Posttraumatic Stress Disorder and Community Collective Efficacy following the 2004 Florida Hurricanes

There is a paucity of research investigating the relationship of community-level characteristics such as collective efficacy and posttraumatic stress following disasters. We examine the association of collective efficacy with probable posttraumatic stress disorder and posttraumatic stress disorder symptom severity in Florida public health workers (n = 2249) exposed to the 2004 hurricane season using a multilevel approach. Anonymous questionnaires were distributed electronically to all Florida Department of Health personnel nine months after the 2004 hurricane season. The collected data were used to assess posttraumatic stress disorder and collective efficacy measured at both the individual and zip code levels. The majority of participants were female (80.42%), and ages ranged from 20 to 78 years (median = 49 years); 73.91% were European American, 13.25% were African American, and 8.65% were Hispanic. Using multi-level analysis, our data indicate that higher community-level and individual-level collective efficacy were associated with a lower likelihood of having posttraumatic stress disorder (OR = 0.93, CI = 0.88–0.98; and OR = 0.94, CI = 0.92–0.97, respectively), even after adjusting for individual sociodemographic variables, community socioeconomic characteristic variables, individual injury/damage, and community storm damage. Higher levels of community-level collective efficacy and individual-level collective efficacy were also associated with significantly lower posttraumatic stress disorder symptom severity (b = −0.22, p<0.01; and b = −0.17, p<0.01, respectively), after adjusting for the same covariates. Lower rates of posttraumatic stress disorder are associated with communities with higher collective efficacy. Programs enhancing community collective efficacy may be an important part of prevention practices and possibly lead to a reduction in the rate of posttraumatic stress disorder post-disaster

Increased Incidence of Lymphosarcoma in Long-Term Murine Survivors of Lethal Radiation: A Classification of Subtypes

poster abstractResidual bone marrow damage (RBMD) persists for years following exposure to radiation and is thought to be due to decreased self-renewal of hematopoietic stem cells (HSC). We previously examined RBMD in murine survivors of lethal radiation modeling a terrorist event [800cGy total-body irradiation (TBI)]. We reported severely deficient HSC potential up to 20mo post-TBI compared to non-TBI age-matched controls, evidenced by minimal engraftment skewed to myeloid cells. CBC and BM cellularity were decreased in TBI mice, most dramatically in old age (>16mo). The percentage of some hematopoietic progenitors was consistently increased in TBI mice (~1.4x higher than non-TBI) possibly due to an increased cell cycling rate compared to non-TBI cells. Of interest, we now report the occurrence of a thymic mass developing in 13-24% of TBI mice 2-19 months post-TBI, compared to <1% of non-TBI. We characterized the Lymphosarcoma into the following groups based on the St. Jude pathology subclassification: Diffuse Lymphosarcoma involving multiple organs, Thymic lymphoma (usually associated with thymic and around the heart), Lymphosarcoma (potentially starting in the spleen and peri-pancreatic lymph nodes (Ab=abdomen)), and follicular lymphoma seen as a diffuse proliferation of lymphocytes in the white pulp area in the spleen. Thymic lymphomas were the most common, followed by Lymphosarcoma (Ab), follicular lymphoma (restricted to white pulp area in the spleen) and diffuse Lymphosarcoma. Immunostain markers revealed the thymic lymphomas were from T-cell lineage and the abdominal Lymphosarcoma were mainly from B-cell lineage. A few mice had disease involving the bone marrow. Taken together, these data suggest that the increased cycling among primitive hematopoietic cells in survivors of lethal radiation may contribute to stem cell exhaustion and subsequent RBMD, as well as predispose survivors to hematopoietic neoplasias

Survival efficacy of the PEGylated G-CSFs Maxy-G34 and neulasta in a mouse model of lethal H-ARS, and residual bone marrow damage in treated survivors

In an effort to expand the worldwide pool of available medical countermeasures (MCM) against radiation, the PEGylated G-CSF (PEG-G-CSF) molecules Neulasta and Maxy-G34, a novel PEG-G-CSF designed for increased half-life and enhanced activity compared to Neulasta, were examined in a murine model of the Hematopoietic Syndrome of the Acute Radiation Syndrome (H-ARS), along with the lead MCM for licensure and stockpiling, G-CSF. Both PEG-G-CSFs were shown to retain significant survival efficacy when administered as a single dose 24 h post-exposure, compared to the 16 daily doses of G-CSF required for survival efficacy. Furthermore, 0.1 mg kg of either PEG-G-CSF affected survival of lethally-irradiated mice that was similar to a 10-fold higher dose. The one dose/low dose administration schedules are attractive attributes of radiation MCM given the logistical challenges of medical care in a mass casualty event. Maxy-G34-treated mice that survived H-ARS were examined for residual bone marrow damage (RBMD) up to 9 mo post-exposure. Despite differences in Sca-1 expression and cell cycle position in some hematopoietic progenitor phenotypes, Maxy-G34-treated mice exhibited the same degree of hematopoietic stem cell (HSC) insufficiency as vehicle-treated H-ARS survivors in competitive transplantation assays of 150 purified Sca-1+cKit+lin-CD150+cells. These data suggest that Maxy-G34, at the dose, schedule, and time frame examined, did not mitigate RBMD but significantly increased survival from H-ARS at one-tenth the dose previously tested, providing strong support for advanced development of Maxy-G34, as well as Neulasta, as MCM against radiation

