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.

The Relations Among Childhood Maltreatment and Later Intimate Partner Violence Victimization With and Without a Weapon in a Sample of Pregnant Black Individuals.

Black pregnant and postpartum individuals are at risk for intimate partner violence (IPV), and those with a history of childhood maltreatment and IPV are even more likely to be re-victimized during pregnancy. However, it is unknown if specific types of child maltreatment predict later IPV with and without a weapon better than others. The current study sought to (i) document the prevalence of childhood maltreatment and IPV and (ii) examine the relations among types of childhood maltreatment and later IPV with and without a weapon within a sample of Black individuals seeking prenatal care at a large public hospital in the southeastern United States. Participants (n = 186; mean age = 27.2 years, SD = 5.3) completed measures assessing childhood maltreatment and IPV with and without a weapon. Approximately 68.5% of participants (n = 124) endorsed experiencing childhood maltreatment, while 42.6% (n = 78) endorsed experiencing IPV. The bivariate relations among five childhood maltreatment types (i.e., sexual, physical, and emotional abuse, physical and emotional neglect) and IPV with and without a weapon were assessed. All childhood maltreatment subtype scores-except childhood physical neglect-were significantly higher among participants who reported a history of IPV with or without a weapon compared to participants who denied a history of IPV with or without a weapon. Logistic regression models revealed childhood sexual abuse emerged as the only significant predictor of experiencing IPV with a weapon (B = 0.10, p = .003) and IPV without a weapon (B = 0.11, p = .001). For every point increase in childhood sexual abuse subtype score, the odds of experiencing IPV with and without a weapon increased by 10% (OR = 1.10, 95%CI [1.04, 1.18]) and 12% (OR = 1.12, [1.05, 1.20]), respectively. Findings suggest that screening for childhood sexual abuse may provide a critical opportunity for maternity care providers to identify individuals at increased risk for IPV victimization with and without a weapon.

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.

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).

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.

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.

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.

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.

Exaggerated amygdala activation to ambiguous facial expressions is a familial vulnerability factor for posttraumatic stress disorder.

OBJECTIVE: Previous research has reported hyperresponsivity in the amygdala and hyporesponsivity in ventral portions of the medial prefrontal cortex to threat-related stimuli in posttraumatic stress disorder (PTSD). Whether such findings generalize to more ambiguous stimuli and whether such brain activation abnormalities reflect familial vulnerabilities, trauma-exposure, or acquired characteristics of PTSD remain unclear. In this study, we measured brain responses to emotionally ambiguous stimuli (i.e., surprised facial expressions) in identical twin pairs discordant for trauma exposure to elucidate the origin of brain activation abnormalities. METHODS: Participants with PTSD (n = 12) and their trauma-unexposed identical cotwins (n = 12), as well as trauma-exposed participants without PTSD (n = 15) and their trauma-unexposed identical cotwins (n = 15), passively viewed surprised and neutral facial expressions during functional magnetic resonance imaging (fMRI). Afterward, participants labeled and rated each facial expression on valence and arousal. RESULTS: Amygdala activation to Surprised and Neutral facial expressions (versus Fixation) was greater in the participants with PTSD and their trauma-unexposed identical cotwins without PTSD, compared to the control twin pairs. In contrast, medial frontal gyrus (MFG) activation to Surprised facial expressions (versus Fixation) was diminished in the PTSD group relative to the other three groups. CONCLUSIONS: Amygdala hyperresponsivity to emotionally ambiguous facial expressions may be a familial vulnerability factor that increases the likelihood of developing PTSD after experiencing a traumatic event. In contrast, MFG hyporesponsivity may be an acquired characteristic of the disorder.

Right inferior frontal gyrus and ventromedial prefrontal activation during response inhibition is implicated in the development of PTSD symptoms.

