Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer.

Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.

The sleep physiology of nightmares in veterans with psychological trauma: Evaluation of a dominant model using participant-applied electroencephalography in the home environment.

Nightmares are a core feature of posttraumatic stress disorder, are poorly understood, and are associated with serious negative outcomes. Their biology has been difficult to study, and the feasibility of capturing them in the naturalistic home environment has been poor. This said, the published research and dominant scientific model has focused on nightmares as a manifestation of noradrenergic hyperarousal during rapid eye movement sleep. The current study used at-home, participant-applied devices to measure nightmare physiology in posttraumatic stress disorder treatment-seeking veterans, by examining heartrate measures as indicators of noradrenergic tone, and sleep-stage characteristics and stability in the sleep preceding time-stamped nightmare awakenings. Our data indicate the high feasibility of participant-administered, at-home measurement, and showed an unexpected stability of -rapid eye movement sleep along with no evidence of heartrate elevations in sleep preceding nightmare awakenings. Altogether, these data highlight new opportunities for the study of nightmares while questioning the sufficiency of dominant models, which to date are largely theoretically based.

Impact of hormonal contraceptives on sex differences in fear conditioning and fear extinction in PTSD.

Sex differences in the neurobiological mechanisms involved in fear conditioning and extinction have been suggested to contribute to differential vulnerability for the development of posttraumatic stress disorder (PTSD) in women compared with men. Reproductive hormones, such as estradiol, have been shown to facilitate fear conditioning and extinction learning and may explain some of these differences. However, the effect of commonly used hormonal contraceptives on the neurobiological mechanisms of fear conditioning and extinction is poorly understood. A laboratory study was conducted in trauma-exposed men and women with and without full or partial PTSD to examine effects of sex and use of hormonal birth control on fear conditioning, fear extinction learning, and extinction retention. Participants underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS-) with shock. Extinction learning occurred 72 h later, and extinction retention was tested 1 wk after extinction. Women on hormonal contraceptives (HCs) demonstrated enhanced acquisition of fear conditioning and enhanced extinction of fear as compared with women off hormonal birth control and men. While clinical implications have yet to be determined, these results suggest that hormonal contraceptives may facilitate learning during both fear acquisition and extinction. Understanding the impact of sex and hormones on fear conditioning and extinction processes may lead to new insights into the pathophysiology of PTSD and result in advancements in treatment that may vary by sex.

Work by day and sleep by night, do not sleep too little or too much: Effects of sleep duration, time of day and circadian synchrony on flanker-task performance in internet brain-game users from teens to advanced age.

Research elucidating the effects of sleep and circadian rhythm on cognitive performance is advancing, yet many important questions remain. Using flanker-task performance scores from a large internet sample (N = 48,881) with repeated measures of cognitive performance and linked prior-night self-reported sleep duration, we analysed the relationship between sleep duration, time of day of task performance, and chronotype synchrony with performance in participants aged 15-80 years. Results indicate a performance peak at 7 hr habitual sleep duration, and point to a variable effect of deviation from habitual sleep duration depending on users' habitual sleep duration and age. Time-of-day effects were notable for a steady decline in performance up until 01:00 hours-02:00 hours for the group as a whole, which was accounted for by nighttime deterioration on trials requiring inhibitory executive functioning, particularly in older subjects. Analyses did not demonstrate an advantage for playing in synchrony with self-identified chronotype. Results strengthen findings indicating an inverted U-shaped relationship between sleep duration and cognitive performance across a broad spectrum of age groups. These findings underscore the importance of daytime task performance for tasks requiring inhibitory function, especially in elderly people. Findings highlight the utility of large-scale internet data in contributing to sleep and circadian science.

Inflammation as a predictor of disease course in posttraumatic stress disorder and depression: A prospective analysis from the Mind Your Heart Study.

