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Biomedical subjects

K L Mossman

Publications and source records attributed to K L Mossman.

At least 19 recordsLinked to original sources
PubMed2001

Deconstructing radiation hormesis.

This paper explores some factors that may explain why the possibility of hormesis has not been embraced by the radiation protection community. If shown to be sustainable, hormesis might ameliorate several serious issues plaguing radiation protection including the high economic cost of environmental regulatory compliance and public fear of radiation exposure. Some but not all analyses of data from various sources, including the Japanese survivors of the atomic bombs and residential radon studies, suggest that low levels of ionizing radiation may be beneficial to human health. The evidence, however, has not been viewed as compelling for the following reasons: (1) Data in support of radiation hormesis in human populations is limited and much of it is based on re-evaluation of selected epidemiological data that has been used to test a different hypothesis; (2) Hormetic effects are weak and inconsistent, and are subject to large statistical uncertainties as is the case for carcinogenic effects at small doses; (3) A consensus is lacking on how hormesis should be defined and quantified; and (4) It is unclear how hormesis can be incorporated into the regulatory framework when beneficial health effects exceed the requirement for protection of health.

Adaptation, Physiological↗
PubMed2001

Herpes simplex virus triggers and then disarms a host antiviral response.

Virus infection induces an antiviral response that is predominantly associated with the synthesis and secretion of soluble interferon. Here, we report that herpes simplex virus type 1 virions induce an interferon-independent antiviral state in human embryonic lung cells that prevents plaquing of a variety of viruses. Microarray analysis of 19,000 human expressed sequence tags revealed induction of a limited set of host genes, the majority of which are also induced by interferon. Genes implicated in controlling the intracellular spread of virus and eliminating virally infected cells were among those induced. Induction of the cellular response occurred in the absence of de novo cellular protein synthesis and required viral penetration. In addition, this response was only seen when viral gene expression was inhibited, suggesting that a newly synthesized viral protein(s) may function as an inhibitor of this response.

Animals↗
PubMed2000

Evidence that herpes simplex virus VP16 is required for viral egress downstream of the initial envelopment event.

During infection with herpes simplex virus type 1 (HSV-1), VP16 serves multiple functions, including transcriptional activation of viral immediate early genes and downregulation of the virion host shutoff protein vhs. Furthermore, VP16 has been shown to be involved in some aspect of virus assembly and/or maturation. Experiments with a VP16 null virus, 8MA, suggested that VP16 plays a direct role in virion assembly, since removal of VP16 from the HSV-1 genome results in reduced levels of encapsidated DNA and a failure to produce extracellular enveloped particles. However, VP16 null mutants display a severe translational arrest due to unrestrained vhs activity, thus complicating interpretation of these data. We examine here the role of VP16 in virion assembly and egress in the context of a vhs null background, using the virus 8MA/DeltaSma (VP16(-) vhs(-)). Comparison of 8MA and 8MA/DeltaSma with respect to viral DNA accumulation and encapsidation and accumulation of the major capsid protein, VP5, revealed that the 8MA lethal phenotype is only partially due to uncontrolled vhs activity, indicating that VP16 is required in HSV-1 virion formation. Electron microscopy confirmed these results and further showed that VP16 is required for HSV-1 egress beyond the perinuclear space. In addition, we describe the isolation and characterization of an 8MA derivative capable of propagation on Vero cells, due to second site mutations in the vhs and UL53 (gK) genes. Taken together, these results show that VP16 is required for viral egress downstream of the initial envelopment step and further underscore the importance of VP16 in controlling vhs activity within an infected cell.

Animals↗
PubMed2000

Herpes simplex virus ICP0 mutants are hypersensitive to interferon.

