Combat Experiences and their Relationship to Post-Traumatic Stress Disorder Symptom Clusters in UK Military Personnel Deployed to Afghanistan.

The association of post-traumatic stress disorder (PTSD) symptom clusters with combat and other operational experiences among United Kingdom Armed Forces (UK AF) personnel who deployed to Afghanistan in 2009 were examined. Previous studies suggest that the risk of developing PTSD rises as combat exposure levels increase. To date, no UK research has investigated how specific classes of combat and operational experiences relate to PTSD symptom clusters. The current study was a secondary analysis of data derived from a two-arm cluster, randomized-controlled trial of a postdeployment operational stress-reduction intervention in deployed UK AF personnel. 2510 UK AF personnel provided combat exposure data and completed the PTSD checklist (civilian version) immediately post-deployment while 1635 of the original cohort completed further followed-up measures four to six months later. A 14-item combat experience scale was explored using principle component analysis, which yielded three main categories of experience: (1) violent combat, (2) proximity to wounding or death and (3) encountering explosive devices. The association of combat experience classes to PTSD 5-factor "dysphoric arousal" model (re-experiencing, avoidance, numbing, dysphoric-arousal and anxious-arousal symptoms) was assessed. Greater exposure to violent combat was predictive of re-experiencing and numbing symptoms, while proximity to wounding or death experiences were predictive of re-experiencing and anxious-arousal symptoms. Explosive device exposure was predictive of anxious-arousal symptoms. The present study suggests that categories of combat experience differentially impact on PTSD symptom clusters and may have relevance for clinicians treating military personnel following deployment.

Adapting to Stress: Understanding the Neurobiology of Resilience.

There is significant variation in the way individuals react and respond to extreme stress and adversity. While some individuals develop psychiatric conditions such as posttraumatic stress disorder or major depressive disorder, others recover from stressful experiences without displaying significant symptoms of psychological ill-health, demonstrating stress-resilience. To understand why some individuals exhibit characteristics of a resilient profile, the interplay between neurochemical, genetic, and epigenetic processes over time needs to be explained. In this review, we examine the hormones, neuropeptides, neurotransmitters, and neural circuits associated with resilience and vulnerability to stress-related disorders. We debate how this increasing body of knowledge could also be useful in the creation of a stress-resilient profile. Additionally, identification of the underlying neurobiological components related to resilience may offer a contribution to improved approaches toward the prevention and treatment of stress-related disorders.

The eNAMPT/TLR4 inflammatory cascade drives the severity of intra-amniotic inflammation in pregnancy and predicts infant outcomes.

Introduction: Intra-amniotic inflammation (IAI) or chorioamnionitis is a common complication of pregnancy producing significant maternal morbidity/mortality, premature birth and neonatal risk of chronic lung diseases such as bronchopulmonary dysplasia (BPD). We examined eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a critical inflammatory DAMP and TLR4 ligand, as a potential therapeutic target to reduce IAI severity and improve adverse fetal/neonatal outcomes. Methods: Blood/tissue samples were examined in: 1) women with histologically-proven chorioamnionitis, 2) very low birth weight (VLBW) neonates, and 3) a preclinical murine pregnancy model of IAI. Groups of pregnant IAI-exposed mice and pups were treated with an eNAMPT-neutralizing mAb. Results: Human placentas from women with histologically-proven chorioamnionitis exhibited dramatic NAMPT expression compared to placentas without chorioamnionitis. Increased NAMPT expression in whole blood from VLBW neonates (day 5) significantly predicted BPD development. Compared to untreated LPS-challenged murine dams (gestational day 15), pups born to eNAMPT mAb-treated dams (gestational days 15/16) exhibited a > 3-fold improved survival, reduced neonate lung eNAMPT/cytokine levels, and reduced development and severity of BPD and pulmonary hypertension (PH) following postnatal exposure to 100% hyperoxia days 1-14. Genome-wide gene expression studies of maternal uterine and neonatal cardiac tissues corroborated eNAMPT mAb-induced reductions in inflammatory pathway genes. Discussion: The eNAMPT/TLR4 inflammatory pathway is a highly druggable contributor to IAI pathobiology during pregnancy with the eNAMPT-neutralizing mAb a novel therapeutic strategy to decrease premature delivery and improve short- and long-term neonatal outcomes. eNAMPT blood expression is a potential biomarker for early prediction of chronic lung disease among premature neonates.