BACKGROUND: Prior research has focused largely on the pro-inflammatory states of PTSD and depression, with few studies evaluating the direction of inflammation's association with these disorders. To clarify whether inflammation plays a role in the development of PTSD or depression, we assessed the predictive value of inflammatory biomarkers on the courses of these conditions in a cohort of Veterans. METHODS: This research was part of the Mind Your Heart Study, a prospective cohort study designed to examine PTSD-related health outcomes. Between 2008 and 2010, 746 San Francisco area Veterans Administration patients were enrolled. At baseline, inflammatory biomarkers were measured from fasting morning venous blood draws, and cortisol and catecholamine levels were measured from 24-hour urine samples. PTSD was diagnosed using the PTSD Checklist at baseline and annual follow-up. Depression was evaluated using the 9-item Patient Health Questionnaire at baseline and follow-up. Ordinal logistic regression models were used to assess the predictive value of baseline biomarker levels on clinically relevant courses of PTSD and depression categorized and ordered as none, resolved, developed, and chronic. RESULTS: After adjustment for age and sex, elevated levels of white blood cell count (OR = 1.27(1.10-1.47), p = 0.001), C-reactive protein (OR = 1.20(1.04-1.39), p = 0.02), fibrinogen (OR = 1.19(1.03-1.38), p = 0.02), and ESR (OR = 1.17(1.00-1.36, p = 0.05), and decreased levels of urine cortisol (OR = 0.84(0.71-0.99), p = 0.04) were significant predictors of poorer courses of PTSD. Elevated levels of WBC count (OR = 1.31(1.14-1.50), p < 0.001), CRP (OR = 1.24(1.07-1.43), p = 0.003), fibrinogen (OR = 1.26(1.09-1.46), p = 0.002), and catecholamines (OR = 1.17(1.01-1.36), p = 0.04) were significant predictors of poorer courses of depression. After additionally controlling for physical activity, elevated WBC count (p = 0.002) and decreased levels of urine cortisol (p = 0.05) remained significant predictors of PTSD course, and elevated WBC count (p = 0.001), CRP (p = 0.03), and fibrinogen (p = 0.02) remained significant predictors of depression course. After adjusting for all significant variables, elevated WBC count (p = 0.02) was a significant predictor of a poorer course of PTSD, and elevated WBC count (p = 0.04) and platelet count (p = 0.03) were significant predictors of a poorer course of depression. CONCLUSIONS: Increased levels of several inflammatory biomarkers were associated with significantly increased odds of clinically worse courses of PTSD and depression. Inflammation may be a target for prevention and treatment of these mental health disorders.

Looking into the One-way Mirror: A Pilot Study on the Impact of Reflecting Teams on Family Members.

Reflecting Teams (RTs) are an internationally recognized clinical consultation methodology, first developed by Tom Andersen in 1985. Over the last three decades, family therapists around the world have used RTs to enhance treatment. However, this innovation to family therapy practice is not well-standardized nor evaluated. The pilot study described in this article is an attempt to expand on the previous studies on RTs, and quantitatively examines RTs conducted with family therapy participants at a university medical center psychiatric institute. Preliminary analyses indicate that after participating in a single RT, family members may feel more hopeful, believe they can better support each other in times of stress, have more confidence in working together, and resolve conflicts. Additionally, the analyses suggest that family members may feel better understood and have more ideas about how to have a conversation with their family members, even though, after the RT, they may not view their family differently. These preliminary results suggest that further studies should explore the influence of RTs on family functioning.

Los "equipos reflexivos" (Reflecting Teams, RTs) son una metodología de consulta clínica reconocida a nivel internacional que fue desarrollada por primera vez por Tom Andersen en 1985 (Andersen, 1992). Durante las últimas tres décadas, los terapeutas familiares de todo el mundo han usado los equipos reflexivos para optimizar el tratamiento (p. ej.: Brownlee, Vis, & McKenna, 2009; Höger, Temme, Reiter, & Steiner, 1994). Sin embargo, esta innovación en la práctica de terapia familiar no está bien estandarizada ni evaluada. El estudio piloto descrito en este artículo es un intento de ampliar estudios previos sobre los equipos reflexivos y de analizar cuantitativamente los equipos reflexivos implementados con los participantes de una terapia familiar en un instituto psiquiátrico y un centro médico universitario. Los análisis preliminares indican que después de participar en un solo equipo reflexivo, los familiares pueden sentirse más optimistas, creer que pueden apoyarse mejor mutuamente en momentos de estrés, tener más confianza en trabajar juntos y resolver conflictos. Los integrantes de la familia también pueden sentirse mejor comprendidos y tener más ideas acerca de cómo conversar con sus familiares. Sin embargo, después del equipo reflexivo, es posible que no vean a su familia de forma diferente. Estos resultados preliminares sugieren que otros estudios deberían analizar la influencia de los equipos reflexivos en el funcionamiento familiar.

Association among anterior cingulate cortex volume, psychophysiological response, and PTSD diagnosis in a Veteran sample.

