Following a mass-casualty nuclear disaster, effective medical triage has the potential to save tens of thousands of lives. In order to best use the available scarce resources, there is an urgent need for biodosimetry tools to determine an individual’s radiation dose. Initial triage for radiation exposure will include location during the incident, symptoms, and physical examination. Stepwise triage will include point of care assessment of less than or greater than 2 Gy, followed by secondary assessment, possibly with high throughput screening, to further define an individual’s dose. Given the multisystem nature of radiation injury, it is unlikely that any single biodosimetry assay can be used as a stand-alone tool to meet the surge in capacity with the timeliness and accuracy needed. As part of the national preparedness and planning for a nuclear or radiological incident, we reviewed the primary literature to determine the capabilities and limitations of a number of biodosimetry assays currently available or under development for use in the initial and secondary triage of patients. Understanding the requirements from a response standpoint and the capability and logistics for the various assays will help inform future biodosimetry technology development and acquisition. Factors considered include: type of sample required, dose detection limit, time interval when the assay is feasible biologically, time for sample preparation and analysis, ease of use, logistical requirements, potential throughput, point-of-care capability, and the ability to support patient diagnosis and treatment within a therapeutically relevant time point.
This study underscores the incidence of classic features of resistance to thyroid hormone, describes new clinical characteristics of this condition for the first time, and stresses the heterogeneity of the phenotype.
After initially identifying potential biomarkers of radiation exposure through microarray studies of ex vivo irradiated human peripheral white blood cells, we have now measured the in vivo responses of several of these biomarker genes in patients undergoing total body irradiation. Microarray analysis has identified additional in vivo radiation-responsive genes, although the general in vivo patterns of stress-gene induction appear similar to those obtained from ex vivo white blood cell experiments. Additional studies may reveal correlations between responses and either diagnosis or prognosis, and such in vivo validation marks an important step in the development of potentially informative radiation exposure biomarkers.
A large-scale radiological incident would result in an immediate critical need to assess the radiation doses received by thousands of individuals to allow for prompt triage and appropriate medical treatment. Measuring absorbed doses of ionizing radiation will require a system architecture or a system of platforms that contains diverse, integrated diagnostic and dosimetric tools that are accurate and precise. For large-scale incidents, rapidity and ease of screening are essential. The National Institute of Allergy and Infectious Diseases of the National Institutes of Health is the focal point within the Department of Health and Human Services (HHS) for basic research and development of medical countermeasures for radiation injuries. The Biomedical Advanced Research and Development Authority within the HHS Office of the Assistant Secretary for Preparedness and Response coordinates and administers programs for the advanced development and acquisition of emergency medical countermeasures for the Strategic National Stockpile. Using a combination of funding mechanisms, including funds authorized by the Project BioShield Act of 2004 and those authorized by the Pandemic and All-Hazards Preparedness Act of 2006, HHS is enhancing the nation's preparedness by supporting the radiation dose assessment capabilities that will ensure effective and appropriate use of medical countermeasures in the aftermath of a radiological or nuclear incident.
The frequency of chromosome abnormalities due to non-disjunction of maternal chromosomes during meiosis is a function of age, with a sharp increase in the slope of the trisomy-age curve between the ages of 30 and 40 years. The basis of this increase, which is a major cause of birth defects, is unknown at present. In recent years, mutations in mitochondrial (mt) DNA have been associated with a growing number of disorders, including those associated with spontaneous deletions of mtDNA (deltamt DNAs). Intriguingly, these pathogenic deltamtDNAs, which are present at extremely high levels in certain patients, are also present at extremely low levels (detectable only by polymerase chain reaction) in normal individuals. The proportion of such deltamtDNAs in normal muscle is a function of age; the shape of this curve is exponential, with the accelerating part of the curve beginning at approximately 30-40 years. We postulate that, as well as muscle and brain, a similar time-dependent accumulation of deltamtDNAs also occurs in normal oocytes. Since deltamtDNAs are functionally inactive, an accumulation of such aberrant genomes could eventually compromise ATP-dependent energy-utilization in these cells. Furthermore, these deficiencies would also affect the function of the somatic follicular cells that surround, and secrete important paracrine factors to, the oocyte. If there is indeed an age-associated relationship between deltamtDNAs and oocyte age, perhaps errors in meiosis (which is almost certainly an energy, and ATP, dependent process) are related to mutations in mtDNA (primarily deletions, but perhaps point mutations as well) in oocytes and/or the surrounding somatic cells, which result in deficiencies in both mitochondrial function in general and oxidative energy metabolism in particular. This hypothesis would explain many of the non-Mendelian features associated with maternal age-related trisomies, e.g. Down's syndrome.
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