Neuroimaging of posttraumatic stress disorder in adults and youth: progress over the last decade on three leading questions of the field.

Almost three decades have passed since the first posttraumatic stress disorder (PTSD) neuroimaging study was published. Since then, the field of clinical neuroscience has made advancements in understanding the neural correlates of PTSD to create more efficacious treatment strategies. While gold-standard psychotherapy options are available, many patients do not respond to them, prematurely drop out, or never initiate treatment. Therefore, elucidating the neurobiological mechanisms that define the disorder can help guide clinician decision-making and develop individualized mechanisms-based treatment options. To this end, this narrative review highlights progress made in the last decade in adult and youth samples on three outstanding questions in PTSD research: (1) Which neural alterations serve as predisposing (pre-exposure) risk factors for PTSD development, and which are acquired (post-exposure) alterations? (2) Which neural alterations can predict treatment outcomes and define clinical improvement? and (3) Can neuroimaging measures be used to define brain-based biotypes of PTSD? While the studies highlighted in this review have made progress in answering the three questions, the field still has much to do before implementing these findings into clinical practice. Overall, to better answer these questions, we suggest that future neuroimaging studies of PTSD should (A) utilize prospective longitudinal designs, collecting brain measures before experiencing trauma and at multiple follow-up time points post-trauma, taking advantage of multi-site collaborations/consortiums; (B) collect two scans to explore changes in brain alterations from pre-to-post treatment and compare changes in neural activation between treatment groups, including longitudinal follow up assessments; and (C) replicate brain-based biotypes of PTSD. By synthesizing recent findings, this narrative review will pave the way for personalized treatment approaches grounded in neurobiological evidence.

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

BACKGROUND: Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. METHODS: In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. RESULTS: Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. CONCLUSIONS: Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

Alcohol self-administration and nicotine withdrawal alter biomarkers of stress and inflammation and prefrontal cortex changes in Gß subunits.

Background: Although alcohol and nicotine are often used together, the biological consequences of these substances are not well understood. Identifying shared targets will inform cessation pharmacotherapies and provide a deeper understanding of how co-use of alcohol and nicotine impacts health, including biomarkers of stress and inflammation.Objective: We examined the effects of nicotine exposure and withdrawal on alcohol self-administration (SA), stress and inflammatory biomarkers, and a G-protein coupled receptor subunit (Gß) in brain areas associated with drug use.Methods: Male rats were trained to SA alcohol and then received a nicotine pump (n = 7-8 per group). We assessed alcohol intake for 12 days during nicotine exposure and then following pump removal to elicit withdrawal. After the behavioral studies, we assessed plasma leptin, corticosterone, and interleukin-1ß (IL-1ß), and Gß protein expression in the amygdala, nucleus accumbens (NAc), and prefrontal cortex (PFC).Results: Nicotine exposure or withdrawal did not alter alcohol intake (p > .05). Alcohol and nicotine withdrawal elevated corticosterone levels (p = .015) and decreased Gß levels in the PFC (p = .004). In the absence of nicotine, alcohol SA suppressed IL-1ß levels (p = .039). Chronic exposure to nicotine or withdrawal during alcohol SA did not alter leptin levels or Gß expression in the amygdala or NAc (p's > .05).Conclusions: The combination of alcohol SA and nicotine withdrawal produced a persistent increase in stress biomarkers and a suppression in Gß expression in the PFC, providing an important first step toward understanding the common biological mechanisms of alcohol/nicotine misuse.

Indirect effect of race-related stress on traumatic stress and depression symptoms via subjective social status in a Black community sample.

