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STUDY OBJECTIVES: Veterans are at an increased risk for traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD), both of which are associated with sleep disturbances and increased pain. Furthermore, sleep disturbances and pain are reciprocally related such that each can exacerbate the other. Although both TBI and PTSD are independently linked to sleep disturbances and pain, it remains unclear whether Veterans with comorbid TBI+PTSD show worse sleep disturbances and pain compared to those with only TBI or PTSD. We hypothesized that sleep and pain would be worse in Veterans with comorbid TBI+PTSD compared to Veterans with only TBI or PTSD. METHODS: Veterans (n = 639) from the VA Portland Health Care System completed overnight polysomnography and self-report questionnaires. Primary outcome variables were self-reported sleep disturbances and current pain intensity. Participants were categorized into four trauma-exposure groups: (1) neither: without TBI or PTSD (n = 383); (2) TBI: only TBI (n = 67); (3) PTSD: only PTSD (n = 126); and (4) TBI+PTSD: TBI and PTSD (n = 63). RESULTS: The PTSD and TBI+PTSD groups reported worse sleep compared to the TBI and neither groups. The TBI+PTSD group reported the greatest pain intensity compared to the other groups. CONCLUSIONS: These data suggest sleep and pain are worst in Veterans with TBI and PTSD, and that sleep is similarly impaired in Veterans with PTSD despite not having as much pain. Thus, although this is a complex relationship, these data suggest PTSD may be driving sleep disturbances, and the added effect of TBI in the comorbid group may be driving pain in this population. CITATION: Balba NM, Elliott JE, Weymann KB, Opel RA, Duke JW, Oken BS, Morasco BJ, Heinricher MM, Lim MM. Increased sleep disturbances and pain in Veterans with comorbid traumatic brain injury and posttraumatic stress disorder. J Clin Sleep Med. 2018;14(11):1865–1878.

Sleep disturbances following traumatic brain injury (TBI) in Veterans are very common and often persist as chronic sequelae. In addition, sensory sensitivity, ie, discomfort upon exposure to light and noise, is common after TBI. However, the relationship between sleep disturbances and sensory sensitivity in Veterans following TBI has not yet been examined, yet both are established early markers of neurodegeneration.Veterans (n = 95) in the chronic phase of recovery from TBI at the VA Portland Health Care System completed an overnight polysomnography and provided self-report data on sensory (eg, light and noise) sensitivity, and sleep disturbances. Participants were categorized into four sensory sensitivity groups: (1) "neither," neither light nor noise sensitivity (n = 36); (2) "light," only light sensitivity (n = 12); (3) "noise," only noise sensitivity (n = 24); and (4) "both," light and noise sensitivity (n = 23).Veterans with TBI reported sleep disturbances that were significantly correlated with the severity of their sensory sensitivity and associated with posttraumatic stress disorder (PTSD). Multiple linear regression revealed insomnia severity to be the strongest predictor of the relationship between sleep disturbances and sensory sensitivity. Furthermore, sensory sensitivity was associated with a higher mean heart rate during sleep, even after controlling for PTSD status.These data are the first to report the prevalence and association between sensory sensitivity and sleep disturbances in Veterans with TBI. These data also suggest that the underlying mechanism of the sleep-sensory relationship could be due in part to comorbid PTSD and autonomic nervous system hyperarousal.

Posttraumatic stress disorder (PTSD) is a debilitating and common consequence of military service. PTSD is associated with increased incidence of mood disturbances (e.g., anxiety). Additionally, veterans with PTSD often have poor-quality sleep and poor emotion regulation ability. We sought to assess whether such sleep and emotion regulation deficits contribute to mood disturbances. In 144 veterans, using a double moderation model, we tested the relationship between PTSD and anxiety and examined whether sleep quality and emotion regulation interact to moderate this relationship. We found that PTSD predicts higher anxiety in veterans with poor and average sleep quality who utilize maladaptive emotion regulation strategies. However, there was no relationship between PTSD and anxiety in individuals with good sleep quality, regardless of emotion regulation. Similarly, there was no relationship between PTSD and anxiety in individuals with better emotion regulation, regardless of sleep quality. Results were unchanged when controlling for history of traumatic brain injury (TBI), despite the fact that those with both PTSD and TBI had the poorest emotion regulation overall. Taken together, these results suggest that good-quality sleep may be protective against poor emotion regulation in veterans with PTSD. Sleep may therefore be a target for therapeutic intervention in veterans with PTSD and heightened anxiety.