Posttraumatic stress disorder (PTSD) is associated with fear response system dysregulation. Research has shown that the anterior cingulate cortex (ACC) may modulate the fear response and that individuals with PTSD have abnormalities in ACC structure and functioning. Our objective was to assess whether ACC volume moderates the relationship between PTSD and fear-potentiated psychophysiological response in a sample of Gulf War Veterans. 142 Veteran participants who were associated with a larger study associated with Gulf War Illness were exposed to no threat, ambiguous threat, and high threat conditions in a fear conditioned startle response paradigm and also provided MRI imaging data. PTSD was assessed using the Clinician Administered PTSD Scale (CAPS). Decreased caudal ACC volume predicted greater psychophysiological responses with a slower habituation of psychophysiological magnitudes across trials (p < 0.001). PTSD diagnosis interacted significantly with both caudal and rostral ACC volumes on psychophysiological response magnitudes, where participants with PTSD and smaller rostral and caudal ACC volumes had greater psychophysiological magnitudes across trials (p < 0.05 and p < 0.001, respectively) and threat conditions (p < 0.05 and p < 0.005). Our results suggest that ACC volume may moderate both threat sensitivity and threat response via impaired habituation in individuals who have been exposed to traumatic events. More research is needed to assess whether ACC size and these associated response patterns are due to neurological processes resulting from trauma exposure or if they are indicative of a premorbid risk for PTSD subsequent to trauma exposure.

Effects of Threat Context, Trauma History, and Posttraumatic Stress Disorder Status on Physiological Startle Reactivity in Gulf War Veterans.

In the current study, we explored exaggerated physiological startle responses in posttraumatic stress disorder (PTSD) and examined startle reactivity as a biomarker of PTSD in a large veteran sample. We assessed heart rate (HR), skin conductance (SC), and electromyographic (EMG) startle responses to acoustic stimuli under low-, ambiguous-, and high-threat conditions in Gulf War veterans with current (n = 48), past (n = 42), and no history of PTSD (control group; n = 152). We evaluated PTSD status using the Clinician-Administered PTSD Scale and trauma exposure using the Trauma History Questionnaire. Participants with current PTSD had higher HR, ds = 0.28-0.53; SC, d = 0.37; and startle responses than those with past or no history of PTSD. The HR startle response under ambiguous threat best differentiated current PTSD; however, sensitivity and specificity analyses revealed it to be an imprecise indicator of PTSD status, ROC AUC = .66. Participants with high levels of trauma exposure only showed elevated HR and SC startle reactivity if they had current PTSD. Results indicate that startle is particularly elevated in PTSD when safety signals are available but a possibility of danger remains and when trauma exposure is high. However, startle reactivity alone is unlikely to be a sufficient biomarker of PTSD.

A 12-week integrative exercise program improves self-reported mindfulness and interoceptive awareness in war veterans with posttraumatic stress symptoms.

OBJECTIVE: Innovative approaches to the treatment of war-related posttraumatic stress disorder (PTSD) are needed. We report on secondary psychological outcomes of a randomized controlled trial of integrative exercise (IE) using aerobic and resistance exercise with mindfulness-based principles and yoga. We expected-in parallel to observed improvements in PTSD intensity and quality of life-improvements in mindfulness, interoceptive bodily awareness, and positive states of mind. METHOD: A total of 47 war veterans with PTSD were randomized to 12-week IE versus waitlist. Changes in mindfulness, interoceptive awareness, and states of mind were assessed by self-report standard measures. RESULTS: Large effect sizes for the intervention were observed on Five-Facet Mindfulness Questionnaire Non-Reactivity (d = .85), Multidimensional Assessment of Interoceptive Awareness Body Listening (d = .80), and Self-Regulation (d = 1.05). CONCLUSION: In a randomized controlled trial of a 12-week IE program for war veterans with PTSD, we saw significant improvements in mindfulness, interoceptive bodily awareness, and positive states of mind compared to a waitlist.

Metabolic risk factors and posttraumatic stress disorder: the role of sleep in young, healthy adults.