Experiencing racism is linked to lower subjective social status (SSS), defined as one's perception of their position in society. SSS is influenced by power, prestige, and objective socioeconomic status (SES). Previous findings suggest that race-related stress may be related to adverse mental health outcomes through SSS in Black Americans, a population that has been deeply affected by continuing legacies of oppression. The current study examines the indirect association between race-related stress and posttraumatic stress disorder (PTSD) and depression symptoms through SSS in a community sample of largely trauma-exposed Black Americans (N = 173). Hierarchical regression analyses indicated that overall race-related stress significantly predicted lower SSS, higher PTSD symptoms, and higher depression symptoms. Analyses also revealed indirect effects of cultural race-related stress on PTSD and depression symptoms through SSS after controlling for SES. Results suggest that the experience of race-related stress, particularly cultural race-related stress, which involves the degradation and disparagement of one's culture and worldview, is associated with more severe PTSD and depression symptoms potentially due to these experiences decreasing Black Americans' SSS. Findings support the need for systemic intervention strategies to disrupt the cultural oppression of Black Americans and improve the societal value and mental health of this population.

Omega-3 fatty acids in contrast to omega-6 protect against pneumococcal pneumonia.

PURPOSE: The aim of this study was to assess if long-term supplementation of omega-3 fatty acids or a diet rich in omega-6 fatty acids ameliorates disease severity in a murine model of pneumococcal pneumonia. We hypothesize that long-term dietary supplementation of omega-3 fatty acids will reduce inflammation, disease severity and improve survival compared to omega-6 fatty acids. METHODS: Mice receiving diets supplemented with Omega-3 or Omega-6 for two months were intranasally infected with Streptococcus pneumoniae. We analyzed survival, bacterial burden, histopathology and inflammatory biomarkers. RESULTS: Our results showed that Omega-3 supplementation had increased survival (p = 0.005), less bacteremia (p = 0.0001) and lower bacterial burden in the lungs (p = 0.0002) when compared to the Omega-6 supplementation. Overall, Omega-3 reduced lung pathology, in particular peribronchial inflammation and cell death. Analyses of lung homogenates showed the Omega-3 cohort had decreased levels of the inflammatory cytokine interleukin-6 and an increase in anti-inflammatory cytokine interleukin-10. CONCLUSIONS: Supplementation of mouse diets with Omega-3 fatty acids improved survival, bacterial invasion in the blood and lungs as well as decreased overall lung tissue inflammation and cell death when compared to the Omega-6 supplemented diets. Translation of these findings in humans may improve outcomes of patients at risk for pneumonia.

Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling.

RATIONALE: Up to one-third of patients hospitalized with pneumococcal pneumonia experience major adverse cardiac events (MACE) during or after pneumonia. In mice, Streptococcus pneumoniae can invade the myocardium, induce cardiomyocyte death, and disrupt cardiac function following bacteremia, but it is unknown whether the same occurs in humans with severe pneumonia. OBJECTIVES: We sought to determine whether S. pneumoniae can (1) translocate the heart, (2) induce cardiomyocyte death, (3) cause MACE, and (4) induce cardiac scar formation after antibiotic treatment during severe pneumonia using a nonhuman primate (NHP) model. METHODS: We examined cardiac tissue from six adult NHPs with severe pneumococcal pneumonia and three uninfected control animals. Three animals were rescued with antibiotics (convalescent animals). Electrocardiographic, echocardiographic, and serum biomarkers of cardiac damage were measured (troponin T, N-terminal pro-brain natriuretic peptide, and heart-type fatty acid binding protein). Histological examination included hematoxylin and eosin staining, immunofluorescence, immunohistochemistry, picrosirius red staining, and transmission electron microscopy. Immunoblots were used to assess the underlying mechanisms. MEASUREMENTS AND MAIN RESULTS: Nonspecific ischemic alterations were detected by electrocardiography and echocardiography. Serum levels of troponin T and heart-type fatty acid binding protein were increased (P < 0.05) after pneumococcal infection in both acutely ill and convalescent NHPs. S. pneumoniae was detected in the myocardium of all NHPs with acute severe pneumonia. Necroptosis and apoptosis were detected in the myocardium of both acutely ill and convalescent NHPs. Evidence of cardiac scar formation was observed only in convalescent animals by transmission electron microscopy and picrosirius red staining. CONCLUSIONS: S. pneumoniae invades the myocardium and induces cardiac injury with necroptosis and apoptosis, followed by cardiac scarring after antibiotic therapy, in an NHP model of severe pneumonia.

Neuraminidase A-Exposed Galactose Promotes Streptococcus pneumoniae Biofilm Formation during Colonization.

