Richard J. Hatchett

Medical Countermeasures for Radiation Combined Injury: Radiation with Burn, Blast, Trauma and/or Sepsis. Report of an NIAID Workshop, March 26–27, 2007

Abstract DiCarlo, A. L., Hatchett, R. J., Kaminski, J. M., Ledney, G. D., Pellmar, T. C., Okunieff, P. and Ramakrishnan, N. Medical Countermeasures for Radiation Combined Injury: Radiation with Burn, Blast, Trauma and/or Sepsis. Report of an NIAID Workshop, March 26–27, 2007. Radiat. Res. 169, 712–721 (2008). Non-clinical human radiation exposure events such as the Hiroshima and Nagasaki bombings or the Chernobyl accident are often coupled with other forms of injury, such as wounds, burns, blunt trauma, and infection. Radiation combined injury would also be expected after a radiological or nuclear attack. Few animal models of radiation combined injury exist, and mechanisms underlying the high mortality associated with complex radiation injuries are poorly understood. Medical countermeasures are currently available for management of the non-radiation components of radiation combined injury, but it is not known whether treatments for other insults will be effective when the injury is combined with radiation exposure. Further research is needed to elucidate mechanisms behind the synergistic lethality of radiation combined injury and to identify targets for medical countermeasures. To address these issues, the National Institute of Allergy and Infectious Diseases convened a workshop to make recommendations on the development of animal models of radiation combined injury, possible mechanisms of radiation combined injury, and future directions for countermeasure research, including target identification and end points to evaluate treatment efficacy.

Medical Countermeasures against Nuclear Threats: Radionuclide Decorporation Agents

Abstract Cassatt, D. R., Kaminski, J. M., Hatchett, R. J., DiCarlo, A. L., Benjamin, J. M. and Maidment, B. W. Medical Countermeasures against Nuclear Threats: Radionuclide Decorporation Agents. Radiat. Res. 170, 540–548 (2008). Exposure to radionuclides disseminated by a radiological dispersion device or deposited as fallout after a nuclear power plant accident or detonation of an improvised nuclear device could result in internal contamination of a significant number of individuals. Internalized radionuclides may cause both acute and chronic radiation injury and increase an individuals risk of developing cancer. This damage and risk can be mitigated by the use of decorporation agents that reduce internal contamination. Unfortunately, most effective agents decorporate only a limited range of radionuclides, and some are formulated in ways that would make administration in mass casualty situations challenging. There is a need for new radionuclide decorporation agents, reformulations of existing agents, and/or expansion of the labeled indications for existing treatments. Researchers developing novel or improved decorporation agents should also understand the regulatory pathway for these products. This workshop, the first in nearly half a century to focus exclusively on radionuclide decorporation, brought together researchers and scientific administrators from academia, government and industry as well as senior regulatory affairs officers and U.S. Food and Drug Administration personnel. Meeting participants reviewed recent progress in the development of decorporation agents and contemplated the future of the field.

Rapid radiation dose assessment for radiological public health emergencies: roles of NIAID and BARDA.

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 nations 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.

Stimulation of adult rat ventricular myocyte protein synthesis and phosphoinositide hydrolysis by the endothelins

The effects of endothelin-1 (ET-1) on protein synthesis and phosphoinositide (PI) hydrolysis were investigated in ventricular myocytes isolated by collagenase digestion of adult rat hearts. The maximum stimulation of protein synthesis by ET-1 was about 35% and the EC50 value was about 0.3 nM. The stimulation was exerted at the translational stage since it was insensitive to inhibition by actinomycin D. The maximum stimulation of PI hydrolysis by ET-1 as measured by the formation of [3H]inositol phosphates was about 11-fold and the EC50 value was about 0.7 nM. The ET-1 analogue sarafotoxin-6b stimulated protein synthesis by a maximum of 27% and stimulated PI hydrolysis about 8- to 9-fold. The EC50 values were 1.6 nM and 0.6 nM, respectively. Other endothelins stimulated protein synthesis and PI hydrolysis in the following order of potency: ET-1 approximately ET-2 > ET-3. This order of potency suggests that the stimulation of both protein synthesis and PI hydrolysis is mediated through the ETA receptor. Although both angiotensin II and [Arg]vasopressin stimulated PI hydrolysis significantly, the stimulation was less than 60%, i.e., much less than the stimulation by ET-1 and its analogues. Neither insulin nor substance P stimulated PI hydrolysis. Stimulation of protein synthesis by ET-1 and its analogues correlated strongly with the stimulation of PI hydrolysis and we suggest that the stimulation of protein synthesis may be dependent on the stimulation of PI hydrolysis. We hypothesize that the mechanism may involve a protein kinase C-mediated increase in intracellular pH.

Radiologic and nuclear events: contingency planning for hematologists/oncologists

Untoward events involving radioactive material, either accidental or intentional, are potentially devastating. Hematologists and oncologists are uniquely suited to help manage radiation victims, as myelosuppression is a frequent complication of radiation exposure. In the aftermath of a large event, such as a nuclear detonation, there may be a national call for surge capacity that involves hematologists/oncologists across the country in the disaster response. In preparation, the National Marrow Donor Program and American Society for Blood and Marrow Transplantation have established the Radiation Injury Treatment Network (RITN), a voluntary consortium of transplant centers, donor centers, and umbilical cord blood banks. RITN is partnered with the Office of the Assistant Secretary for Preparedness and Response in the United States Department of Health and Human Services to develop treatment guidelines, educate healthcare professionals, coordinate situation response, and provide comprehensive evaluation and care for radiation injury victims. We outline the current plans for event response and describe scenarios, including catastrophic events that would require extensive support from hematologists/oncologists across the country. In addition, we highlight important reference resources and discuss current efforts to develop medical countermeasures against radiation toxicity. Practitioners and institutions across the country are encouraged to become involved and participate in the planning.

