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PubMed1989

Design and conduct of occupational epidemiology studies: IV. The analysis of case-control data.

This paper reviews the basic methods of analysis of data from case-control studies. The standard analytic methods are outlined first for a single stratum. The discussion is then extended to stratified analysis, multiple exposure levels, and analyses allowing for disease induction and latency periods. Finally, logistic regression is discussed as an extension of the more basic forms of analysis. The methods are illustrated with data from a study of lung cancer among asbestos textile plant workers.

Biometry↗
PubMed2005

The influence of 4-hydroxy-2-nonenal on proliferation, differentiation and apoptosis of human osteosarcoma cells.

The product of lipid peroxidation, 4-hydroxy-2-nonenal (HNE) is known to cause cell death at high concentrations, while at lower concentrations it can influence cell proliferation and differentiation. In our experiments we used human osteosarcoma cells (HOS), to test the influence of HNE on cell proliferation, differentiation and induction of apoptosis. Apoptosis induction was estimated by TiterTACS TUNEL test. The cells were in parallel counted and the DAPI staining method was used to distinguish between apoptotic and necrotic cells as well as to define the proportion of cells in mitosis. To test the influence of HNE on HOS cell differentiation, cells were treated every second day with HNE. After 10 days, the cells were stained for alkaline phosphatase, a marker for osteoblast differentiation. Cell growth inhibition was caused by supraphysiological concentrations of 10 or 100 microM HNE, while apoptosis was induced with supraphysiological as well as by the physiological amount of the aldehyde (1 microM). Necrosis appeared when cells were treated with 10 or 100 microM, but not with 1 microM HNE. The proportion of cells in mitosis gradually declined with increased HNE concentration. Multiple exposures of HOS cells to 10 microM HNE prevented HOS cell differentiation. These results indicated that HNE inhibits proliferation and differentiation of HOS cells in the same concentration dependent manner as it causes apoptosis. We thus assume that HNE might be one of the important signaling molecules regulating the growth of the human osteosarcoma cells.

Aldehydes↗
PubMed1980

Enhancement of carcinogenesis in cultured respiratory tract epithelium by 12-0-tetradecanoylphorbol-13-acetate.

The enhancement of chemical carcinogenesis was demonstrated in vitro in rat tracheal epithelium exposed in organ culture to N-methyl-N'-nitro- N-nitrosoguanidine (MNNG) followed by multiple exposures to 12-O-tetradecanoyl-phorbol-13-acetate (TPA). The explants were exposed to 0 or 0.0001 mu g MNNG per ml for 6 h on days 3 and 6 of culture, and then to 0 or 1.0 mu g TPA per ml for I h on days 9, 15, 21, and 27 of culture. Primary cell cultures were then established from epithelial outgrowths of these explants. Morphologically altered cells were seen in the primary cell cultures derived from MNNG + TPA-exposed explants on an average of 130 days after MNNG exposure. In primary cultures derived from explants exposed to either TPA or MNNG alone, morphologically altered cells were seen at 190 days and 210 days, respectively. No morphologically altered cells were seen in solvent control primary cell cultures. Only cultures containing morphologically altered cells could be repeatedly subcultured. Cell lines established from these cultures were inoculated i.m. into immunosuppressed isogeneic hosts at 150, 200, 250, 310, and 365 days following carcinogen exposure. All five explants exposed to both MNNG and TPA produced at least one cell line which formed carcinomas when inoculated 365 days following exposure, while only two of the five explants produced tumorigenic cell lines in the MNNG-only group. Cell lines from explants exposed to both MNNG and TPA were tumorigenic an average of 90 days earlier than cell lines from explants exposed to MNNG alone. None of the cell lines obtained from the explants exposed only to TPA were tumorigenic. These studies show that, following carcinogen exposure, TPA can enhance the oncogenesis of cultured respiratory tract epithelium in terms of increasing the frequency of transformation and decreasing the time at which transformation could first be observed.