Streptococcus pneumoniae is an opportunistic pathogen that colonizes the nasopharynx. Herein we show that carbon availability is distinct between the nasopharynx and bloodstream of adult humans: glucose is absent from the nasopharynx, whereas galactose is abundant. We demonstrate that pneumococcal neuraminidase A (NanA), which cleaves terminal sialic acid residues from host glycoproteins, exposed galactose on the surface of septal epithelial cells, thereby increasing its availability during colonization. We observed that S. pneumoniae mutants deficient in NanA and ß-galactosidase A (BgaA) failed to form biofilms in vivo despite normal biofilm-forming abilities in vitro Subsequently, we observed that glucose, sucrose, and fructose were inhibitory for biofilm formation, whereas galactose, lactose, and low concentrations of sialic acid were permissive. Together these findings suggested that the genes involved in biofilm formation were under some form of carbon catabolite repression (CCR), a regulatory network in which genes involved in the uptake and metabolism of less-preferred sugars are silenced during growth with preferred sugars. Supporting this notion, we observed that a mutant deficient in pyruvate oxidase, which converts pyruvate to acetyl-phosphate under non-CCR-inducing growth conditions, was unable to form biofilms. Subsequent comparative transcriptome sequencing (RNA-seq) analyses of planktonic and biofilm-grown pneumococci showed that metabolic pathways involving the conversion of pyruvate to acetyl-phosphate and subsequently leading to fatty acid biosynthesis were consistently upregulated during diverse biofilm growth conditions. We conclude that carbon availability in the nasopharynx impacts pneumococcal biofilm formation in vivo Additionally, biofilm formation involves metabolic pathways not previously appreciated to play an important role.

Endothelial adhesion molecules and multiple organ failure in patients with severe sepsis.

OBJECTIVE: To determine if serum levels of endothelial adhesion molecules were associated with the development of multiple organ failure (MOF) and in-hospital mortality in adult patients with severe sepsis. DESIGN: This study was a secondary data analysis of a prospective cohort study. SETTING: Patients were admitted to two tertiary intensive care units in San Antonio, TX, between 2007 and 2012. PATIENTS: Patients with severe sepsis at the time of intensive care unit (ICU) admission were enrolled. Inclusion criteria were consistent with previously published criteria for severe sepsis or septic shock in adults. Exclusion criteria included immunosuppressive medications or conditions. INTERVENTIONS: None. MEASUREMENTS: Baseline serum levels of the following endothelial cell adhesion molecules were measured within the first 72h of ICU admission: Intracellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1), and Vascular Endothelial Growth Factor (VEGF). The primary and secondary outcomes were development of MOF (⩾2 organ dysfunction) and in-hospital mortality, respectively. MAIN RESULTS: Forty-eight patients were enrolled in this study, of which 29 (60%) developed MOF. Patients that developed MOF had higher levels of VCAM-1 (p=0.01) and ICAM-1 (p=0.01), but not VEGF (p=0.70) compared with patients without MOF (single organ failure only). The area under the curve (AUC) to predict MOF according to VCAM-1, ICAM-1 and VEGF was 0.71, 0.73, and 0.54, respectively. Only increased VCAM-1 levels were associated with in-hospital mortality (p=0.03). These associations were maintained even after adjusting for APACHE and SOFA scores using logistic regression. CONCLUSIONS: High levels of serum ICAM-1 was associated with the development of MOF. High levels of VCAM-1 was associated with both MOF and in-hospital mortality.

Requirement for Serratia marcescens cytolysin in a murine model of hemorrhagic pneumonia.