PEGylated G-CSF (BBT-015), GM-CSF (BBT-007), and IL-11 (BBT-059) analogs enhance survival and hematopoietic cell recovery in a mouse model of the hematopoietic syndrome of the acute radiation syndrome

Hematopoietic growth factors (HGF) are recommended therapy for high dose radiation exposure, but unfavorable administration schedules requiring early and repeat dosing limit the logistical ease with which they can be used. In this report, using a previously described murine model of H-ARS, survival efficacy and effect on hematopoietic recovery of unique PEGylated HGF were investigated. The PEGylated-HGFs possess longer half-lives and more potent hematopoietic properties than corresponding non-PEGylated-HGFs. C57BL/6 mice underwent single dose lethal irradiation (7.76-8.72 Gy, Cs, 0.62-1.02 Gy min) and were treated with various dosing regimens of 0.1, 0.3, and 1.0 mg kg of analogs of human PEG-G-CSF, murine PEG-GM-CSF, or human PEG-IL-11. Mice were administered one of the HGF analogs at 24-28 h post irradiation, and in some studies, additional doses given every other day (beginning with the 24-28 h dose) for a total of three or nine doses. Thirty-day (30 d) survival was significantly increased with only one dose of 0.3 mg kg of PEG-G-CSF and PEG-IL-11 or three doses of 0.3 mg kg of PEG-GM-CSF (p ≤ 0.006). Enhanced survival correlated with consistently and significantly enhanced WBC, NE, RBC, and PLT recovery for PEG-G- and PEG-GM-CSF, and enhanced RBC and PLT recovery for PEG-IL-11 (p ≤ 0.05). Longer administration schedules or higher doses did not provide a significant additional survival benefit over the shorter, lower dose, schedules. These data demonstrate the efficacy of BBT's PEG-HGF to provide significantly increased survival with fewer injections and lower drug doses, which may have significant economic and logistical value in the aftermath of a radiation event

Lifelong residual bone marrow damage in murine survivors of the hematopoietic acute radiation syndrome (H-ARS): a compilation of studies comprising the Indiana University experience

Accurate analyses of the delayed effects of acute radiation exposure (DEARE) in survivors of the hematopoietic acute radiation syndrome (H-ARS) are hampered by low numbers of mice for examination due to high lethality from the acute syndrome, increased morbidity and mortality in survivors, high cost of husbandry for long-term studies, biological variability, and inconsistencies of models from different laboratories complicating meta-analyses. To address this, a compilation of 38 similar H-ARS studies conducted over a seven-year period in the authors’ laboratory, comprising more than 1,500 irradiated young adult C57BL/6 mice and almost 600 day-30 survivors, was assessed for hematopoietic DEARE at various times up to 30 months of age. Significant loss of long-term repopulating potential of phenotypically-defined primitive hematopoietic stem cells (HSC) was documented in H-ARS survivors, as well as significant decreases in all hematopoietic lineages in peripheral blood, prominent myeloid skew, significantly decreased bone marrow cellularity and numbers of lineage-negative Sca-1+ cKit+ CD150+ cells (KSLCD150+; the phenotype known to be enriched for HSC), and increased cycling of KSLCD150+ cells. Studies interrogating the phenotype of bone marrow cells capable of initiation of suspension cultures and engraftment in competitive transplantation assays documented the phenotype of HSC in H-ARS survivors to be the same as that in non-irradiated age-matched controls. This compilation study adds rigor and validity to our initial findings of persistent hematopoietic dysfunction in H-ARS survivors that arises at the level of the HSC and which affects all classes of hematopoietic cells for the life of the survivor

An Update on Cancer Cluster Activities at the Centers for Disease Control and Prevention