OBJECTIVE: Posttraumatic stress disorder (PTSD) is associated with indicators of poor physical health and sleep disturbance. This study investigated the relationship between PTSD and metabolic risk factors and examined the role of sleep duration in medically healthy and medication-free adults. METHODS: Participants with PTSD (n = 44, mean age = 30.6 years) and control participants free of lifetime psychiatric history (n = 50, mean age = 30.3 years) recorded sleep using sleep diary for 10 nights and actigraphy for 7 nights. We assessed metabolic risk factors including fasting triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein cholesterol, as well as abdominal fat using dual-energy x-ray absorptiometry. RESULTS: PTSD was associated with shorter sleep duration (based on self-report, not actigraphy) and higher metabolic risks (controlling for body fat percentage), including increased triglycerides (p = .03), total cholesterol (p < .001), LDL cholesterol (p = .006), very low density lipoprotein cholesterol (p = .002), and cholesterol/high-density lipoprotein ratio (p = .024). In addition, sleep duration was associated with metabolic risks in PTSD (significant correlations ranged from r = -0.20 to r = -0.40) but did not fully account for the association between PTSD and metabolic measures. CONCLUSIONS: Metabolic risk factors are associated with PTSD even in early adulthood, which highlights the need for early intervention. Future longitudinal research should assess whether sleep disturbance in PTSD is a mechanism that contributes to heightened metabolic risk to elucidate the pathway from PTSD to higher rates of medical disorders such as obesity, diabetes, and heart disease.

Topiramate treatment of alcohol use disorder in veterans with posttraumatic stress disorder: a randomized controlled pilot trial.

BACKGROUND: The course of posttraumatic stress disorder (PTSD) is frequently and severely complicated by co-occurring alcohol use disorder (AUD), yet there are few reports of pharmacologic treatments for these comorbid conditions. The objective of this pilot study was to obtain a preliminary assessment of the efficacy and safety of topiramate in reducing alcohol use and PTSD symptoms in veterans with both disorders. METHODS: This was a prospective 12-week, randomized, double-blind, placebo-controlled pilot trial of flexible-dose topiramate up to 300 mg/d in 30 veterans with PTSD and AUD. The primary outcome measure was frequency of drinking. Secondary outcomes consisted of other measures of alcohol use and PTSD symptom severity. RESULTS: Within-group analyses showed that topiramate treatment was associated with significant reductions in frequency and amount of alcohol use and alcohol craving from baseline through week 12. Between-group analyses showed that topiramate reduced frequency of alcohol use and alcohol craving significantly more than placebo and tended to reduce drinking amount. Topiramate treatment was also associated with decreased PTSD symptom severity and tended to reduce hyperarousal symptoms compared with placebo. Topiramate transiently impaired learning and memory, with significant recovery by the end of treatment. CONCLUSIONS: These preliminary results indicate that in veterans with co-occurring PTSD and AUD, topiramate may be effective in reducing alcohol consumption, alcohol craving, and PTSD symptom severity-particularly hyperarousal symptoms. Topiramate was associated with transient cognitive impairment but was otherwise well tolerated.

Immunologic landscape of human hepatic hemangiomas and epithelioid hemangioendotheliomas.

BACKGROUND: The missing requirement for resection for the majority of hepatic hemangiomas (HH) and tissue scarcity for rare diseases such as hepatic epithelioid hemangioendotheliomas (HEHE) complicate the characterization of the spatial immunovascular niche of these benign and malignant vascular neoplastic diseases. METHODS: Two tissue cohorts containing 98 HHs and 13 HEHEs were used to study entity-specific and disease stage-specific endothelial cell (EC) phenotype and immune cell abundance. Using semiquantitative assessment, annotation-based cell classifiers, digital cell detection on whole slides, and tissue microarrays, we quantified 23 immunologic and vascular niche-associated markers and correlated this with clinicopathologic data. RESULTS: Both HH and HEHE ECs were characterized by a CD31high, CD34high, FVIII-related antigenhigh expression phenotype with entity-specific expression differences of sinusoidal EC markers Stabilin1, Stabilin2, CD32, and Lymphatic Vessel Endothelial Hyaluronan Receptor 1 (LYVE-1). Cell detection identified an HH margin-prevailing immunologic response dominated by Myeloperoxidase+ (MPO+) macrophages, CD3+ and CD8+ T cell subsets, and B cells (CD20+, CD79A+). In HEHE, increased CD68+ and CD20+ cell demarcation of lesion margins was observed, while CD3+ and CD8+ T cells were equally detectable both marginally and intralesionally. Stage-specific pairwise correlation analysis of HH and HEHE revealed disease entity-specific immunologic infiltration patterns as seen by high CD117+ cell numbers in HH, while HEHE samples showed increased CD3+ T cell infiltration. CONCLUSIONS: ECs in HH and HEHE share a continuous EC expression phenotype, while the expression of sinusoidal EC markers is more highly retained in HEHE. These phenotypic differences are associated with a unique and disease-specific immunovascular landscape.

ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma.

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.

ROR2 regulates cellular plasticity in pancreatic neoplasia and adenocarcinoma.

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia (SPEM)-like identity in the pancreas. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.

Sex differences in objective measures of sleep in post-traumatic stress disorder and healthy control subjects.

A growing literature shows prominent sex effects for risk for post-traumatic stress disorder and associated medical comorbid burden. Previous research indicates that post-traumatic stress disorder is associated with reduced slow wave sleep, which may have implications for overall health, and abnormalities in rapid eye movement sleep, which have been implicated in specific post-traumatic stress disorder symptoms, but most research has been conducted in male subjects. We therefore sought to compare objective measures of sleep in male and female post-traumatic stress disorder subjects with age- and sex-matched control subjects. We used a cross-sectional, 2 × 2 design (post-traumatic stress disorder/control × female/male) involving83 medically healthy, non-medicated adults aged 19-39 years in the inpatient sleep laboratory. Visual electroencephalographic analysis demonstrated that post-traumatic stress disorder was associated with lower slow wave sleep duration (F(3,82)  = 7.63, P = 0.007) and slow wave sleep percentage (F(3,82)  = 6.11, P = 0.016). There was also a group × sex interaction effect for rapid eye movement sleep duration (F(3,82)  = 4.08, P = 0.047) and rapid eye movement sleep percentage (F(3,82)  = 4.30, P = 0.041), explained by greater rapid eye movement sleep in post-traumatic stress disorder females compared to control females, a difference not seen in male subjects. Quantitative electroencephalography analysis demonstrated that post-traumatic stress disorder was associated with lower energy in the delta spectrum (F(3,82)  = 6.79, P = 0.011) in non-rapid eye movement sleep. Slow wave sleep and delta findings were more pronounced in males. Removal of post-traumatic stress disorder subjects with comorbid major depressive disorder, who had greater post-traumatic stress disorder severity, strengthened delta effects but reduced rapid eye movement effects to non-significance. These findings support previous evidence that post-traumatic stress disorder is associated with impairment in the homeostatic function of sleep, especially in men with the disorder. These findings suggest that group × sex interaction effects on rapid eye movement may occur with more severe post-traumatic stress disorder or with post-traumatic stress disorder comorbid with major depressive disorder.

Posttraumatic stress disorder is associated with emotional eating.

The present study investigated the relationship between posttraumatic stress disorder (PTSD) and emotional eating in a sample of medically healthy and medication-free adults. Participants with PTSD (n = 44) and control participants free of lifetime psychiatric history (n = 49) completed a measure of emotional eating. Emotional eating is the tendency to eat or overeat in response to negative emotions. PTSD participants exhibited greater emotional eating than control participants (η(2)  = .20) and emotional eating increased with higher PTSD symptom severity (R(2)  = .11). Results supported the stress-eating-obesity model whereby emotional eating is a maladaptive response to stressors. Over time, this could lead to weight gain, particularly abdominal stores, and contribute to higher risk for comorbid medical disorders. Findings suggest the importance of future longitudinal research to understand whether emotional eating contributes to the high rates of obesity, diabetes, and heart disease in PTSD.

Simultaneous magnetic resonance imaging of pH, perfusion and renal filtration using hyperpolarized 13C-labelled Z-OMPD.

pH alterations are a hallmark of many pathologies including cancer and kidney disease. Here, we introduce [1,5-13C2]Z-OMPD as a hyperpolarized extracellular pH and perfusion sensor for MRI which allows to generate a multiparametric fingerprint of renal disease status and to detect local tumor acidification. Exceptional long T1 of two minutes at 1 T, high pH sensitivity of up to 1.9 ppm per pH unit and suitability of using the C1-label as internal frequency reference enables pH imaging in vivo of three pH compartments in healthy rat kidneys. Spectrally selective targeting of both 13C-resonances enables simultaneous imaging of perfusion and filtration in 3D and pH in 2D within one minute to quantify renal blood flow, glomerular filtration rates and renal pH in healthy and hydronephrotic kidneys with superior sensitivity compared to clinical routine methods. Imaging multiple biomarkers within a single session renders [1,5-13C2]Z-OMPD a promising new hyperpolarized agent for oncology and nephrology.