Serratia marcescens, a member of the carbapenem-resistant Enterobacteriaceae, is an important emerging pathogen that causes a wide variety of nosocomial infections, spreads rapidly within hospitals, and has a systemic mortality rate of ≤41%. Despite multiple clinical descriptions of S. marcescens nosocomial pneumonia, little is known regarding the mechanisms of bacterial pathogenesis and the host immune response. To address this gap, we developed an oropharyngeal aspiration model of lethal and sublethal S. marcescens pneumonia in BALB/c mice and extensively characterized the latter. Lethal challenge (>4.0 × 10(6) CFU) was characterized by fulminate hemorrhagic pneumonia with rapid loss of lung function and death. Mice challenged with a sublethal dose (<2.0 × 10(6) CFU) rapidly lost weight, had diminished lung compliance, experienced lung hemorrhage, and responded to the infection with extensive neutrophil infiltration and histopathological changes in tissue architecture. Neutrophil extracellular trap formation and the expression of inflammatory cytokines occurred early after infection. Mice depleted of neutrophils were exquisitely susceptible to an otherwise nonlethal inoculum, thereby demonstrating the requirement for neutrophils in host protection. Mutation of the genes encoding the cytolysin ShlA and its transporter ShlB resulted in attenuated S. marcescens strains that failed to cause profound weight loss, extended illness, hemorrhage, and prolonged lung pathology in mice. This study describes a model of S. marcescens pneumonia that mimics known clinical features of human illness, identifies neutrophils and the toxin ShlA as a key factors important for defense and infection, respectively, and provides a solid foundation for future studies of novel therapeutics for this important opportunistic pathogen.

Chromogranin A levels and mortality in patients with severe sepsis.

CONTEXT: Chromogranin A (CgA) is a novel biomarker with potential to assess mortality risk of patients with severe sepsis. OBJECTIVE: Assess association of CgA levels and mortality risk of severely septic patients. METHODS: Serum CgA levels were measured in 50 hospitalized, severely septic patients with organ failure <48 h. RESULTS: Higher CgA levels trended toward higher ICU and hospital mortality. Patients without cardiovascular disease who died in the ICU had higher median (IQR) CgA levels 602.3 (343.3, 1134.3) ng/ml versus 205.5 (130.7, 325.9) ng/ml, p = 0.01. CONCLUSIONS: High CgA levels predict ICU mortality in severely septic patients without prior cardiovascular disease.

Indirect effect of negative evaluations of therapy on the association between racial stress and posttraumatic stress disorder symptoms in pregnant Black persons.

OBJECTIVE: Black pregnant individuals are at disproportionate risk for posttraumatic stress disorder (PTSD) compared to other groups. A wealth of literature suggests racial stress contributes to this inequity, but cultural and structural mechanisms, such as perceived barriers to mental health treatment, underlying the relationship between racial stress and PTSD symptoms remain understudied. Negative evaluations of psychotherapy and stigma represent potential mechanisms, though no previous studies have examined these associations. To address this gap, we tested an indirect effect of racial stress on PTSD symptoms through perceived barriers to mental health treatment in pregnant Black individuals. METHOD: Mediation analyses were used to assess an indirect relationship between racial stress and PTSD symptoms through perceived barriers to mental health treatment. RESULTS: At the bivariate level, racial stress was significantly associated with PTSD symptoms (r = .20, p = .03) and negative evaluations of therapy (r = .22, p = .02), but not with stigma (r = .140, p = .147). Negative evaluations of therapy were also associated with PTSD symptoms (r = .43, p < .001). There was an indirect effect of racial stress on PTSD symptoms through a negative evaluation of therapy, ß = .08, SE = 0.04, CI [0.01, 0.18]. More specifically, racial stress was associated with a more negative evaluation of therapy, which was in turn associated with more PTSD symptoms. CONCLUSIONS: Results highlight the need for accessible and culturally competent mental health care for pregnant Black individuals. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Functional Domains of Substance Use and their Implications to Trauma: A Systematic Review of Neuroimaging Studies.

Substance use disorder (SUD) is a significant health problem, and trauma exposure is a known risk factor for the escalation of substance use. However, the shared neural mechanisms through which trauma is associated with substance use are still unknown. Therefore, we systematically review neuroimaging studies focusing on three domains that may contribute to the overlapping mechanisms of SUD and trauma-reward salience, negative emotionality, and inhibition. Using PRISMA guidelines, we identified 45 studies utilizing tasks measuring these domains in alcohol, tobacco, and cannabis use groups. Greater reward, lesser regulation of inhibitory processes, and mixed findings of negative emotionality processes in individuals who use substances versus controls were found. Specifically, greater orbitofrontal cortex, ventral tegmental area, striatum, amygdala, and hippocampal activation was found in response to reward-related tasks, and reduced activation was found in the inferior frontal gyrus and hippocampus in response to inhibition-related tasks. Importantly, no studies in trauma-exposed individuals met our review criteria. Future studies examining the role of trauma-related factors are needed, and more studies should explore inhibition- and negative-emotionality domains in individuals who use substances to uncover clinically significant alterations in these domains that place an individual at greater risk for developing a SUD.