Animals↗
PubMed1993

Increased accumulation of p53 protein in cisplatin-resistant ovarian cell lines.

We have examined p53 protein levels in cell lines selected for resistance to the chemotherapeutic drug cis-diamminedichloroplatinum (II), cisplatin. The majority of the independent cisplatin-resistant clones isolated by a single selection with cisplatin from the ovarian tumour cell line A2780 showed increased levels of p53 protein compared to the parental cell line. Elevated p53 protein levels were also observed in cisplatin-resistant ovarian human tumour lines isolated after multiple exposures to cisplatin (A2780/cp70 and OVIP/DDP). Direct PCR sequencing of p53 cDNAs showed that both the A2780/cp70 and the parental A2780 cell lines had a wild-type p53 gene sequence. The OVIP and OVIP/DDP lines both had a heterozygous mutation at codon 126. Cell-cycle analysis after gamma-irradiation or cisplatin treatment showed evidence of a G1/S and G2/M cell-cycle checkpoint in both A2780/cp70 and the sensitive parental cell lines. However, the resistant cell line A2780/cp70 showed less inhibition of DNA synthesis after gamma-irradiation than the sensitive cell line. Transfection of a mutant p53 gene construct (containing a mutation at codon 143, val to ala) into the A2780/cp70 resistant cells conferred a significantly increased sensitivity to cisplatin, suggesting that p53 is a direct determinant of cisplatin resistance in these cells. However, expression of this mutant p53 in the A2780 cells did not affect sensitivity.

Cell Cycle↗
PubMed1982

Stroboscopic illumination for the assessment of hyperactivated motility of mouse spermatozoa.

Spermatozoa showing hyperactivated motility can be recognized in multiple-exposure micrographs. The cells were confined in 10-micrometer-deep chambers, illuminated in darkfield conditions, and photographed using a stroboscope (10 Hz). Hyperactivation, as judged from the pattern of ten superimposed images, could be promoted by raising the ionic strength of the medium but did not occur in the absence of calcium.

Animals↗
PubMed1993

Cytomegalovirus recurrence in seropositive pregnant women attending obstetric clinics.

To understand reasons for cytomegalovirus (CMV) recurrence, a cohort of 350 CMV-seropositive pregnant women attending obstetric clinics in Taiwan was examined for cervical or urinary CMV shedding. Urine specimens were collected from 350 women and cervical secretion specimens were collected from 220 women. We measured the association of various factors with CMV recurrence, which was defined as viral shedding identified by the presence of a CMV-specific gene sequence amplified by the polymerase chain reaction in seropositive individuals. CMV recurrence status was independently associated with a sexual activity composite variable, which was defined by three sexual activity indicators: age at first sexual intercourse, total years of sexual experience, and average frequency of sexual intercourse prior to pregnancy. Pregnant women with a history of genital tract infection were more likely than women without such history to experience cervical CMV recurrence. Similarly, pregnant women with previous urinary tract infections were more likely to experience urinary CMV recurrence. The findings indicate that multiple exposure to CMV by sexual activity prior to pregnancy is an important determinant of CMV recurrence during pregnancy.

Antibodies, Viral↗
PubMed2004

High prevalence of mixed genotype infections in hepatitis B virus infected intravenous drug users.

The clinical relevance of hepatitis B virus (HBV) genotypes has been documented; however, the prevalence of mixed HBV genotype infections in at-risk groups remains controversial. The HBV genotypes were determined in 325 HBV-infected intravenous drug users (IVDU) who were at a greater risk of multiple exposures to different HBV genotypes by using a newly developed line probe assay. The distribution of HBV genotype was as follows: genotype A alone in 2 (0.6%); genotype B alone in 256 (78.8%); genotype C alone in 10 (3.1%); mixed genotype A and B in 18 (5.5%); genotype B and C in 30 (9.2%); genotype B and D in 1 (0.3%); genotype A and C in 1 (0.3%); and mixed infections of genotype A, B, and C in 3 (0.9%). Clonal analysis confirmed further the existence of mixed genotype infection and recombination between different genotypes. Compared with our previous data, the line probe assay seemed more sensitive than polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay in identifying HBV genotype (98.8% vs. 65.0%) and detecting mixed genotype infections (16.3% vs. 0%). In conclusion, the prevalence of mixed HBV infections is substantially higher in IVDU in endemic areas, and the line probe assay is a useful method for rapid genotyping of HBV, with particular reference to the detection of mixed genotype infections.

