16-1 cells to B[]P inhibited cell proliferation. Inhibition occurred at 20-fold lower concentrations in the normal ECE cells compared to ECE16-1 cells. The proliferation of cervical cells which express mutated p53 was unaffected by B[]P. Neither cervical stromal cells nor endometrial stromal cells were affected by these compounds. The effects of B on normal ECE cell proliferation correlated with increased terminal differentiation as measured by increased envelope formation. In contrast, B[]P exposure did not induce envelope formation in immortalized ECE16-1 cells or in cervical tumor cells. Pretreatment of both ECE and ECE16-1 cells with 2,3,7,8-tetrachlorodibenzo--dioxin, which induces P450 expression and activity, did not alter B metabolism in either normal or immortalized cells. Furthermore, equivalent levels of DNA adducts were formed by B[]P in ECE and ECE16-1 cells. Neither the extent of adduct formation nor the rate of their removal differed in normal and Immortalized cervical cells. There fore, the diminished growth inhibition of the ECE16-1 cells as compared to normal ECE cells by B[] is not due to changes in cytochrome P450 of the 1A family metabolism or DNA adduct number. Furthermore, analysis of the p53 levels in both normal and ECE16-1 cells revealed that p53 levels are higher in normal versus immortalized ectocervical cells, and p53 is induced in both cell types following B[]P treatment. Thus reduced p53 levels in ECE16-1 cells may contribute to a lack of growth suppression following B[]P treatment. These results demonstrate that HPV16 immortalization diminishes ectocervical epithelial cell responsiveness to toxicant damage (i.e. decreased cell proliferation and increased terminal differentiation). As a result, ECE16-1 cells that sustain genotoxic damage which leads to DNA adduct formation continue to proliferate and may be at increased risk for mutations and further progression towards a fully transformed phenotype. [ABSTRACT FROM PUBLISHER]

Nitrated polycyclic aromatic hydrocarbons are environmental pollutants that have been shown to arise from a variety of sources, including diesel exhaust emissions and urban air. Most of these compounds are mutagenic in tests, and several have been shown to be carcinogenic in animals. We have investigated the kinetics of the metabolism of two of these compounds, 1-nitropyrene and 3-nitrofluoranthene, using rabbit liver aldehyde oxidase, an emyme that has been shown to catalyze the bioactivation of 1-nitropyrene. The nitroreduction of 20 μM [4,5,9,10--H]1-nitropyrene or 20 μM [4-H]3-nitrofluoranthene by aldehyde oxidase required the presence of flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD), and was inhibited by oxygen in a concentration-dependent manner. In contrast, the aldehyde oxidase oxidation of the electron donor 1-methylnicotinamide did not require FMN or FAD, indicating that the aldehyde oxidase was not isolated as an apoenzyme. The aldehyde oxidase and , for 1-nitropyrene were 4.2 μM and 16.3 pmol/min/unit enzyme, while the respective values for 3-nitrofluoranthene nitroreduction were 1.9 μM and 5.4 pmol/min/unit enzyme. The requirement for flavins in the nitroreduction of 1-nitropyrene and 3-nitrofluoranthene suggests that reduced free flavins may be required in cytosolic nitroreduction of 1-nitropyrene and 3-nitrofluoranthene. More importantly, the inhibition of nitroreduction by concentrations of oxygen that are representative of intracellular concentrations strongly suggests that the reasons for the apparent lack of 1-nitropyrene nitroreduction may be due to oxygen-mediated oxidation of a reduced metabolite of 1-nitropyrene. [ABSTRACT FROM PUBLISHER]