Towards predicting PTSD symptom severity using portable EEG-derived biomarkers.

Posttraumatic Stress Disorder (PTSD) is a heterogeneous mental health disorder that occurs following traumatic experience. Understanding its neurobiological basis is crucial to advance early diagnosis and treatment. Electroencephalography (EEG) can be used to explore the neurobiological basis of PTSD. However, only limited research has explored mobile EEG, which is important for scalability. This proof-of-concept study delves into mobile EEG-derived biomarkers for PTSD and their potential implications. Over four weeks, we measured PTSD symptoms using the PTSD checklist for DSM-5 (PCL-5) at multiple timepoints, and we recorded multiple EEG sessions from 21 individuals using a mobile EEG device. In total, we captured 38 EEG sessions, each comprising two recordings that lasted approximately 180 seconds, to evaluate reproducibility. Next, we extracted Shannon entropy, as a measure of the randomness or unpredictability of the signal and spectral power for the fronto-temporal regions of interest, including electrodes at AF3, AF4, T7, and T8 for each EEG recording session. We calculated the partial correlation between the EEG variables and PCL-5 measured closest to the EEG session, using age, sex, and the grouping variable 'batch' as covariates. We observed a significant negative correlation between Shannon entropy in fronto-temporal regions and PCL-5 scores. Specifically, this association was evident in the AF3 (r = -0.456, FDR-corrected p = 0.01), AF4 (r = -0.362, FDR-corrected p = 0.04), and T7 (r = -0.472, FDR-corrected p = 0.01) regions. Additionally, we found a significant negative association between the alpha power estimated from AF4 and PCL-5 (r=-0.429, FDR-corrected p=0.04). Our findings suggest that EEG data acquired using a mobile EEG device is associated with PTSD symptom severity, offering valuable insights into the neurobiological mechanisms underlying PTSD.

Reward neurocircuitry predicts longitudinal changes in alcohol use following trauma exposure.

BACKGROUND: Trauma is a risk factor for developing maladaptive alcohol use. Preclinical research has shown that stress alters the processing of midbrain and striatal reward and incentive signals. However, little research has been conducted on alterations in reward-related neurocircuitry post-trauma in humans. Neuroimaging markers may be particularly useful as they can provide insight into the mechanisms that may make an individual vulnerable to developing trauma-related psychopathologies. This study aimed to identify reward-related neural correlates associated with changes in alcohol use after trauma exposure. METHODS: Participants were recruited from U.S. emergency departments for the AURORA study (N=286, 178 female). Trauma-related change in alcohol use at 8 weeks post-trauma relative to pre-trauma was quantified as a change in 30-day total drinking per the PhenX Toolkit Alcohol 30-Day Quantity and Frequency Measure. Reward-related neurocircuitry activation and functional connectivity (FC) were assessed 2 weeks post-trauma using fMRI during a monetary reward task using region of interest and whole-brain voxelwise analyses. RESULTS: Greater increase in alcohol use from pre-trauma to 8 weeks post-trauma was predicted by (1) greater ventral tegmental area (VTA) and (2) greater cerebellum activation during Gain>Loss trials measured 2 weeks post-trauma and (3) greater seed-based FC between the VTA and lateral occipital cortex and precuneus. CONCLUSIONS: Altered VTA activation and FC early post-trauma may be associated with reward-seeking and processing, contributing to greater alcohol use post-trauma. These data provide novel evidence of neural correlates that underlie increased alcohol use early post-trauma that may be targeted via early interventions to prevent the development of maladaptive alcohol use.