Adult↗
PubMed1976

Screening random asymptomatic women under 50 by annual mammographies: does it make sense?

The effectiveness of screening random asymptomatic women for breast cancer using mammography has been analyzed using a new mathematical-computer technology. The technology is based on a general mathematical theory of screening recently developed by Blumenson combined with a mathematical model for breast cancer developed by Blumenson and Bross over the past decade. The technology makes it relatively simple to try alternative strategies for age at onset of screening, screening interval, etc. and to calculate the relative effectiveness of the strategy. When the benefits of alternative strategies with periodic screening beginning at different ages were compared with the increasing risk of iatrogenic disease from multiple exposure to low levels of radiation, it was concluded that screening of asymptomatic women should begin no earlier than age 50.

Age Factors↗
PubMed1992

Ischemia/reperfusion: a new hypothesis for the developmental toxicity of cocaine.

It has been shown that multiple exposures of gravid rats to cocaine during late gestation result in significant incidences of severe malformations. Hind limb reduction defects were frequent findings in this study. Other studies have shown that comparable abnormalities can be induced in experimental animals by various procedures including vascular clamping, direct fetal exposure to epinephrine, uterine handling following laparotomy, as well as by exposure to hyperbaric oxygen. This paper reviews these and other studies, and presents a novel mechanistic hypothesis that explains their common findings. It is proposed that in each instance, conceptual hypoxia results from hypoperfusion caused by transient vasoconstriction. Following the resumption of normal perfusion, reactive oxygen species are generated by the ischemia/reperfusion mechanisms thought to underlie many pathobiologic lesions. It is proposed that the conceptus is particularly vulnerable to the toxicity of oxygen radicals because of its low antioxidant activities and the highly reduced state of its undifferentiated cells. Sensitivity to cocaine and uterine handling appears to be enhanced during late gestation and it is hypothesized that this results from changes in oxygenation and iron content that increase both the substrate and catalyst for generation of reactive oxygen species.

Animals↗
PubMed1996

Evaluation of the hazard quotient method for risk assessment of selenium.

Environmental contamination with selenium from industrial and agricultural sources has poisoned fish and wildlife at several locations in the United States. Monitoring and risk assessment activities are currently being conducted by many state and Federal agencies. The U.S. Environmental Protection Agency (EPA) recommends a hazard quotient (HQ) method (waterborne concentration divided by the national water quality criterion) to assess the toxic threat of individual waterborne elements, including selenium. An evaluation of the EPA HQ method was conducted by comparing it to a recently published protocol (Protocol) for selenium assessment. Hazard estimates obtained using HQ were found to be invalid because the EPA water quality criterion is outdated, and the procedure uses mean rather than maximum waterborne concentrations. The HQ method seriously underestimates hazard and could lead to risk management decisions that would not protect fish and wildlife from selenium toxicity. The Protocol method provides an accurate assessment because it evaluates hazard by examining multiple exposure pathways on a site-specific basis. Until a revised (lowered) national water quality criterion is available, the EPA HQ method should not be used for selenium. Even then, with the availability of the Protocol, HQ analysis should be restricted to data sets where water is the primary or sole source of information on environmental concentrations of selenium.

Environmental Monitoring↗
PubMedDate not supplied

The effects of radiation damage on the structure of frozen hydrated HSV-1 capsids.