Sleep Spindles Favor Emotion Regulation Over Memory Consolidation of Stressors in Posttraumatic Stress Disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a trauma-induced condition, characterized by intrusive memories and trauma-associated anxiety. Non-rapid eye movement (NREM) sleep spindles might play a crucial role in learning and consolidating declarative stressor information. However, sleep and possibly sleep spindles are also known to regulate anxiety, suggestive of a dual role for sleep spindles in the processing of stressors. Specifically, in individuals with high PTSD symptom burden, spindles might fail to regulate anxiety levels after exposure and instead might maladaptively consolidate stressor information. METHODS: To disentangle the role of spindles in declarative memory versus anxiety regulation after stressor exposure and to examine the role of PTSD in these processes, we measured nap sleep after a cohort of 45 trauma-exposed participants were exposed to laboratory stress. Participants (high vs. low PTSD symptoms) completed 2 visits: a stress visit involving exposure to negatively valent images before nap and a control visit. In both visits, sleep was monitored via electroencephalography. A stressor recall session occurred after the nap in the stress visit. RESULTS: Stage 2 NREM (NREM2) spindle rates were higher in stress versus control sleep, indicative of stress-induced changes in spindles. In participants with high PTSD symptoms, NREM2 spindle rates in stress sleep predicted poorer recall accuracy of stressor images relative to participants with low PTSD symptoms, while correlating with greater reduction in stressor-induced anxiety levels after sleep. CONCLUSIONS: Contrary to our expectations, although spindles are known to play a role in declarative memory processes, our findings highlight an important role for spindles in sleep-dependent anxiety regulation in PTSD.

Lifetime exposure to traumatic psychological stress is associated with elevated inflammation in the Heart and Soul Study.

Exposure to traumatic psychological stress increases risk for disease events and mortality in patients with cardiovascular disease (CVD). While the biological mechanisms of these effects are not known, inflammation may play a key role as it is both elevated by psychological stress and involved in the development and progression of CVD. In a prospective study of patients with stable CVD (n=979), we examined if higher lifetime trauma exposure was associated with elevated levels of inflammation at baseline and at five-year follow-up, and with greater increases in inflammation over time. Inflammation was indexed by a composite score incorporating the inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and resistin. In follow-up analyses, we adjusted for sociodemographic factors, psychiatric disorders and health behaviors that were significantly associated with trauma exposure. Higher trauma exposure was associated with elevated inflammation at baseline (ß=.09, p=.01) and at five-year follow-up (ß=.09, p=.03). While levels of inflammation increased from baseline to follow-up in the sample, there was no significant association between trauma exposure and rate of change in inflammation. Findings were robust to adjustments for sociodemographic factors and psychiatric disorders, but health behaviors appeared to contribute to the association between trauma and inflammation at follow-up. This is the first large-scale demonstration of an association between lifetime trauma exposure and inflammation. High lifetime exposure to traumatic stress may contribute to an accelerated rate of CVD progression through elevated inflammation.

Killing in combat may be independently associated with suicidal ideation.

BACKGROUND: The United States military has lost more troops to suicide than to combat for the second year in a row and better understanding combat-related risk factors for suicide is critical. We examined the association of killing and suicide among war veterans after accounting for PTSD, depression, and substance use disorders. METHODS: We utilized a cross-sectional, retrospective, nationally representative sample of Vietnam veterans from the National Vietnam Veterans Readjustment Study (NVVRS). In order to perform a more in depth analysis, we utilized a subsample of these data, the NVVRS Clinical Interview Sample (CIS), which is representative of 1.3 million veterans who were eligible for the clinical interview by virtue of living in proximity to an interview site, located within 28 standard metropolitan regions throughout the United States. RESULTS: Veterans who had higher killing experiences had twice the odds of suicidal ideation, compared to those with lower or no killing experiences (OR = 1.99, 95% CI = 1.07-3.67), even after adjusting for demographic variables, PTSD, depression, substance use disorders, and adjusted combat exposure. PTSD (OR = 3.42, 95% CI = 1.09-10.73), depression (OR = 11.49, 95% CI = 2.12-62.38), and substance use disorders (OR = 3.98, 95% CI = 1.01-15.60) were each associated with higher odds of suicidal ideation. Endorsement of suicide attempts was most strongly associated with PTSD (OR = 5.52, 95% CI = 1.21-25.29). CONCLUSIONS: Killing experiences are not routinely examined when assessing suicide risk. Our findings have important implications for conducting suicide risk assessments in veterans of war. Depression and Anxiety 00:1-6, 2012. © 2012 Wiley Periodicals, Inc.