Prior differences in previous trauma exposure primarily drive the observed racial/ethnic differences in posttrauma depression and anxiety following a recent trauma.

BACKGROUND: Racial and ethnic groups in the USA differ in the prevalence of posttraumatic stress disorder (PTSD). Recent research however has not observed consistent racial/ethnic differences in posttraumatic stress in the early aftermath of trauma, suggesting that such differences in chronic PTSD rates may be related to differences in recovery over time. METHODS: As part of the multisite, longitudinal AURORA study, we investigated racial/ethnic differences in PTSD and related outcomes within 3 months after trauma. Participants (n = 930) were recruited from emergency departments across the USA and provided periodic (2 weeks, 8 weeks, and 3 months after trauma) self-report assessments of PTSD, depression, dissociation, anxiety, and resilience. Linear models were completed to investigate racial/ethnic differences in posttraumatic dysfunction with subsequent follow-up models assessing potential effects of prior life stressors. RESULTS: Racial/ethnic groups did not differ in symptoms over time; however, Black participants showed reduced posttraumatic depression and anxiety symptoms overall compared to Hispanic participants and White participants. Racial/ethnic differences were not attenuated after accounting for differences in sociodemographic factors. However, racial/ethnic differences in depression and anxiety were no longer significant after accounting for greater prior trauma exposure and childhood emotional abuse in White participants. CONCLUSIONS: The present findings suggest prior differences in previous trauma exposure partially mediate the observed racial/ethnic differences in posttraumatic depression and anxiety symptoms following a recent trauma. Our findings further demonstrate that racial/ethnic groups show similar rates of symptom recovery over time. Future work utilizing longer time-scale data is needed to elucidate potential racial/ethnic differences in long-term symptom trajectories.

Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD.

Women are at increased risk of developing post-traumatic stress disorder (PTSD) following a traumatic event. Recent studies suggest that this may be mediated, in part, by circulating estrogen levels. This study evaluated the hypothesis that individual variation in response to estrogen levels contributes to fear regulation and PTSD risk in women. We evaluated DNA methylation from blood of female participants in the Grady Trauma Project and found that serum estradiol levels associates with DNA methylation across the genome. For genes expressed in blood, we examined the association between each CpG site and PTSD diagnosis using linear models that adjusted for cell proportions and age. After multiple test correction, PTSD associated with methylation of CpG sites in the HDAC4 gene, which encodes histone deacetylase 4, and is involved in long-term memory formation and behavior. DNA methylation of HDAC4 CpG sites were tagged by a nearby single-nucleotide polymorphism (rs7570903), which also associated with HDAC4 expression, fear-potentiated startle and resting-state functional connectivity of the amygdala in traumatized humans. Using auditory Pavlovian fear conditioning in a rodent model, we examined the regulation of Hdac4 in the amygdala of ovariectomized (OVX) female mice. Hdac4 messenger RNA levels were higher in the amygdala 2 h after tone-shock presentations, compared with OVX-homecage control females. In naturally cycling females, tone-shock presentations increased Hdac4 expression relative to homecage controls for metestrous (low estrogen) but not the proestrous (high estrogen) group. Together, these results support an estrogenic influence of HDAC4 regulation and expression that may contribute to PTSD in women.

Genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs.

Positive affect denotes a state of pleasurable engagement with the environment eliciting positive emotion such as contentment, enthusiasm or happiness. Positive affect is associated with favorable psychological, physical and economic outcomes in many longitudinal studies. With a heritability of ⩽64%, positive affect is substantially influenced by genetic factors; however, our understanding of genetic pathways underlying individual differences in positive affect is still limited. Here, through a genome-wide association study of positive affect in African-American participants, we identify a single-nucleotide polymorphism, rs322931, significantly associated with positive affect at P<5 × 10-8, and replicate this association in another cohort. Furthermore, we show that the minor allele of rs322931 predicts expression of microRNAs miR-181a and miR-181b in human brain and blood, greater nucleus accumbens reactivity to positive emotional stimuli and enhanced fear inhibition. Prior studies have suggested that miR-181a is part of the reward neurocircuitry. Taken together, we identify a novel genetic variant for further elucidation of genetic underpinning of positive affect that mediates positive emotionality potentially via the nucleus accumbens and miR-181.

The impact of environmental and behavioural cofactors on the development of cervical disorders in HR-HPV-infected women in Serbia.