Interferon (IFN) is an important immune system molecule capable of inducing an antiviral state within cells. Herpes simplex virus type 1 (HSV-1) replication is somewhat reduced in tissue culture in the presence of IFN, presumably due to decreased viral transcription. Here, we show mutations that inactivate immediate-early (IE) gene product ICP0 render HSV-1 exquisitely sensitive to IFN inhibition, resulting in greatly decreased levels of viral mRNA transcripts and the resulting polypeptides and a severe reduction in plaque formation ability. Mutations in other HSV-1 genes, including the genes coding for virion transactivator VP16 and the virion host shutoff protein vhs, IE gene ICP22, and the protein kinase UL13 gene, do not increase the IFN sensitivity of HSV-1. Interestingly, ICP0 mutants demonstrate the same level of sensitivity to IFN as wild-type virus on U2OS cells, an osteosarcoma cell line that is known to complement mutations in ICP0 and VP16. Thus, in some cell types, functional ICP0 is required for HSV-1 to efficiently bypass the inhibitory effects of IFN in order to ensure its replication. The significance of this link between ICP0 and IFN resistance is discussed.

Animals↗
PubMed1999

Truncation of the C-terminal acidic transcriptional activation domain of herpes simplex virus VP16 renders expression of the immediate-early genes almost entirely dependent on ICP0.

The herpes simplex virus (HSV) proteins VP16 and ICP0 play key roles in stimulating the onset of the viral lytic cycle. We sought to explore the regulatory links between these proteins by studying the phenotypes of viral mutants in which the activation functions of both were simultaneously inactivated. This analysis unexpectedly revealed that truncation of the C-terminal transcriptional activation domain of VP16 (allele V422) in an ICP0-deficient background almost completely eliminated immediate-early gene expression and virus replication in Vero and HEL cells. The doubly mutant viral genome persisted in a quiescent state for at least 10 days in HEL cells infected at high multiplicity and could be reactivated by superinfection with wild-type HSV. In contrast, the in1814 VP16 mutation produced a markedly less severe phenotype in the same ICP0-deficient background. These data demonstrate that expression of the immediate-early genes requires ICP0 when the C-terminal activation domain of VP16 is deleted and raise the possibility that the in1814 form of VP16 retains a residual ability to stimulate gene expression during virus infection.

Animals↗
PubMed1998

The linear no-threshold debate: where do we go from here?

For the past several years, the LNT (linear no-threshold) theory has come under attack within the scientific community. Analysis of a number of epidemiological studies of the Japanese survivors of the atomic bombings and workers exposed to low level radiation suggest that the LNT philosophy is overly conservative, and low-level radiation may be less dangerous than commonly believed. Proponents of current standards argue that risk conservatism is justified because low level risks remain uncertain and it is prudent public health policy; LNT opponents maintain that regulatory compliance costs are excessive, and there is now substantial scientific information arguing against the LNT model. Regulators use the LNT theory in the standards setting process to predict numbers of cancers due to exposure to low level radiation because direct observations of radiation-induced cancers in populations exposed to low level radiation are difficult. The LNT model is simplistic and provides a conservative estimate of risk. Abandoning the LNT philosophy and relaxing regulations would have enormous economic implications. However, alternative models to predict risk at low dose are as difficult to justify as the LNT model. Perhaps exposure limits should be based on model-independent approaches. There is no requirement that exposure limits be based on any predictive model. It is prudent to base exposure limits on what is known directly about health effects of radiation exposure of human populations.

Data Interpretation, Statistical↗
PubMed1997

Radiation protection of radiosensitive populations.

Radiosensitive populations (defined as subpopulations with increased radiogenic risk for cancer) may include individuals with known genetic predispositions for cancer (e.g., breast cancer), and persons with certain diseases, such as ataxia telangiectasia, which are characterized by enhanced radiation sensitivity and increased risk for cancer. Although approximately 10% of the population may be radiosensitive, current radiological protection limits, based on the "average" individual, should be retained. Radiation is a weak environmental carcinogen. Diet and cigarette smoking each account for 15-18 times more cancer deaths. Radiosensitivity is a much less important host factor than age and genetic predisposition. Workers should be allowed to "declare" a predisposition for cancer. Workers who have declared radiosensitivities should be provided with additional information regarding job-related risks and strategies to reduce dose. "Declared" employees should not be subjected to different terms and conditions of employment.

Ataxia Telangiectasia↗
PubMed1991

Regulatory control of indoor Rn.