The metabolism of [H]1-nitropyrene by specific forms of human cytochrome P450 was investigated using virus expression of P450 cDNAs in HepG2 cells. Cell lysates were invected individually with recombinant virus containing human P450 cDNA (P450 IA2, IIA3, IIB7, IIC8, IIC9, IID6, IIE1, IIF1, IIIA3, IIIA4, IIIA5 and IVB1). Only IIIA3 and IIIA4 demonstrated significant activity in the C-oxidationof 1-nitropyrene. The principal metabolite from both P450 forms was 1-nitropyren-3-ol, produced in at least 4-fold greaterabundance than the mixture of 1-nitropyren-6-ol and 1-nitropyren-8-ol, or the K-region dihydrodlols. This is in contrast to the metabolism in many species where 6-ol and 8-ol formation predominate over 3-ol formation. In fact, in rats and rabbits, P450 forms quite distinct from the IIIA P450s catalyze the majority of the metabolism of this pollutant. This is the first demonstration of the role of individual human P450 forms in the metabolism of a representative chemical in this Important class of environmental pollutants. The importance of these observations in the overall carcinogenic risk of humans tothese chemicals remains to be established. These studies further more establish a marked species difference in the metabolism of nitrated polycycic aromatic hydrocarbons. [ABSTRACT FROM PUBLISHER]

The liver microsomal metabolism of the environmental carcinogen 3-nitrofluoranthene has been investigated. Five phenolic metabolites were isolated and characterized by their mass and NMR spectra as: 3-nitrofluoranthen-1-ol, 3-nitrofluoranthen-6-ol, 3-nitrofluoranthen-(7 or 10)-ol, 3-nitrofluoranthen-8-ol and 3-nitrofluoranthen-9-ol. While the microsomes isolated from Sprague-Dawley rat liver and C57B16 mouse liver preferentially metabolized the 3-nitrofluoranthene to 3-nitrofluoranthen-8-ol and 3-nitro-fluoranthen-9-ol, the microsomes from Hartley guinea-pig liver preferentially metabolized 3-nitrofluoranthene to 3-nitrofluoranthen-6-ol. 3-Nitrofluoranthen-1-ol was a minor metabolite in each of the incubations. The results indicate the presence of the nitro group on fluoranthene directs the metabolism away from the C1–C5 positions, and more towards the C6–C10 positions. [ABSTRACT FROM PUBLISHER]

Fumonisin B (FB1) is one of a number of mycotoxins produced by fungi, especially Fusarium sp. As a contaminant of many maizederived products, this toxin is associated with a variety of animal diseases, including esophageal cancer and possibly neural tube defects in humans. We have investigated the embryotoxic potential of this compound in New Zealand White rabbits. Animals were dosed by gavage daily on GD 3–19 with purilied FB1 at 0.10, 0.50, or 1.00 mg/kg/day. Maternal lethality occurred at the 0.50 and 1.00 mg/kg/day doses. When examined on GD 29, there were no differences in maternal body weight, maternal weight gain, maternal organ weights, number of nonlive iinplantations, and number of malformations. Fetal weight was decreased at 0.50 and 1.00 mg/kg/day (13 and 16%, respectively); this was true for male and female pups. Fetal liver and kidney weights were also decreased at these doses. Analysis of embryonic sphinganine to sphingosine ratios demonstrated no differences between control and treated embryos on GD 20, although these ratios were increased in maternal urine, serum, and kidney when compared to control animals. These data suggest that FB1 did not cross the placenta and that the observed decreased fetal weight was probably the result of maternal toxicity, rather than any developmental toxicity produced by FB1. [ABSTRACT FROM PUBLISHER]

The potent mutagens, 1-nitropyrene and 6-nitrobenzo[a]-pyrene, are shown to induce the transformation of cultured normal human diploid fibroblasts to a state of anchorage- independent growth and cellular invasiveness. The transformation frequencies are greatly enhanced by addition of bovine milk xanthine oxidase, a mammalian nitroreductase. [ABSTRACT FROM PUBLISHER]

Presents an abstract on the report `Functional Reach in Wheelchair Users: The Effects of Trunk and Lower Extremity Stabilization,' by K.A. Curtis, C.M. Kindin, D.E. White.

Studies the effects of eight-week upperbody concentric resistance training program on wheelchair performance in children with cerebral palsy, spina or bifida. Number of children studied; Conclusions.