Fatigue is the most common symptom related to cytotoxic chemotherapeutic treatment of cancer. Peripheral inflammation associated with cytotoxic chemotherapy is likely a causal factor of fatigue. The neural mechanisms by which cytotoxic chemotherapy associated inflammation induces fatigue behavior are not known. This lack of knowledge hinders development of interventions to reduce or prevent this disabling symptom. Infection induced fatigue/lethargy in rodents is mediated by suppression of hypothalamic orexin activity. Orexin is critical for maintaining wakefulness and motivated behavior. Though there are differences between infection and cytotoxic chemotherapy in some symptoms, both induce peripheral inflammation and fatigue. Based on these similarities we hypothesized that cytotoxic chemotherapy induces fatigue by disrupting orexin neuron activity. We found that a single dose of a cytotoxic chemotherapy cocktail (cyclophosphamide, adriamycin, 5-fluorouracil—CAF) induced fatigue/lethargy in mice and rats as evidenced by a significant decline in voluntary locomotor activity measured by telemetry. CAF induced inflammatory gene expression—IL-1R1 (p

Summary Benzothiadiazole (BTH) is a novel chemical activator of disease resistance in tobacco, wheat and other important agricultural plants. In this report, it is shown that BTH works by activating SAR in Arabidopsis thaliana. BTH-treated plants were resistant to infection by turnip crinkle virus, Pseudomonas syringae pv ‘tomato’ DC3000 and Peronospora parasitica. Chemical treatment induced accumulation of mRNAs from the SAR-associated genes, PR-1, PR-2 and PR-5. BTH treatment induced both PR-1 mRNA accumulation and resistance against P. parasitica in the ethylene response mutants, etr1 and ein2, and in the methyl jasmonate-insensitive mutant, jar1, suggesting that BTH action is independent of these plant hormones. BTH treatment also induced both PR-1 mRNA accumulation and P. parasitica resistance in transgenic Arabidopsis plants expressing the nahG gene, suggesting that BTH action does not require salicylic acid accumulation. However, because BTH-treatment failed to induce either PR-1 mRNA accumulation or P. parasitica resistance in the non-inducible immunity mutant, nim1, it appears that BTH activates the SAR signal transduction pathway.

Summary Systemic acquired resistance (SAR) appears to be a ubiquitous higher plant defence response. Resistance is dependent on the high-level expression of SAR genes. Mutations, transgenes or chemicals that cause high-level SAR gene expression also cause resistance to pathogens. Furthermore, when SAR is eliminated, through the reduction of salicylic acid accumulation or activity, generalized severe disease-susceptibility occurs. Therefore, SAR appears to be an essential component of the defensive repertoire that ensures plant health in nature. Chemicals that activate SAR in the field, as well as crop varieties with constitutive SAR gene expression, will provide new solutions to disease problems for growers in the near future.

Little is known about the signal transduction events that lead to the establishment of the broad-spectrum, inducible plant immunity called systemic acquired resistance (SAR). Salicylic acid (SA) accumulation has been shown to be essential for the expression of SAR and plays a key role in SAR signaling. Hydrogen peroxide has been proposed to serve as a second messenger of SA. However, our results do not support such a role in the establishment of SAR. Further elucidation of SAR signal transduction has been facilitated by the identification and characterization of mutants. The lesions simulating disease (lsd). resistance response mutant class exhibits spontaneous lesions similar to those that occur during the hypersensitive response. Interestingly, some lsd mutants lose their lesioned phenotype when SA accumulation is prevented by expression of the nahG gene (encoding salicylate hydroxylase), thereby providing evidence for a feedback loop in SAR signal transduction. Characterization of a mutant non-responsive to SAR activator treatments has provided additional evidence for common signaling components between SAR and gene-for-gene resistance.