Regulation of indoor Rn is explored in the context of cost-effectiveness of regulatory action. Evaluation of cost (i.e., mitigation expenses) and benefits (i.e., savings associated with medical expenses and lost productivity related to lung cancer) at various action levels indicate that regulatory programs would be economically inefficient and unreasonable if standards were established at or below the current EPA action guide (150 Bq m-3 or less). For the approximately 95% of U.S. homes with Rn levels near or below 150 Bq m-3, government programs should continue to focus on public information and consumer protection. For the small number of homes with high Rn levels, government programs should focus on identifying high risk homes and encouraging homeowners to reduce Rn levels. Because of the potential for substantial risk reduction, such efforts would be cost-effective in these homes.

Air Pollution, Radioactive↗
PubMed1990

Nuclear literacy.

Explore the source record for details and available documents.

Communication Barriers↗
PubMed1989

Carcinogenic effects of scattered dose associated with radiation therapy.

Ionizing radiation has long been recognized as a weak carcinogen, and the risk of developing a radiation induced neoplasm after exposure to therapeutic radiation has been established. In the case of therapeutic radiation for treatment of existing malignancies, concomitant risk factors for second malignancies can confound the effect of radiation alone. This study presents a model for evaluating the isolated contribution of ionizing radiation to the induction of second malignancies in cancer patients, and presents estimates of the expected number of second malignancies induced in selected sensitive sites by scatter radiation during radiotherapy for cancer. The study focused on the year 1987, during which it was estimated that 192,761 new cancer patients received radiotherapy as part of their initial treatment plan. The model predicted that radiation may induce 63-84 secondary breast cancers, 64-72 secondary thyroid cancers, 94-157 secondary lung cancers, and 489-707 secondary leukemias over the remaining lifetime of this patient population. This represents a lifetime incidence of 0.7% for leukemia, and 0.3% for the solid tumors. This incidence must be placed in perspective with the current concepts of cancer management, such as combined modality therapy that may carry a risk of carcinogenesis greater than either modality alone, and when the alternatives to radiotherapy may be nonexistent or may be cosmetically or functionally undesirable. The information presented may be used in weighing the risks and benefits of alternative treatments for cancer.

Female↗
PubMed1988

Education and training in health physics--a look to the future.

The next 15 to 20 y promise to be a challenging period in health physics education. The U.S. Department of Energy, in a review of current and projected labor market conditions for professional health physicists and health physics technicians, reports current shortages of professional health physicists in the civilian nuclear industry and predicts a high potential for shortages during the next 15 y. The academic health physics community is also faced with the following issues that compound the difficulty in meeting the high employment demands for qualified health physicists in the near future. (1). A decreasing number of programs--In the past few years, several programs have folded or have undergone reorganization, thus reducing the availability of quality programs to train health physicists and health physics technicians. (2). Decreasing federal funding--Government funding of health physics programs is limited, necessitating programs to obtain support from the private sector or from within the colleges and universities themselves. (3). Accreditation of programs--Should programs be accredited to standardize quality and program content? (4). Recruiting quality students--What can programs do to attract high-quality students into the health physics profession? In this paper, each of these issues is examined and possible solutions proposed. Our discussion is primarily meant to be provocative--in this way we hope to stimulate much-needed discourse as a first step in addressing and solving these problems which face the academic health physics community.

Education↗
PubMed1988

Radiation-induced reduction of the glial population during development disrupts the formation of olfactory glomeruli in an insect.

Interactions between neurons and between neurons and glial cells have been shown by a number of investigators to be critical for normal development of the nervous system. In the olfactory system of Manduca sexta, sensory axons have been shown to induce the formation of synaptic glomeruli in the antennal lobe of the brain (Hildebrand et al., 1979). Oland and Tolbert (1987) found that the growth of sensory axons into the developing antennal lobe causes changes in glial shape and disposition that presage the establishment of glomeruli, each surrounded by a glial envelope. Several lines of evidence lead us to hypothesize that the glial cells of the lobe may be acting as intermediaries in developmental interactions between sensory axons and neurons of the antennal lobe. In the present study, we have tested this hypothesis by using gamma-radiation to reduce the number of glial cells at a time when neurons of the antennal system are postmitotic but glomeruli have not yet developed. When glial numbers are severely reduced, the neuropil of the resulting lobe lacks glomeruli. Despite the presence of afferent axons, the irradiated lobe has many of the features of a lobe that developed in the absence of afferent axons. Our findings indicate that the glial cells must play a necessary role in the inductive influence of the afferent axons.

Animals↗