Radiation damage imposes stringent limits on the information content of electron micrographs of biological specimens. In this study, we have investigated its effects on frozen, hydrated specimens and three-dimensional reconstructions calculated from cryomicrographs using capsids of herpes simplex virus as a model system. Multiple-exposure series of micrographs of both B-capsids (which contain no DNA) and C-capsids (which are fully packaged) were recorded and reconstructions were calculated from the first exposures, corresponding to a cumulative electron dose of 6-7 e-/A2, and from later exposures (25-40 e-/A2). Experimental procedures were standardized to ensure that perceived changes in the micrographs and reconstructions would be attributable to radiation damage alone. The effects of the higher doses in both the micrographs and the reconstructions were expressed as a progressive blurring of the finer details, corresponding to a delocalization of structure in the ice-embedded specimens. The resolutions of the reconstructions were quantified according to a form of the Fourier ring correlation coefficient criterion, according to which the first-exposure reconstructions had resolutions of 30-36 A. The fifth-exposure B-capsid reconstruction had comparable nominal resolution, although it exhibited progressively lower correlations at higher spatial frequencies. Qualitatively similar changes in the series of C-capsid reconstructions were observed although they were more pronounced, presumably because these micrographs had lower contrast and signal-to-noise ratios. We infer that the observed changes in the images and reconstructions and the concomitant loss in contrast in the immediate vicinity of the capsid surface may reflect radiation-induced perturbation of molecular structure and/or the release of peptide fragments. Nevertheless, the observed changes are relatively subtle, at least at the operational resolution of this study; overall, our results support earlier indications (M. F. Schmid et al. J. Struct. Biol. 108, 62-68, 1992) that prospects are quite good for tilt-series reconstructions from cryoelectron micrographs, including six to eight views of the same specimen.

Capsid↗
PubMed2001

The development and evaluation of a new aerosol irritant assay with minimal animal stress.

Current aerosol irritant assays trap animals in noxious atmospheres and put a lot of stress on them. For this reason, the Minimal Animal Stress Irritant Assay Chamber (MASIAC) was developed based on the principle of avoidance, and evaluated. The MASIAC reproducibly detected citric acid with more sensitivity than conventionally used assays. With a group of mice tested simultaneously, the responses were not significantly affected by the presence of other mice. In addition, following multiple exposures to citric acid, the mice either sensitized to the irritant, or learned to avoid it. This suggests a number of areas where the MASIAC could be applied, including behavioral and asthma research. If this new method turns out to be as good as currently used assays, it could provide investigators with an alternative, more humane method of evaluating pulmonary irritants.

Aerosols↗
PubMed2002

The use of noncancer endpoints as a basis for establishing a reference concentration for formaldehyde.

Published studies involving formaldehyde were selected for quality and relevance for determining whether noncancer endpoints could be used to derive a reference concentration for formaldehyde. Chamber studies provided the highest quality data for determining the presence of eye, nose, or throat irritation at a known level of formaldehyde. Some individuals begin to sense irritation at about 0.5 ppm, 5-20% report eye irritation at 0.5 to 1 ppm, and greater certainty for sensory irritation appears at 1 ppm or greater. These levels of formaldehyde do not appear to impact asthmatics even though these individuals are thought to be more sensitive to irritants. Mild, reversible changes in pulmonary function (forced expiratory volume at 1 s and midexpiratory flow) can occur in sensitized individuals at levels approaching 2 ppm. Studies in the manufacturing setting, while confounded by multiple exposures, provide useful information for setting boundaries for sensory irritation or changes in pulmonary function. Community surveys do not provide the specificity nor sensitivity needed to establish a reference concentration. Histological studies of the nasal mucosa suffer significant methodological and technological shortcomings in addition to issues commonly associated with the design of residential and workplace studies. Based on the review of chamber, community, and workplace studies of human exposures to formaldehyde, it is not possible to identify a specific no observed adverse effect level or lowest observed adverse effect level for formaldehyde. Ranges of exposures associated with acute sensory irritation can be derived and do include sensitive subpopulations. However, given the quality and variability of the data, human studies alone, especially those involving sensory irritation, are not adequate to serve as a reference concentration for estimating risk, or lack thereof, for a lifetime of exposure to formaldehyde. Alternative approaches, such as modeling cellular changes observed in animal studies, may be more useful for quantitative risk assessment of noncancer endpoints and should be used as an adjunct to interpreting human sensory studies.

