The association between stress and physical fitness testing in the 2005 Department of Defense population survey

Objective. The purpose of this study was to examine the association of perceived stress and passing the fitness test in a cohort of Department of Defense active duty members. Reports of this association have been suggested in numerous articles. Methods. The 2005 DoD Survey of Health Related Behaviors Among Active Duty Military Personnel was used to examine the association between the participants’ perceived levels of stress from family and/or work related sources and the respondents’ last required fitness test taking into account potential confounder of the association. Measures of association were obtained from logistic regression models. Results. Participants who experienced “some” or “a lot” of stress either from work sources (OR 0.69, 95% CI: 0.58-0.87) or from personal/family sources (OR 0.70, 95% CI: 0.57-0.86) were less likely to pass the fitness test when compared to their counterparts who experienced “none” or “a little” stress. Additionally, those who reported “some” or “a lot” of stress either from work sources (OR 0.54, 95% CI: 0.41-0.70) or from personal/family sources (OR 0.54, 95% CI: 0.44-0.67) that interfered with their military duties were also less likely to pass the fitness test. The multivariate adjustment only slightly reduced the unadjusted association. Conclusions . An association exists between perceived stress levels and outcome of fitness testing. The higher the level of stress perceived, the less likely the person will be to pass the fitness test. Stress-related intervention might be useful to help the military members to achieve the level of fitness needed to perform their duties.^

BIOLOGICAL MECHANISMS AND CLINICAL IMPLICATIONS OF BCR-ABL-INDUCED MITOCHONDRIAL OXIDATIVE STRESS AND CELL SURVIVAL IN CHRONIC MYELOID LEUKEMIA

Chronic myeloid leukemia (CML), a myeloproliferative disorder, represents approximately 15-20% of all adult leukemia. The development of CML is clearly linked to the constitutively active protein-tyrosine kinase BCR-ABL, which is encoded by BCR-ABL fusion gene as the result of chromosome 9/22 translocation (Philadelphia chromosome). Previous studies have demonstrated that oxidative stress-associated genetic, metabolic and biological alterations contribute to CML cell survival and drug refractory. Mitochondria and NAD(P)H oxidase (NOX) are the major sources of BCR-ABL-induced cellular reactive oxygen species (ROS) production. However, it is still unknown how CML cells maintain the altered redox status, while escaping from the persistent oxidative stress-induced cell death. Therefore, elucidation of the mechanisms by which CML cells cope with oxidative stress will provide new insights into CML leukemogenesis. The major goal of this study is to identify the survival factors protecting CML cells against oxidative stress and develop novel therapeutic strategies to overcome drug resistance. Several experimental models were used to test CML cell redox status and cellular sensitivity to oxidative stress, including BCR-ABL inducible cell lines, BCR-ABL stably transformed cell lines and BCR-ABL-expressing CML blast crisis cells with differential BCL-XL/BCL-2 expressions. Additionally, an artificial CML cell model with heterogenic BCL-XL/BCL-2 expression was established to assess the correlation between differential survival factor expression patterns and cell sensitivity to Imatinib and oxidative stress. In this study, BCL-XL and GSH have been identified as the major survival factors responsive to BCR-ABL-promoted cellular oxidative stress and play a dominant role in regulating the threshold of oxidative stress-induced apoptosis. Cell survival factors BCL-XL and BCL-2 differentially protect mitochondria under oxidative stress. BCL-XL is an essential survival factor in preventing excessive ROS-induced cell death while BCL-2 seems to play a relatively minor role. Furthermore, the redox modulating reagent β-phenethyl isothiocyanate (PEITC) has been found to efficiently deplete GSH and induce potent cell killing effects in drug-resistant CML cells. Combination of PEITC with BCL-XL/BCL2 inhibitor ABT737 or suppression of BCL-XL by BCR-ABL inhibitor Gleevec dramatically sensitizes CML cells to apoptosis. These results have suggested that elevation of BCL-XL and cellular GSH are important for the development of CML, and that redox-directed therapy is worthy of further clinical investigations in CML.