Systemic acquired resistance (SAR) is a broad-spectrum, systemic defense response that is activated in many plant species after pathogen infection. We have previously described Arabidopsis mutants that constitutively express SAR and concomitantly develop lesions simulating disease (lsd). Here, we describe two new mutants, lsd6 and lsd7, that develop spontaneous necrotic lesions and possess elevated levels of salicylic acid (SA) as well as heightened disease resistance, similar to the previously characterized lsd and accelerated cell death (acd2) mutants. Genetic analysis of lsd6 and lsd7 showed that the mutant phenotypes segregated as simple dominant traits. When crossed with transgenic Arabidopsis plants containing the SA-degrading enzyme salicylate hydroxylase, the F1 progeny showed suppression of both SAR gene expression and resistance. In addition, salicylate hydroxylase suppressed lesion formation in the F1 progeny, suggesting that SA or some SA-dependent process may have a role in pathogen-associated cell death. Surprisingly, lesions were restored in the lsd6 F1 progeny after the application of either 2,6-dichloroisonicotinic acid or SA. Lesions were not restored by treatment with either compound in the lsd7 F1 plants. Our findings demonstrate that steps early in the signal transduction pathway leading to SAR and disease resistance are potentiated by later events, suggesting feedback control of lesion formation.

Transgenic tobacco and Arabidopsis thaliana expressing the bacterial enzyme salicylate hydroxylase cannot accumulate salicylic acid (SA). This defect not only makes the plants unable to induce systemic acquired resistance, but also leads to increased susceptibility to viral, fungal, and bacterial pathogens. The enhanced susceptibility extends even to host-pathogen combinations that would normally result in genetic resistance. Therefore, SA accumulation is essential for expression of multiple modes of plant disease resistance.

Expression of pathogenesis-related protein 1a (PR-1a), a protein of unknown biochemical function, is induced to high levels in tobacco in response to pathogen infection. The induction of PR-1a expression is tightly correlated with the onset of systemic acquired resistance (SAR), a defense response effective against a variety of fungal, viral, and bacterial pathogens. While PR-1a has been postulated to be involved in SAR, and is the most highly expressed of the PR proteins, evidence for its role is lacking. In this report, we demonstrate that constitutive high-level expression of PR-1a in transgenic tobacco results in tolerance to infection by two oomycete pathogens, Peronospora tabacina and Phytophthora parasitica var. nicotianae.

Fertile transgenic maize plants (T0) and progeny (T1) were obtained using microprojectile bombardment and callus selection on hygromycin B. To quickly identify progeny expressing the transgene, embryos from T3 generation kernels were excised 20 days after pollination and exposed to different concentrations of hygromycin B. Surviving and non-surviving embryos were assayed for the presence of the hygromycin phosphotransferase (aphIV) gene using polymerase chain reaction. Embryos that germinated and survived on 25, 50, or 100 mg/liter hygromycin possessed theaphIV gene. Embryos that did not germinate lacked the gene. Progeny surviving selection were transferred to the greenhouse and tested for expression of the gene using a leaf disc assay. The results demonstrated that the gene construct was expressed in both embryo and leaf tissue and that selection during germination successfully eliminated progeny lacking the gene of interest. This method is also useful for rapid-cycling of maize generations.

In many interactions of plants with pathogens, the primary host defense reaction is accompanied by plant cell death at the site of infection. The resulting lesions are correlated with the establishment of an inducible resistance in plants called systemic acquired resistance (SAR), for which salicylic acid (SA) accumulation is a critical signaling event in Arabidopsis and tobacco. In Arabidopsis, the lesions simulating disease (lsd) mutants spontaneously develop lesions in the absence of pathogen infection. Furthermore, lsd mutants express SAR marker genes when lesions are present and are resistant to the same spectrum of pathogens as plants activated for SAR by necrogenic pathogen infection. To assess the epistatic relationship between SA accumulation and cell death, transgenic Arabidopsis unable to accumulate SA due to the expression of the salicylate hydroxylase (nahG) gene were used in crosses with the dominant mutants lsd2 or lsd4. Progeny from the crosses were inhibited for SAR gene expression and disease resistance. However, these progeny retained the spontaneous cell death phenotype similar to siblings not expressing nahG. Because lesions form in the absence of SA accumulation for lsd2 and lsd4, a model is suggested in which lesion formation in these two mutants is determined prior to SA accumulation in SAR signal transduction. By contrast, the loss of SAR gene expression and disease resistance in nahG-expressing lsd mutants indicates that these traits are dependent upon SA accumulation in the SAR signal transduction pathway.