Air Pollutants, Occupational↗
PubMed1997

Pharmacokinetic and toxicity studies of AZT (zidovudine) following perfusion of human term placenta for 14 hours.

Multiple exposures to AZT (Zidovudine) for 14 hr were examined in the dually perfused human term placental lobule in order to determine the pharmacokinetics of transfer, as well as several viability parameters of toxicity. In each experiment, three separate additions of AZT at a concentration of 3.8 mM was added to the maternal reservoir, and perfusate samples were obtained from both the maternal and the fetal compartments for determinations of AZT, glucose, lactate, oxygen, and human chorionic gonadotropin (hCG) concentrations. During 14 hr of continuous exposure to this high concentration of AZT, the production of hCG was significantly reduced by 75% when compared to the 2-hr control period before the administration of AZT. In addition, lactate production was reduced by 45% after AZT administration. Such changes in hCG and lactate production were not observed in separate experiments conducted over the same time interval, but with no AZT added. Based upon a lack of total perfusion fluid loss, changes in fetal arterial pressure, and histopathology, placental lobule integrity was maintained throughout the perfusion period. Further, AZT readily crossed the placenta into the fetal compartment reaching equilibrium with maternal levels within 60-90 min after addition of each administration of AZT. Based upon AZT levels in the fetal perfusate, AZT does not accumulate against a concentration gradient and therefore appears to be diffusion limited. Placental tissues obtained from perfused, partially perfused, and nonperfused regions at the conclusion of the experiment were analyzed for AZT levels. Substantial AZT levels in the nonperfused tissues indicated that AZT is a freely diffusible compound. The results of the current study demonstrate that high concentrations of AZT alter placental function resulting in reduced production of hCG and lactate.

Anti-HIV Agents↗
PubMed2001

Pharmacokinetics, metabolism, and carcinogenicity of arsenic.

The carcinogenicity of arsenic in humans has been unambiguously demonstrated in a variety of epidemiological studies encompassing geographically diverse study populations and multiple exposure scenarios. Despite the abundance of human data, our knowledge of the mechanism(s) responsible for the carcinogenic effects of arsenic remains incomplete. A deeper understanding of these mechanisms is highly dependent on the development of appropriate experimental models, both in vitro and in vivo, for future mechanistic investigations. Suitable in vitro models would facilitate further investigation of the critical chemical species (arsenate/arsenite/MMA/DMA) involved in the carcinogenic process, as well as the evaluation of the generation and role of ROS. Mechanisms underlying the clastogenic effects of arsenic, its role in modulating DNA methylation, and the phenomenon of inducible tolerance could all be more completely investigated using in vitro models. The mechanisms involved in arsenic's inhibition of ubiquitin-mediated proteolysis demand further attention, particularly with respect to its effects on cell proliferation and DNA repair. Exploration of the mechanisms responsible for the protective or anticarcinogenic effects of arsenic could also enhance our understanding of the cellular and molecular interactions that influence its carcinogenicity. In addition, appropriate in vivo models must be developed that consider the action of arsenic as a promoter and/or progressor. In vivo models that allow further investigation of the comutagenic effects of arsenic are also especially necessary. Such models may employ initiation-promotion-progression bioassays or transgenic animals. Both in vitro and in vivo models have the potential to greatly enhance our current understanding of the cellular and molecular interactions of arsenic and its metabolites in target tissues. However, refinement of our knowledge of the mechanistic aspects of arsenic carcinogenicity is not alone sufficient; an understanding of the pharmacokinetics and target tissue doses of the critical chemical species is essential. Additionally, a more thorough characterization of species differences in the tissue kinetics of arsenic and its methylated metabolites would facilitate the development of more accurate and relevant PBPK models. Improved models could be used to further investigate the existence of a methylation threshold for arsenic and its relevance to arsenic carcinogenicity in humans. The significance of alterations in relative tissue concentrations of SAM and SAH deserves further attention, particularly with respect to their role in modulating methyltransferases involved in arsenic metabolism and DNA methylation. The importance of genetic polymorphisms and nutrition in influencing methyltransferase activities must not be overlooked. In vivo models are necessary to evaluate these factors; transgenic or knockout models would be particularly useful in the investigation of methylation polymorphisms. Further evaluation of methylation polymorphisms in human populations is also warranted. Other in vivo models incorporating dietary manipulation could provide valuable insight into the role of nutrition in the carcinogenicity of arsenic. With more complete knowledge of the pharmacokinetics of arsenic metabolism and the mechanisms associated with its carcinogenic effects, development of more reliable risk assessment strategies are possible. Integration of data, both pharmacokinetic and mechanistic in nature, will lead to more accurate descriptions of the interactions that occur between the active chemical species and cellular constituents which lead to the development of cancer. This knowledge, in turn, will facilitate the development of more accurate and reliable risk assessment strategies for arsenic.