Radiation combined injury: overview of NIAID research.

The term “radiation combined injury” (RCI) is used to describe conditions where radiation injury is coupled with other insults such as burns, wounds, infection, or blunt trauma. A retrospective account of injuries sustained following the atomic bombing of Hiroshima estimates that RCI comprised approximately 65% of all injuries observed. Much of the research that has been performed on RCI was carried out during the Cold War and our understanding of the clinical problem RCI presents does not reflect the latest advances in medicine or science. Because concerns have increased that terrorists might employ radiological or nuclear weapons, and because of the likelihood that victims of such terrorism would experience RCI, the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health sponsored a meeting in 2007 to explore the state of the research in this area, identify programmatic gaps, and establish priorities for future research. As a follow-up to that meeting, in 2008 NIAID sponsored an initiative on RCI, leading to the award of several exploratory/developmental grants, the goals of which are to better understand biological synergy involved in RCI-induced damage, develop improved animal models for various type of RCI, and advance identification and testing of potential countermeasures to treat injuries that would be expected following a radiological or nuclear event. This program has already yielded new insight into the nature of combined injuries and has identified a number of novel and existing compounds that may be effective treatments for this condition.

NIAID/NIH radiation/nuclear medical countermeasures product research and development program.

One of the greatest national security threats to the United States is the detonation of an improvised nuclear device or a radiological dispersal device in a heavily populated area. The U.S. Government has addressed these threats with a two-pronged strategy of preventing organizations from obtaining weapons of mass destruction and preparing in case an event occurs. The National Institute of Allergy and Infectious Diseases (NIAID) contributes to these preparedness efforts by supporting basic research and development for chemical, biological, radiological, and nuclear countermeasures for civilian use. The Radiation Countermeasures Program at NIAID has established a broad research agenda focused on the development of new medical products to mitigate and treat acute and long-term radiation injury, promote the clearance of internalized radionuclides, and facilitate accurate individual dose and exposure assessment. This paper reviews the recent work and collaborations supported by the Radiation Countermeasures Program.

Modeling and public health emergency responses: lessons from SARS.

Abstract Modelers published thoughtful articles after the 2003 SARS crisis, but had limited if any real-time impact on the global response and may even have inadvertently contributed to a lingering misunderstanding of the means by which the epidemic was controlled. The impact of any intervention depends on its efficiency as well as efficacy, and efficient isolation of infected individuals before they become symptomatic is difficult to imagine. Nonetheless, in exploring the possible impact of quarantine, the product of efficiency and efficacy was varied over the entire unit interval. Another mistake was repeatedly fitting otherwise appropriate gamma distributions to times to event regardless of whether they were stationary or not, particularly onset-isolation intervals whose progressive reduction evidently contributed to SARS control. By virtue of their unknown biology, newly-emerging diseases are more challenging than familiar human scourges. Influenza, for example, recurs annually and has been modeled more thoroughly than any other infectious disease. Moreover, models were integrated into preparedness exercises, during which working relationships were established that bore fruit during the 2009 A/H1N1 pandemic. To provide the most accurate and timely advice possible, especially about the possible impact of measures designed to control diseases caused by novel human pathogens, we must appreciate the value and difficulty of policy-oriented modeling. Effective communication of insights gleaned from modeling SARS will help to ensure that policymakers involve modelers in future outbreaks of newly-emerging infectious diseases. Accordingly, we illustrate the increasingly timely care-seeking by which, together with increasingly accurate diagnoses and effective isolation, SARS was controlled via heuristic arguments and descriptive analyses of familiar observations.

Radiation Injury Treatment Network (RITN): Healthcare professionals preparing for a mass casualty radiological or nuclear incident

Purpose: To describe the history, composition, and activities of the Radiation Injury Treatment Network (RITN). The Radiation Injury Treatment Network® is a cooperative effort of the National Marrow Donor Program and the American Society for Blood and Marrow Transplantation. The goals of RITN are to educate hematologists, oncologists, and stem cell transplant practitioners about their potential involvement in the response to a radiation incident and provide treatment expertise. Injuries to the marrow system readily occur when a victim is exposed to ionising radiation. This focus therefore leverages the expertise of these specialists who are accustomed to providing the intensive supportive care required by patients with a suppressed marrow function. Following a radiological incident, RITN centres may be asked to: Accept patient transfers to their institutions; provide treatment expertise to practitioners caring for victims at other centres; travel to other centres to provide medical expertise; or provide data on victims treated at their centres. Moving forward, it is crucial that we develop a coordinated interdisciplinary approach in planning for and responding to radiological and nuclear incidents. The ongoing efforts of radiation biologists, radiation oncologists, and health physicists can and should complement the efforts of RITN and government agencies. Conclusion: RITN serves as a vital partner in preparedness and response efforts for potential radiological and nuclear incidents.

The U.S. government's medical countermeasure portfolio management for nuclear and radiological emergencies: synergy from interagency cooperation.

Following the attacks of 11 September 2001, emergency preparedness within the U.S. Department of Health and Human Services, as well as at the Department of Defense and other federal agencies, received higher visibility, new mandates and increased funding. Emergency deployment teams increased the frequency of drills to enable better response to the health consequences of mass-casualty incidents. Interagency coordination has also continued to increase to more efficiently and effectively leverage federal resources toward emergency medical preparedness for both civilian and military populations.