Background: Inhibition is a critical executive control process and an established neurobiological phenotype of PTSD, yet to our knowledge, no prospective studies have examined this using a contextual cue task that enables measurement of behavioural response and neural activation patterns across proactive and reactive inhibition. Objective: The current longitudinal study utilised functional magnetic resonance imaging (fMRI) to examine whether deficits in proactive and reactive inhibition predicted PTSD symptoms six months after trauma. Method: Twenty-three (65% males) medical patients receiving emergency medical care from a level 1 trauma centre were enrolled in the study and invited for an MRI scan 1-2-months post-trauma. PTSD symptoms were measured using self-report at scan and 6-months post-trauma. A stop-signal anticipation task (SSAT) during an fMRI scan was used to test whether impaired behavioural proactive and reactive inhibition, and reduced activation in right inferior frontal gyrus (rIFG), ventromedial prefrontal cortex (vmPFC), and bilateral hippocampus, were related to PTSD symptoms. We predicted that lower activation levels of vmPFC and rIFG during reactive inhibition and lower activation of hippocampus and rIFG during proactive inhibition would relate to higher 6-month PTSD symptoms. Results: No significant associations were found between behavioural measures and 6-month PTSD. Separate linear regression analyses showed that reduced rIFG activation (F1,21 = 9.97, R2 = .32, p = .005) and reduced vmPFC activation (F1,21 = 5.19, R2 = .20, p = .03) significantly predicted greater 6-month PTSD symptoms; this result held for rIFG activation controlling for demographic variables and baseline PTSD symptoms (ß = -.45, p = .04) and Bonferroni correction. Conclusion: Our findings suggest that impaired rIFG and, to a lesser extent, vmPFC activation during response inhibition may predict the development of PTSD symptoms following acute trauma exposure. Given the small sample size, future replication studies are needed. HIGHLIGHTS: Impaired inhibition may be an important risk factor for the development of PTSD following trauma, with less right inferior frontal gyrus and ventromedial prefrontal cortex activation during response inhibition predicting PTSD development.

Antecedentes: La inhibición es un proceso de control ejecutivo crítico, y un fenotipo neurobiológico establecido del TEPT, sin embargo, en nuestro conocimiento no hay estudios prospectivos que hayan examinado esto usando una tarea con claves contextuales que permita medir la respuesta conductual y los patrones de activación neuronal en la inhibición proactiva y reactiva.Objetivo: El siguiente estudio es de diseño longitudinal y utilizó resonancia magnética funcional (fMRI por sus siglas en inglés) para examinar si los déficit en inhibición proactiva y reactiva predijeron los síntomas de TEPT 6 meses después del trauma.Método: 23 pacientes (65% hombres) que recibieron cuidado médico de emergencia en un centro de trauma nivel 1 se enrolaron en el estudio y se les invitó a una RNM (resonancia nuclear magnética) 1­2 meses después del trauma. Los síntomas de TEPT se midieron usando auto-reporte al momento de la exploración y 6 meses después del trauma. Se uso una tarea de anticipación de señal de parada (SSAT por sus siglas en inglés) durante la RNM funcional para evaluar si la alteración en la inhibición proactiva y reactiva, y la reducción de la activación en el giro frontal inferior derecho (rIFG por sus siglas en inglés), la corteza prefrontal ventromedial (vmPFC por sus siglas en inglés), y el hipocampo bilateral, estuvieron relacionadas a los síntomas de TEPT. Predijimos que niveles bajos de activación de vmPFC y rIFG durante la inhibición proactiva se relacionaría con mayores síntomas de TEPT a los 6 meses.Resultados: No se encontraron asociaciones significativas entre medidas conductuales y TEPT a los 6 meses. Los análisis de regresión lineal separados mostraron que una activación reducida de rIFG (F1,21 = 9.97, R2 = .32, p = .005) y una activación reducida de vmPFC (F1,21 = 5.19, R2 = .20, p = .03) predijeron significativamente mayores síntomas de TEPT a los 6 meses; este resultado fue corroborado para la activación de rIFG controlando para variables demográficas y síntomas basales de TEPT (ß = −.45, p = .04) y para la corrección de Bonferroni.Conclusión: Nuestros hallazgos sugieren que una rIFG deficiente y, en menor grado, la activación del vmPFC durante la inhibición de la respuesta pueden predecir el desarrollo de síntomas de TEPT tras la exposición a un trauma agudo. Dado lo pequeño de la muestra, se requieren futuros estudios de replicación.

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.

Targeting the anterior cingulate with bipolar and high-definition transcranial direct current stimulation.

Research on the feasibility of using transcranial direct current stimulation to modulate the function of the anterior cingulate cortex is limited in part due to its anatomical depth. However, high-definition transcranial direct current stimulation may be better able to reach the anterior cingulate cortex and modulate its function and behavioral outputs. The purpose of this study was to assess the feasibility of using high-definition transcranial direct current stimulation, as compared to traditional bipolar transcranial direct current stimulation, to modulate behavioral measures of anterior cingulate cortex function. In a mixed design, 36 participants received either high-definition transcranial direct current stimulation or bipolar transcranial direct current stimulation, and experienced anodal, cathodal, and sham stimulation over the course of three visits. Two behavioral tasks were used to assess anterior cingulate cortex function before and after stimulation: the multi-source interference task and an emotional facial expression interference task. High-definition transcranial direct current stimulation and bipolar transcranial direct current stimulation groups did not differ in their performance (as measured via response times and error rates) on either task. High-definition transcranial direct current stimulation and bipolar transcranial direct current stimulation were similarly ineffective in modulating behavior related to the anterior cingulate cortex. Future research should explore other transcranial direct current stimulation montages including extracephalic montages (e.g. shoulder, neck) for targeted stimulation of the anterior cingulate cortex.