The Centers for Disease Control and Prevention (CDC) continues to be aware of the need for response to public concern as well as to state and local agency concern about cancer clusters. In 1990 the CDC published the “Guidelines for Investigating Clusters of Health Events,” in which a four-stage process was presented. This document has provided a framework that most state health departments have adopted, with modifications pertaining to their specific situations, available resources, and philosophy concerning disease clusters. The purpose of this present article is not to revise the CDC guidelines; they retain their original usefulness and validity. However, in the past 15 years, multiple cluster studies as well as scientific and technologic developments have affected cluster science and response (improvements in cancer registries, a federal initiative in environmental public health tracking, refinement of biomarker technology, cluster identification using geographic information systems software, and the emergence of the Internet). Thus, we offer an addendum for use with the original document. Currently, to address both the needs of state health departments as well as public concern, the CDC now a) provides a centralized, coordinated response system for cancer cluster inquiries, b) supports an electronic cancer cluster listserver, c) maintains an informative web page, and d) provides support to states, ranging from laboratory analysis to epidemiologic assistance and expertise. Response to cancer clusters is appropriate public health action, and the CDC will continue to provide assistance, facilitate communication among states, and foster the development of new approaches in cluster science

The H-ARS Dose Response Relationship (DRR): Validation and Variables

Manipulations of lethally-irradiated animals, such as for administration of pharmaceuticals, blood sampling, or other laboratory procedures, have the potential to induce stress effects that may negatively affect morbidity and mortality. To investigate this in a murine model of the hematopoietic acute radiation syndrome, 20 individual survival efficacy studies were grouped based on the severity of the administration (Admn) schedules of their medical countermeasure (MCM) into Admn 1 (no injections), Admn 2 (1-3 injections), or Admn 3 (29 injections or 6-9 oral gavages). Radiation doses ranged from LD30/30 to LD95/30. Thirty-day survival of vehicle controls in each group was used to construct radiation dose lethality response relationship (DRR) probit plots, which were compared statistically to the original DRR from which all LDXX/30 for the studies were obtained. The slope of the Admn 3 probit was found to be significantly steeper (5.190) than that of the original DRR (2.842) or Admn 2 (2.009), which were not significantly different. The LD50/30 for Admn 3 (8.43 Gy) was less than that of the original DRR (8.53 Gy, p < 0.050), whereas the LD50/30 of other groups were similar. Kaplan-Meier survival curves showed significantly worse survival of Admn 3 mice compared to the three other groups (p = 0.007). Taken together, these results show that stressful administration schedules of MCM can negatively impact survival and that dosing regimens should be considered when constructing DRR to use in survival studies

A Potential Role for Excess Tissue Iron in Development of Cardiovascular Delayed Effects of Acute Radiation Exposure

Murine hematopoietic-acute radiation syndrome (H-ARS) survivors of total body radiation (TBI) have a significant loss of heart vessel endothelial cells, along with increased tissue iron, as early as 4 months post-TBI. The goal of the current study was to determine the possible role for excess tissue iron in the loss of coronary artery endothelial cells. Experiments utilized the H-ARS mouse model with gamma radiation exposure of 853 cGy (LD50/30) and time points from 1 to 12 weeks post-TBI. Serum iron was elevated at 1 week post-TBI, peaked at 2 weeks, and returned to non-irradiated control values by 4 weeks post-TBI. A similar trend was seen for transferrin saturation, and both results correlated inversely with red blood cell number. Perls’ Prussian Blue staining used to detect iron deposition in heart tissue sections showed myocardial iron was present as early as 2 weeks following irradiation. Pretreatment of mice with the iron chelator deferiprone decreased tissue iron, but not serum iron, at 2 weeks. Coronary artery endothelial cell density was significantly decreased as early as two weeks vs. non-irradiated controls (P<0.05), and the reduced density persisted to 12 weeks after irradiation. Deferiprone treatment of irradiated mice prevented the decrease in endothelial cell density at 2 and 4 weeks post-TBI compared to irradiated, non-treated mice (P<0.03). Taken together, the results suggest excess tissue iron contributes to endothelial cell loss early following TBI and may be a significant event impacting the development of delayed effects of acute radiation exposure

Cardiac and Renal Delayed Effects of Acute Radiation Exposure: Organ Differences in Vasculopathy, Inflammation, Senescence and Oxidative Balance

We have previously shown significant pathology in the heart and kidney of murine hematopoietic-acute radiation syndrome (H-ARS) survivors of 8.7-9.0 Gy total-body irradiation (TBI). The goal of this study was to determine temporal relationships in the development of vasculopathy and the progression of renal and cardiovascular delayed effects of acute radiation exposure (DEARE) at TBI doses less than 9 Gy and to elucidate the potential roles of senescence, inflammation and oxidative stress. Our results show significant loss of endothelial cells in coronary arteries by 4 months post-TBI (8.53 or 8.72 Gy of gamma radiation). This loss precedes renal dysfunction and interstitial fibrosis and progresses to abnormalities in the arterial media and adventitia and loss of coronary arterioles. Major differences in radiation-induced pathobiology exist between the heart and kidney in terms of vasculopathy progression and also in indices of inflammation, senescence and oxidative imbalance. The results of this work suggest a need for different medical countermeasures for multiple targets in different organs and at various times after acute radiation injury to prevent the progression of DEARE