Persistent infection with one or more highly oncogenic human papillomaviruses (HPVs) or high-risk-HPV (HR-HPV) is necessary but not a sufficient aetiological agent for the development of cervical neoplasia. A number of viral, host, environmental and behavioural factors are suggested to be associated with the progression of cervical disorder. This study aimed to evaluate the impact of environmental and behavioural cofactors on the development of cervical disorders in HR-HPV-infected women in Serbia. A total of 541 women have been tested by PCR for the presence of HPV on the cervix. HPV genotypes were determined by direct DNA sequencing. Women identified as HR-HPV-positive were further classified into four subgroups according to their cytological status. All relevant information about demographical and behavioural factors was obtained by interviewer-based questionnaire. A number of analytical and descriptive statistical methods were used for processing the data. The cofactors found to be of significance for the progression of cervical disease were older age, body mass index >25, lower educational level, long-term smoking, previous genital infections and cervical interventions. On the other hand, condom use was found to have a protective role. Information about these cofactors might be very important for the development of more efficient cancer prevention programmes and promotion of anti-HPV vaccination.

Herpesviruses viral loads and levels of proinflammatory cytokines in apical periodontitis.

OBJECTIVES: This study aimed to analyse Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) viral loads in symptomatic and asymptomatic apical periodontitis lesions, to determine levels of TNF-α, IL-1ß and IL-6 in these lesions and to investigate a possible correlation between herpesviral copy numbers and levels of proinflammatory cytokines. MATERIALS AND METHODS: A total of 100 samples of apical periodontitis were subjected to HCMV and EBV copy numbers analysis by nested polymerase chain reaction (PCR) and TaqMan real-time PCR. The concentrations of TNF-α, IL-1ß and IL-6 were determined by ELISA method. SPSS software was used for statistical analysis. RESULTS: There were no significant differences in the occurrence of EBV and HCMV between symptomatic and asymptomatic periapical lesions (p = .686, p = .879, respectively). Only 12 of 74 EBV (16.2%) and four of 54 HCMV (13.5%) nested PCR-positive samples showed increased viral copy numbers above the limit of 125 copies/ml. There was no significant correlation between the levels of analysed proinflammatory cytokines and herpesviral copy numbers in our sample. CONCLUSION: The observed low viral loads point to a relatively rare occurrence of active EBV and HCMV infection in our sample. Latent herpesviral infection does not enhance the production of investigated proinflammatory cytokines.

Levels of oxidative stress biomarkers and bone resorption regulators in apical periodontitis lesions infected by Epstein-Barr virus.

AIM: To investigate whether apical periodontitis lesions infected by Epstein-Barr virus (EBV) exhibit higher levels of oxidative stress biomarkers [8-hydroxydeoxyguanosine (8-OHdG) and oxidized glutathione (GSSG)] and bone resorption regulators [receptor activator of nuclear factor (NF-κB) ligand (RANKL) and osteoprotegerin (OPG)] compared to EBV-negative periapical lesions and healthy pulp tissues. METHODOLOGY: The experimental group consisted of 30 EBV-positive and 30 EBV-negative periapical lesions collected in conjunction with apicoectomy. The pulp tissues of 20 impacted third molars were used as healthy controls. The qualitative and quantitative analysis of EBV was performed by nested and real-time polymerase chain reaction (PCR), respectively. The levels of RANKL and OPG were analysed by reverse transcriptase real-time PCR. The levels of 8-OHdG and GSSG were determined by enzyme-linked immunosorbent assay (ELISA). Mann-Whitney U-test and Spearman's correlation were used for statistical analysis. RESULTS: The levels of RANKL, OPG, 8-OHdG and GSSG were significantly higher in apical periodontitis lesions compared to healthy pulp controls (P = 0.001, P < 0.001, P < 0.001 and P < 0.05, respectively). RANKL and OPG mRNA expression was significantly higher in EBV-positive compared to EBV-negative periapical lesions (P < 0.05). There was no significant correlation between EBV copy numbers and levels of RANKL, OPG, 8OH-dG and GSSG in apical periodontitis. CONCLUSION: Levels of bone resorption regulators and oxidative stress biomarkers were increased in apical periodontitis compared to healthy pulp tissues. EBV-positive periapical lesions exhibited higher levels of RANKL and OPG compared to EBV-negative periapical lesions. EBV may contribute to progression of apical periodontitis via enhanced production of bone resorption regulators.

Curative gastric resection for the elderly patients suffering from gastric cancer.