Validating the primary care posttraumatic stress disorder screen for DSM-5 (PC-PTSD-5) in a substance misusing, trauma-exposed, socioeconomically vulnerable population.

The co-occurrence of substance use disorder (SUD) and posttraumatic stress disorder (PTSD) is common, and is associated with greater severity of symptoms, poorer treatment prognosis, and increased risk of return to substance use following treatment. Screening for PTSD is not routinely implemented in substance use treatment programs, despite clinical relevance. Identifying screening tools that minimize patient burden and allow for comprehensive treatment in this patient population is critical. The current study examined the utility of the Primary Care PTSD Screen for DSM-5 (PC-PTSD-5) in identifying probable PTSD in a predominantly Black sample of 81 socioeconomically disadvantaged substance misusing hospital patients. The majority of the sample (75.3 %; n = 61) were found to meet criteria for probable PTSD using a suggested clinical cut score of 33 on the PTSD Checklist for DSM-5 (PCL-5). Diagnostic utility analyses were completed and determined a cut-score of 5 for the PC-PTSD-5 to demonstrate the best performance (SE = 0.62, κ(1) = 0.22; SP =.80, κ(0) = 0.61; EEF = 0.67, κ(0.5) = 0.32) in this sample. Results provide preliminary support for the use of the PC-PTSD-5 as a brief screening tool for probable PTSD in substance misusing patient populations. Routine use of the PC-PTSD-5 during assessment may be beneficial when treatment planning with those undergoing treatment for SUD because comprehensive assessment and treatment will provide a better chance of long-term recovery.

Pre-treatment amygdala activation and habituation predict symptom change in post-traumatic stress disorder.

Trauma-focused psychotherapy approaches are the first-line treatment option for post-traumatic stress disorder (PTSD); however, up to a third of patients remain symptomatic even after completion of the treatment. Predicting which patients will respond to a given treatment option would support personalized treatments and improve the efficiency of healthcare systems. Although previous neuroimaging studies have examined possible pre-treatment predictors of response to treatment, the findings have been somewhat inconsistent, and no other study has examined habituation to stimuli as a predictor. In this study, 16 treatment-seeking adults (MAge = 43.63, n = 10 women) with a primary diagnosis of PTSD passively viewed pictures of emotional facial expressions during functional magnetic resonance imaging (fMRI). After scanning, participants rated facial expressions on both valence and arousal. Participants then completed eight weekly sessions of prolonged exposure (PE) therapy. PTSD symptom severity was measured before and after treatment. Overall, participants showed symptomatic improvement with PE. Consistent with hypotheses, lesser activation in the amygdala and greater activation in the ventromedial prefrontal cortex during the presentation of fearful vs. happy facial expressions, as well as a greater decline in amygdala activation across blocks of fearful facial expressions at baseline, were associated with greater reduction of PTSD symptoms. Given that the repeated presentation of emotional material underlies PE, changes in brain responses with repeated stimulus presentations warrant further studies as potential predictors of response to exposure therapies.

Pneumococcal gene complex involved in resistance to extracellular oxidative stress.

Streptococcus pneumoniae is a gram-positive bacterium which is a member of the normal human nasopharyngeal flora but can also cause serious disease such as pneumonia, bacteremia, and meningitis. Throughout its life cycle, S. pneumoniae is exposed to significant oxidative stress derived from endogenously produced hydrogen peroxide (H(2)O(2)) and from the host through the oxidative burst. How S. pneumoniae, an aerotolerant anaerobic bacterium that lacks catalase, protects itself against hydrogen peroxide stress is still unclear. Bioinformatic analysis of its genome identified a hypothetical open reading frame belonging to the thiol-specific antioxidant (TlpA/TSA) family, located in an operon consisting of three open reading frames. For all four strains tested, deletion of the gene resulted in an approximately 10-fold reduction in survival when strains were exposed to external peroxide stress. However, no role for this gene in survival of internal superoxide stress was observed. Mutagenesis and complementation analysis demonstrated that all three genes are necessary and sufficient for protection against oxidative stress. Interestingly, in a competitive index mouse pneumonia model, deletion of the operon had no impact shortly after infection but was detrimental during the later stages of disease. Thus, we have identified a gene complex involved in the protection of S. pneumoniae against external oxidative stress, which plays an important role during invasive disease.