An assessment of post-disaster psychological stress in hazardous waste operations and emergency response (HAZWOPER) workers

Personnel involved in natural or man-made disaster response and recovery efforts may be exposed to a wide variety of physical and mental stressors that can exhibit long-lasting and detrimental psychopathological outcomes. In a disaster situation, huge numbers of "secondary" responders can be involved in contaminant clean-up and debris removal and can be at risk of developing stress-related mental health outcomes. The Occupational Safety and Health Administration (OSHA) worker training hierarchy typically required for response workers, known as "Hazardous Waste Operations and Emergency Response" (HAZWOPER), does not address the mental health and safety concerns of workers. This study focused on the prevalence of traumatic stress experienced by secondary responders that had received or expressed interest in receiving HAZWOPER training through the National Institute of Environmental Health Sciences Worker Education and Training Program (NIEHS WETP). ^ The study involved the modification of two preexisting and validated survey tools to assess secondary responder awareness of physical, mental, and traumatic stressors on mental health and sought to determine if a need existed to include traumatic stress-related mental health education in the current HAZWOPER training regimen. The study evaluated post-traumatic stress disorder (PTSD), resiliency, mental distress, and negative effects within a secondary responder population of 176 respondents. Elevated PTSD levels were seen in the study population as compared to a general responder population (32.9% positive vs. 8%-22.5% positive). Results indicated that HAZWOPER-trained disaster responders were likely to test positive for PTSD, whereas, untrained responders with no disaster experience and responders who possessed either training or disaster experience only were likely to test PTSD negative. A majority (68.75%) of the population tested below the mean resiliency to cope score (80.4) of the average worker population. Results indicated that those who were trained only or who possessed both training and disaster work experience were more likely to have lower resiliency scores than those with no training or experience. There were direct correlations between being PTSD positive and having worked at a disaster site and experiencing mental distress and negative effects. However, HAZWOPER training status does not significantly correlate with mental distress or negative effect. ^ The survey indicated clear support (91% of respondents) for mental health education. The development of a pre- and post-deployment training module is recommended. Such training could provide responders with the necessary knowledge and skills to recognize the symptomology of PTSD, mental stressors, and physical and traumatic stressors, thus empowering them to employ protective strategies or seek professional help if needed. It is further recommended that pre-deployment mental health education be included in the current HAZWOPER 24- and 40-hour course curriculums, as well as, consideration be given towards integrating a stand-alone post-deployment mental health education training course into the current HAZWOPER hierarchy.^

OXIDATIVE STRESS BASED STRATEGIES FOR ENHANCING THE EFFICACY OF HISTONE DEACETYLASE INHIBITORS (HDACi)

Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that primarily act upon acetylation of histones, however they also increase levels of intracellular reactive oxygen species (ROS). We hypothesized that agents that cause oxidative stress might enhance the efficacy of HDACi. To test this hypothesis, we treated acute lymphocytic leukemia cells (ALL) with HDACi and adaphostin (ROS generating agent). The combination of two different HDACi (vorinostat or entinostat) with adaphostin synergistically induced apoptosis in ALL. This synergistic effect was blocked when cells were pre-treated with the caspase-9 inhibitor, LEHD. In addition, we showed that loss of the mitochondrial membrane potential is the earliest event observed starting at 12 h. Following this event, we observed increased levels of superoxide at 16 h, and ultimately caspase-3 activation. Pre-treatment with the antioxidant N-acetylcysteine (NAC) blocked ROS generation and reversed the loss of mitochondrial membrane potential for both combinations. Interestingly, DNA fragmentation and caspase-3 activity was only blocked by NAC in cells treated with vorinostat-adaphostin; but not with entinostat-adaphostin. These results suggest that different redox mechanisms are involved in the induction of ROS-mediated apoptosis. To further understand these events, we studied the role of the antioxidants glutathione (GSH) and thioredoxin (Trx). We found that the combination of entinostat-adaphostin induced acetylation of the antioxidant thioredoxin (Trx) and decreased intracellular levels of GSH. However, no effect on Trx activity was observed in either combination. In addition, pre-treatment with GSH ethyl ester, a soluble form of GSH, did not block DNA fragmentation. Together these results suggested that GSH and Trx are not major players in the induction of oxidative stress. Array data examining the expression of genes involved in oxidative stress demonstrated a differential regulation between cells treated with vorinostat-adaphostin and entinostat-adaphostin. Some of the genes differentially expressed between the combinations include aldehyde oxidase 1, glutathione peroxidase-5, -6, peroxiredoxin 6 and myeloperoxidase. Taken together, these experimental results indicate that the synergistic activity of two different HDACi with adaphostin is mediated by distinct redox mechanisms in ALL cells. Understanding the mechanism involved in these combinations will advance scientific knowledge of how the action of HDACi could be augmented in leukemia models. Moreover, this information could be used for the development of effective clinical trials combining HDACi with other anticancer agents.