Animals↗
PubMed1985

Immunological aspects of type 1 and 2 diabetes mellitus.

IDDM occurs predominantly among individuals being class II antigen HLA-DR 3 and/or 4 positive, while NIDDM is not associated with HLA-D. Although the HLA-DR 3 or 4 specificities are prerequisites for IDDM to develop, their high frequencies (about 60%) in the background population preclude tissue typing as a predictive test, underlined by the observation that less than 50% of monozygotic twins are concordant for IDDM. The presence of a number of immune abnormalities argues that the causes of IDDM may be sought in an altered immune reaction against antigens present in the pancreatic B cells and/or in the environment. The majority of IDDM patients of short duration show both cellular and humoral autoimmunity against the pancreatic B cells. Similar phenomena may be observed in patients initially diagnosed as NIDDM and treated with oral hypoglycemic agents. It has been speculated that these patients have a retarded form of IDDM. It is possible that the combination of specific Class II antigen molecule(s) and an invading antigen (virus, bacterium, chemical etc.) presented to the immune system triggers the formation of effector cells such as B lymphocytes and cytotoxic T lymphocytes which also cross-react with the pancreatic B cells. Multiple exposures to this or related antigens throughout several years may eventually lead a sufficient loss of pancreatic B cells to cause insulin dependence.

Antibody Formation↗
PubMed1978

Halothane hepatitis.

Halothane (2-bromo-2-chloro-1:1:1-trifluoroethane) is a volatile, nonflammable anaesthetic agent which has been widely used for the last 20 years. Halothane hepatitis has been a matter of continuing controversy, but now it seems to be generally accepted as a clinical entity. Characteristically the halothane hepatitis occurs after multiple exposures to halothane within short time. The pathogenesis of the liver cell damage is obscure. It is estimated that the incidence of halothane hepatitis is about one per 8000 halothane anaesthesias and the lethality about one per 40000. Prophylaxis consists of avoiding repeated halothane anaesthesias within short time and to avoid re-exposure to halothane if otherwise unexplained liver damage has occurred after halothane.

Chemical and Drug Induced Liver Injury↗
PubMed1983

Anaphylactoid reactions associated with bisantrene infusions.

Nine of ninety-three patients receiving Bisantrene on an every three week schedule developed an anaphylactoid reaction with a variety of symptoms. Most reactions occurred in patients who had multiple exposures to Bisantrene. Investigators utilizing Bisantrene in ongoing clinical trials should be aware of this life threatening toxicity.

Anaphylaxis↗