The improvement of the socio-economic conditions and the progress of medicine have extended the life span of the world's population and as a result, the number of patients with malignant neoplasms has increased. Gastric cancer is the third most common cancer (after lung and prostate) and the second leading cause of death caused by cancer (after lung bronchogenic cell carcinoma) in males; while it's the fifth cancer by frequency and the fourth cause of cancer death in females. It presents a peculiar geographical distribution with a lower incidence in Western Europe and North America, and higher incidence in the Far East, South America and Eastern Europe. Its incidence in Italy is 122 cases per 100000 inhabitants in males and 83 cases per 100000 inhabitants in females (in Italy). It occurs more frequently in old age, is quite rare in individuals under the age of 45. The aim of this work is to analyze the clinical and pathological characteristics of gastric carcinoma and the feasibility of curative surgery in patients over 75, identifying the factors affecting mortality, morbidity, survival and quality of life after surgery. These data have been compared with those of younger patients to assess the correct type of surgery.

Attention bias toward threat is associated with exaggerated fear expression and impaired extinction in PTSD.

BACKGROUND: Post-traumatic stress disorder (PTSD) develops in a minority of traumatized individuals. Attention biases to threat and abnormalities in fear learning and extinction are processes likely to play a critical role in the creation and/or maintenance of PTSD symptomatology. However, the relationship between these processes has not been established, particularly in highly traumatized populations; understanding their interaction can help inform neural network models and treatments for PTSD. METHOD: Attention biases were measured using a dot probe task modified for use with our population; task stimuli included photographs of angry facial expressions, which are emotionally salient threat signals. A fear-potentiated startle paradigm was employed to measure atypical physiological response during acquisition and extinction phases of fear learning. These measures were administered to a sample of 64 minority (largely African American), highly traumatized individuals with and without PTSD. RESULTS: Participants with PTSD demonstrated attention biases toward threat; this attentional style was associated with exaggerated startle response during fear learning and early and middle phases of extinction, even after accounting for the effects of trauma exposure. CONCLUSIONS: Our findings indicate that an attentional bias toward threat is associated with abnormalities in 'fear load' in PTSD, providing seminal evidence for an interaction between these two processes. Future research combining these behavioral and psychophysiological techniques with neuroimaging will be useful toward addressing how one process may modulate the other and understanding whether these phenomena are manifestations of dysfunction within a shared neural network. Ultimately, this may serve to inform PTSD treatments specifically designed to correct these atypical processes.

Comparison of electrolytic status (Na+, K+, Ca2+, Mg2+) in preterm and term deliveries.

PURPOSE OF INVESTIGATION: The objective of this study was to evaluate the electrolytic status of Na+, K+, Ca+, and Mg2+ in serum and red blood cells in idiopathic preterm and term deliveries. METHODS: The study included 105 pregnant women diagnosed with idiopathic premature delivery (study group) and 36 pregnant women with physiologically term delivery (controls). Samples of mother's blood were collected and analyzed for the level of electrolytes in the serum/plasma and red blood cells. RESULTS: Measured values of magnesium in red blood cells in the study group were far lower than physiological values, intracellular calcium levels were higher in the study group compared to levels measured in the controls. Sodium concentrations in cells were significantly lower in subjects with premature delivery. CONCLUSION: The magnesium intracellular level is the best representative value of magnesium in the body.

Uncertain in the face of change: Lack of contingency shift awareness during extinction is associated with higher fear-potentiated startle and PTSD symptoms in children.

Intolerance of uncertainty is a transdiagnostic risk factor for fear-related disorders and is associated with higher levels of anxiety in children and adolescents. It is unclear how uncertainty relates to development of psychopathology in children who have experienced trauma in early life. The present study used a fear-potentiated startle paradigm in children to examine associations between uncertainty (assessed as unawareness of a change in reinforcement during fear extinction) and symptoms of anxiety and posttraumatic stress disorder (PTSD), as well as startle potentiation to threat and safety cues. Results showed that unaware children had strong positive associations between trauma exposure and PTSD symptoms, whereas aware children did not. Uncertainty interacted with anxiety in that children who were both unaware and had higher anxiety displayed higher fear-potentiated startle to safety cues and did not show discrimination between threat and safety during fear conditioning. These results suggest that anxious children who persist in associating a threat cue with an aversive event during extinction, after repeated presentations of the no longer reinforced conditioned stimulus, may express psychophysiological phenotypes related to PTSD.

PACAP-PAC1R modulates fear extinction via the ventromedial hypothalamus.