The NIM1 (for noninducible immunity) gene product is involved in the signal transduction cascade leading to both systemic acquired resistance (SAR) and gene-for-gene disease resistance in Arabidopsis. We have isolated and characterized five new alleles of nim1 that show a range of phenotypes from weakly impaired in chemically induced pathogenesis-related protein-1 gene expression and fungal resistance to very strongly blocked. We have isolated the NIM1 gene by using a map-based cloning procedure. Interestingly, the NIM1 protein shows sequence homology to the mammalian signal transduction factor I kappa B subclass alpha. NF-kappa B/I kappa B signaling pathways are implicated in disease resistance responses in a range of organisms from Drosophila to mammals, suggesting that the SAR signaling pathway in plants is representative of an ancient and ubiquitous defense mechanism in higher organisms.

Systemic acquired resistance (SAR) is an important component of plant defense against pathogen infection. Accumulation of salicylic acid (SA) is required for the induction of SAR. However, SA is apparently not the translocated signal but is involved in transducing the signal in target tissues. Interestingly, SA accumulation is not required for production and release of the systemic signal. In addition to playing a pivotal role in SAR signal transduction, SA is important in modulating plant susceptibility to pathogen infection and genetic resistance to disease. It has been proposed that SA inhibition of catalase results in H2O2 accumulation and that therefore H2O2 serves as a second messenger in SAR signaling. We find no accumulation of H2O2 in tissues expressing SAR; thus the role of H2O2 in SAR signaling is questionable.

Systemic acquired resistance is a broad spectrum inducible defense response that is associated with the expression of a set of genes (SAR genes). Expression of one of these genes (PR-1a from tobacco) in transgenic tobacco confers increased tolerance to two oomycete pathogens. A direct role for salicylic acid (SA) in signaling SAR has been established in tobacco by analysis of transgenic tobacco expressing salicylate hydroxylase (SAH, an enzyme that inactivates SA by conversion to catechol). Tobacco plants that express SAH are blocked in the accumulation of SA and the development of SAR when responding lo TMV. Furthermore, both Arabidopsis and tobacco expressing SAH have altered pathogen induced lesion morphology, exemplified by larger spreading lesions. Putative mutants in SAR gene expression were isolated by screening M2 Arabidopsis plants for altered expression of PR-1 and PR-2 or for sensitivity to pathogen infection following INA treatment. The putative mutants all into two major classes,constitutive (cim, constitutive immunity) and non-inducible (nim, non-inducible immunity). Several cim mutants exhibits a disease lesion phenotype in the absence of pathogen.

Systemic acquired resistance (SAR) is an inducible plant response to infection by a necrotizing pathogen. In the induced plant, SAR provides broad-spectrum protection against not only the inducing pathogen, but also against other, unrelated pathogens. Both salicylic acid (SA) and SAR-gene expression have been implicated as playing important roles in the initiation and maintenance of SAR. Here, we describe the characterization of transgenic Arabidopsis plants that express the bacterial nahG gene encoding salicylate hydroxylase, an enzyme that can metabolize SA. Strong, constitutive expression of this gene prevents pathogen-induced accumulation of SA and the activation of SAR by exogenous SA. We show that SAR in Arabidopsis can be induced by inoculation with Pseudomonas syringe pv. tomato against infection by a challenge inoculation with Peronospora parasitica. This response is abolished in transgenic, nahG-expressing Arabidopsis, but not in ethylene-insensitive mutants. These experiments support the critical role of SA in SAR and show that ethylene sensitivity is not required for SAR induction. The NahG Arabidopsis plants will be important for future studies aimed at understanding the role of SA in plant disease resistance mechanisms.