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.

Cingulate subregions in posttraumatic stress disorder, chronic stress, and treatment.

Decades of research have revealed that the cingulate cortex is important in posttraumatic stress disorder (PTSD). Initially inspired by basic rodent research examining the mechanisms of fear learning, researchers have attempted to determine the respective roles of the anterior cingulate cortex (ACC), anterior midcingulate cortex (aMCC), and posterior cingulate cortex (PCC) in PTSD. Various neuroimaging techniques have shown the ACC is both functionally hypoactive and structurally diminished in PTSD, while the aMCC is functionally hyperactive and structurally diminished. Relatedly, chronic stress has been shown to be a significant vulnerability factor in the development of PTSD after a traumatic event, inspiring research into the effect of chronic stress on brain activation and structure. Similar to patterns in PTSD, perceived work-related stress, outgroup membership, and lower socioeconomic status appear to negatively affect cingulate function and morphology. While great strides have been made to understand better the ACC, aMCC, and PCC in both PTSD and chronic stress, additional studies are needed to determine the origin of these cingulate abnormalities and whether they can be used as biomarkers in assessing and predicting treatment response in PTSD.

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.

Transcriptional organization of pneumococcal psrP-secY2A2 and impact of GtfA and GtfB deletion on PsrP-associated virulence properties.

Pneumococcal serine-rich repeat protein (PsrP) is a glycoprotein that mediates Streptococcus pneumoniae attachment to lung cells and promotes biofilm formation. Herein, we investigated the transcriptional organization of psrP-secY2A2, the 37-kbp pathogenicity island encoding PsrP and its accessory genes. PCR amplification of cDNA and RNA-seq analysis found psrP-secY2A2 to be minimally composed of three operons: psrP-glyA, glyB, and glyC-asp5. Transcription of all three operons was greatest during biofilm growth and immunoblot analyses confirmed increased PsrP production by biofilm pneumococci. Using gas chromatography-mass spectrometry we identified monomeric N-acetylglucosamine as the primary glycoconjugate present on a recombinant intracellular version of PsrP, i.e. PsrP1-734. This finding was validated by immunoblot using lectins with known carbohydrate specificities. We subsequently deleted gtfA and gtfB, the GTFs thought to be responsible for addition of O-linked N-acetylglucosamine, and tested for PsrP and its associated virulence properties. These deletions negatively affected our ability to detect PsrP1-734 in bacterial whole cell lysates. Moreover, S. pneumoniae mutants lacking these genes pheno-copied the psrP mutant and were attenuated for: biofilm formation, adhesion to lung epithelial cells, and pneumonia in mice. Our studies identify the transcriptional organization of psrP-secY2A2 and show the indispensable role of GtfA and GtfB on PsrP-mediated pneumococcal virulence.

Both nicotine reward and withdrawal are enhanced in a rodent model of diabetes.

RATIONALE: It is presently unclear whether diabetic rats experience greater rewarding effects of nicotine and/or negative affective states produced by nicotine withdrawal. OBJECTIVE: The present study utilized a rodent model of diabetes to examine the rewarding effects of nicotine and negative affective states and physical signs produced by withdrawal. METHODS: Separate groups of rats received systemic administration of either vehicle or streptozotocin (STZ), which destroys insulin-producing beta cells in the pancreas and elevates glucose levels. Place conditioning procedures were utilized to compare the rewarding effects of nicotine (conditioned place preference; CPP) and negative affective states produced by withdrawal (conditioned place aversion; CPA) in vehicle- and STZ-treated rats. CPA and physical signs of withdrawal were compared after administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal in nicotine-dependent rats. A subsequent study utilized elevated plus maze (EPM) procedures to compare anxiety-like behavior produced by nicotine withdrawal in vehicle- and STZ-treated rats. RESULTS: STZ-treated rats displayed greater rewarding effects of nicotine and a larger magnitude of aversive effects and physical signs produced by withdrawal as compared to vehicle-treated controls. STZ-treated rats also displayed higher levels of anxiety-like behavior on the EPM during nicotine withdrawal as compared to controls. CONCLUSION: The finding that both nicotine reward and withdrawal are enhanced in a rodent model of diabetes implies that the strong behavioral effects of nicotine promote tobacco use in persons with metabolic disorders, such as diabetes.