Exposure to traumatic stress can lead to fear dysregulation, which has been associated with posttraumatic stress disorder (PTSD). Previous work showed that a polymorphism in the PACAP-PAC1R (pituitary adenylate cyclase-activating polypeptide) system is associated with PTSD risk in women, and PACAP (ADCYAP1)-PAC1R (ADCYAP1R1) are highly expressed in the hypothalamus. Here, we show that female mice subjected to acute stress immobilization (IMO) have fear extinction impairments related to Adcyap1 and Adcyap1r1 mRNA upregulation in the hypothalamus, PACAP-c-Fos downregulation in the Medial Amygdala (MeA), and PACAP-FosB/ΔFosB upregulation in the Ventromedial Hypothalamus dorsomedial part (VMHdm). DREADD-mediated inhibition of MeA neurons projecting to the VMHdm during IMO rescues both PACAP upregulation in VMHdm and the fear extinction impairment. We also found that women with the risk genotype of ADCYAP1R1 rs2267735 polymorphism have impaired fear extinction.

Community Violence Exposure is Associated with Hippocampus-Insula Resting State Functional Connectivity in Urban Youth.

Our previous work has linked childhood violence exposure in Black youth to functional changes in the hippocampus, a brain region sensitive to stress. However, different contexts of violence exposure (e.g., community, home, school) may have differential effects on circuitry. We investigated the unique effect of community violence in predicting resting-state functional connectivity (rsFC) in the hippocampus. Fifty-two (26F) violence-exposed Black youth ages 8-15 performed resting-state functional neuroimaging scans while looking at a fixation cross for seven minutes with eyes open. Seed-based analyses were conducted to examine the association between total violence exposure and rsFC of the hippocampus to the whole brain. Follow-up hierarchical regression analysis were performed to specifically investigate community violence. Violence exposure was associated with higher hippocampus rsFC with a core node of the Default Mode Network (i.e., posterior cingulate cortex) and lower hippocampal rsFC with a core node of the Salience Network (i.e., insula). Community violence uniquely associated with lower hippocampus-insula rsFC, after controlling for home and school violence, sex and age. Age-related decreases in hippocampus-insula rsFC were also present in youth with lower violence exposure, but not in youth with higher violence exposure. This is one of the first studies to investigate the unique impact of community violence, above home and school violence, on threat circuitry. Our data suggest functional alterations in the hippocampus in violence-exposed youth, and that violence in the community may be a more salient form of threat exposure compared to other forms of violence experienced by youth.

Presence of herpes simplex virus on the oral mucosa in patients undergoing chemotherapy.

BACKGROUND: The aim of this study was to confirm the presence of herpes simplex virus type 1 and 2 on the oral mucosa, in patients undergoing chemotherapy, by means of polymerase chain reaction (PCR). METHODS: The research was carried out on 40 patients receiving chemotherapy as treatment for different malignancies. The status of oral mucosa and viral presence were assessed in all patients at the initial examination (prior to chemotherapy), and at the control examination (two weeks after the initiation of the chemotherapeutic cycle). RESULTS: The presence of HSV-1 was detected in 28 patients (70%) prior to chemotherapy, of whom 7 (25%) manifested oral complications. The control examination showed the presence of HSV-1 in 35 patients (87.5%), of whom 23 (65.7%) presented oral mucosa changes. HSV-2 has not been detected in any of the patients.

Neuroendocrine Underpinnings of Increased Risk for Posttraumatic Stress Disorder in Women.

Women are particularly vulnerable to the effects of psychological trauma and the development of trauma-, stressor-, and anxiety-related mental illnesses such as posttraumatic stress disorder (PTSD). In the current chapter, we examine the female hormonal systems that interact with psychobiological stress response systems to elicit maladaptive behavior and mental disease states in traumatized female populations. In addition, we provide a contemporary translational example of a stress vulnerability genomic profile (coding for pituitary adenylate cyclase-activating polypeptide) that may underlie the specific susceptibilities observed in women. Translational scientific investigations such as those described herein may lead to the identification of risk and resilience factors for PTSD as well as enhanced clinical interventions for treating excessive fear and anxiety.

Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.

Reduced quantity and hydrogen-peroxide production of vaginal lactobacilli in HIV positive women.

It has been suggested that vaginal lactobacilli may influence heterosexual transmission of HIV infection. The aim of this study was to compare the vaginal flora on Gram's stained and isolation rate, quantity and H2O2 production of lactobacilli between HIV positive and HIV negative women. Although, the prevalence of abnormal vaginal flora was increased in HIV infected women, there was no significant difference in isolation rate of vaginal lactobacilli between the two groups (71.87 vs. 83.33%; P>0.05). However, the results of this study showed significantly reduced quantity of lactobacilli in HIV infected women (P<0.01). In particular, the prevalence of H2O2-producing lactobacilli was lower in HIV positive as compared to HIV negative women (80 vs. 56.52%), with borderline significance (P=0.057). Taken together, our findings showed altered vaginal microflora with reduced quantity and hydrogen-peroxide production of vaginal lactobacilli in HIV positive women, but further studies are needed to assess its actual significance and potential benefit from the use of probiotic therapy.

Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder.

Traumatic stress results in hypothalamic pituitary adrenal (HPA) axis abnormalities and an increased risk to both suicidal behaviors and post-traumatic stress disorder (PTSD). Previous work out of our laboratory identified SKA2 DNA methylation associations with suicidal behavior in the blood and brain of multiple cohorts. Interaction of SKA2 with stress predicted suicidal behavior with ~80% accuracy. SKA2 is hypothesized to reduce the ability to suppress cortisol following stress, which is of potentially high relevance in traumatized populations. Our objective was to investigate the interaction of SKA2 and trauma exposure on HPA axis function, suicide attempt and PTSD. SKA2 DNA methylation at Illumina HM450 probe cg13989295 was assessed for association with suicidal behavior and PTSD metrics in the context of Child Trauma Questionnaire (CTQ) scores in 421 blood and 61 saliva samples from the Grady Trauma Project (GTP) cohort. Dexamethasone suppression test (DST) data were evaluated for a subset of 209 GTP subjects. SKA2 methylation interacted with CTQ scores to predict lifetime suicide attempt in saliva and blood with areas under the receiver operator characteristic curve (AUCs) of 0.76 and 0.73 (95% confidence interval (CI): 0.6-0.92, P = 0.003, and CI: 0.65-0.78, P < 0.0001) and to mediate the suppression of cortisol following DST (ß = 0.5 ± 0.19, F = 1.51, degrees of freedom (df) = 12/167, P = 0.0096). Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.

Maturation of IgG avidity to individual rubella virus structural proteins.

BACKGROUND: the structural proteins of rubella virus, the capsid protein C and the envelope glycoproteins E1 and E2 were produced in lepidopteran insect cells using baculovirus expression vectors. The C-terminal ends of the corresponding proteins were fused to a polyhistidine tag for easy and gentle purification by metal ion affinity chromatography. OBJECTIVES: to investigate the maturation of natural and vaccinal IgG avidity against individual authentic and recombinant rubella virus (RV) structural proteins. STUDY DESIGN: the analysis was carried out using a modified immunoblotting technique where the purified baculovirus-expressed proteins were compared with authentic rubella virus proteins. Altogether, 47 well-characterised serum samples from both naturally infected patients and vaccines were studied. RESULTS: after natural RV infection, IgG antibodies specific for the E1 protein were predominant not only in terms of levels, but also in terms of rate and magnitude of avidity maturation. The avidity development of the IgG antibodies was much slower in vaccines than in patients after a natural RV infection. CONCLUSIONS: together, our results indicate that IgG avidity determination in conjunction with immunoblot analysis is useful in the diagnosis of a RV infection. The recombinant proteins showed similar reactivity patterns in the immunoblot analyses as compared with the authentic viral structural proteins, suggesting suitability for serodiagnostics.

Immunoblot analysis of natural and vaccine-induced IgG responses to rubella virus proteins expressed in insect cells.

BACKGROUND: The three structural proteins of rubella virus (RV), the capsid protein C and the envelope glycoproteins E1 and E2, were produced individually in soluble form in Sf9 insect cells using the baculovirus system. All proteins were equipped with a polyhistidine tag at their C-terminal ends to enable gentle purification by metal ion affinity chromatography. In addition, the E1 and E2 proteins were engineered to display the FLAG epitope tag at their N-terminal ends. STUDY DESIGN: The diagnostic potential of the recombinant purified proteins was evaluated by immunoblot and enzyme immuno assays (EIA) using a total of 57 well-characterised serum samples obtained at various time points after natural RV infection, congenital rubella syndrome (CRS), MMR vaccination or from controls with past RV immunity. In addition, acute and convalescent phase serum pools from a total of 20 patients were evaluated. Authentic RV proteins were used as a reference. RESULTS: The recombinant E1 and C proteins were predominant in eliciting the immune response in both postnatal and vaccinal RV infections, being much weaker in the vaccinal ones. The IgG response to the recombinant C protein was very strong after the first month post infection and decreased with time. The immune response against the recombinant E2 protein, however, was generally poor, but notably stronger after congenital infection. Together, the results showed that the individual recombinant protein antigens could be suitable for diagnosis of RV infection and for study of the immune response to rubella vaccination.