Impact of oral simvastatin therapy on acute lung injury in mice during pneumococcal pneumonia.

BACKGROUND: Recent studies suggest that the reported protective effects of statins (HMG-CoA reductase inhibitors) against community-acquired pneumonia (CAP) and sepsis in humans may be due to confounders and a healthy user-effect. To directly test whether statins are protective against Streptococcus pneumoniae, the leading cause of CAP, we examined the impact of prolonged oral simvastatin therapy at physiologically relevant doses in a mouse model of pneumococcal pneumonia. BALB/c mice were placed on rodent chow containing 0 mg/kg (control), 12 mg/kg (low simvastatin diet [LSD]; corresponds to 1.0 mg/kg/day), or 120 mg/kg (high simvastatin diet [HSD]; corresponds to 10 mg/kg/day) simvastatin for four weeks, infected intratracheally with S. pneumoniae serotype 4 strain TIGR4, and sacrificed at 24, 36, or 42 h post-infection for assessment of lung histology, cytokine production, vascular leakage and edema, bacterial burden and bloodstream dissemination. Some mice received ampicillin at 12-h intervals beginning at 48 h post-infection and were monitored for survival. Immunoblots of homogenized lung samples was used to assess ICAM-1 production. RESULTS: Mice receiving HSD had reduced lung consolidation characterized by less macrophage and neutrophil infiltration and a significant reduction in the chemokines MCP-1 (P = 0.03) and KC (P = 0.02) and ICAM-1 in the lungs compared to control mice. HSD mice also had significantly lower bacterial titers in the blood at 36 (P = 0.007) and 42 (P = 0.03) hours post-infection versus controls. LSD had a more modest effect against S. pneumoniae but also resulted in reduced bacterial titers in the lungs and blood of mice after 42 h and a reduced number of infiltrated neutrophils. Neither LSD nor HSD mice had reduced mortality in a pneumonia model where mice received ampicillin 48 h after challenge. CONCLUSIONS: Prolonged oral simvastatin therapy had a strong dose-dependent effect on protection against S. pneumoniae as evidenced by reduced neutrophil infiltration, maintenance of vascular integrity, and lowered chemokine production in the lungs of mice on HSD. Statin therapy also protected through reduced bacterial burden in the lungs. Despite these protective correlates, mortality in the simvastatin-receiving cohorts was equivalent to controls. Thus, oral simvastatin at physiologically relevant doses only modestly protects against pneumococcal pneumonia.

Does Hippocampal Volume in Patients with Posttraumatic Stress Disorder Vary by Trauma Type?

ABSTRACT: Posttraumatic stress disorder (PTSD) is a debilitating disorder that can develop after experiencing a traumatic event and is, in part, characterized by memory disturbances. Given its important role in learning and memory, the hippocampus has been studied extensively in PTSD using volumetric neuroimaging techniques. However, the results of these studies are mixed. The variability in findings across studies could arise from differences in samples with regard to trauma type, but this connection has not yet been formally assessed. To assess this question, we conducted (1) mixed-effects meta-analyses to replicate previous meta-analytic findings of significant differences in hippocampal volumes in PTSD groups versus two different types of control groups (trauma-exposed and -unexposed groups), and (2) mixed-effects subgroup and meta-regression analyses to determine whether trauma type moderated these hippocampal volume differences. Overall, the PTSD groups showed significantly smaller right hippocampal volumes than both control groups and significantly smaller left hippocampal volumes than trauma-unexposed control groups. Subgroup and meta-regression analyses revealed that trauma type did not moderate the effect seen between PTSD and trauma-exposed non-PTSD groups but did moderate the effect between the PTSD and trauma-unexposed control groups: studies that contained participants with PTSD related to combat trauma exhibited significantly smaller effect sizes for right hippocampal volumes compared to the interpersonal violence and "other" trauma-type groups with PTSD. These findings suggest that trauma type may moderate hippocampal volume in trauma-exposed individuals but not in those with PTSD.