Trim39 regulates neuronal apoptosis by acting as a SUMO-targeted E3 ubiquitin-ligase for the transcription factor NFATc3.

NFATc3 is the predominant member of the NFAT family of transcription factors in neurons, where it plays a pro-apoptotic role. Mechanisms controlling NFAT protein stability are poorly understood. Here we identify Trim39 as an E3 ubiquitin-ligase of NFATc3. Indeed, Trim39 binds and ubiquitinates NFATc3 in vitro and in cells where it reduces NFATc3 protein level and transcriptional activity. In contrast, silencing of endogenous Trim39 decreases NFATc3 ubiquitination and increases its activity, thereby resulting in enhanced neuronal apoptosis. We also show that Trim17 inhibits Trim39-mediated ubiquitination of NFATc3 by reducing both the E3 ubiquitin-ligase activity of Trim39 and the NFATc3/Trim39 interaction. Moreover, we identify Trim39 as a new SUMO-targeted E3 ubiquitin-ligase (STUbL). Indeed, mutation of SUMOylation sites in NFATc3 or SUMO-interacting motifs in Trim39 reduces NFATc3/Trim39 interaction and Trim39-induced ubiquitination of NFATc3. In addition, Trim39 preferentially ubiquitinates SUMOylated forms of NFATc3 in vitro. As a consequence, a SUMOylation-deficient mutant of NFATc3 exhibits increased stability and pro-apoptotic activity in neurons. Taken together, these data indicate that Trim39 modulates neuronal apoptosis by acting as a STUbL for NFATc3.

Predictors of COVID-19 vaccine hesitancy in Chad: A cross-sectional study.

Vaccination against the COVID-19 virus is currently the best option to combat the SARS-CoV-2 pandemic worldwide. However, in addition to logistical and economic barriers, hesitancy to be vaccinated threatens to jeopardize efforts to contain the disease. An increasing number of people in Africa are delaying or rejecting recommended vaccines. Since their launch, COVID-19 vaccines have frequently faced rejection worldwide. In this study, we interviewed 5,174 participants from Chad that were representative of the general population, on their perception of COVID-19 vaccines. The survey was conducted from April to May 2021, before the rollout of the COVID-19 vaccination. We found that 47.9% of respondents were willing to receive the COVID-19 vaccine, 29.8% were undecided and 22.3% would not accept the vaccine. We found that urban residents were much more likely to refuse the vaccine than rural residents. We also observed that distrust of COVID-19 vaccines and mistaken beliefs played a crucial role in the reluctance to be vaccinated. Hesitancy to vaccinate against COVID-19 was strongly associated with lack of knowledge, and acceptance of vaccination was primarily associated with fear of the disease. Finally, we identified population profiles among the undecided and the refractors, which will help in developing strategies to combat COVID-19 vaccine resistance.

Psychological distress amongst immigration detainees: a cross-sectional questionnaire study.

OBJECTIVES: To compare levels of depression, anxiety, and post traumatic stress disorder (PTSD) amongst immigration detainees with a comparison group of asylum seekers living within the community. DESIGN: A cross-sectional questionnaire study. METHODS: Sixty-seven detained asylum seekers, 30 detainees who had previously been imprisoned within the UK for criminal offences, and 49 asylum seekers living in the community completed the hospital anxiety and depression scale (HADS) and the impact of event scale-revised (IES-R). Demographic information was collected. RESULTS: High levels of anxiety, depression, and PTSD symptoms were reported by all three groups. Detained asylum seekers had higher scores than asylum seekers living within the community for depression, anxiety, and PTSD symptoms. There was an interaction between length of detention period and prior exposure to interpersonal trauma (IP trauma) on depression scores. CONCLUSIONS: Immigration detainees are highly vulnerable to psychological distress. A review of detention policies is recommended in light of this. Immigration detention may have an independent adverse effect on mental health. It is also possible that individuals with mental health problems may be more likely to be detained. Further research is required to investigate this.

The advective origin of an under-ice spring bloom in the Arctic Ocean using multiple observational platforms.

Under-ice blooms of phytoplankton in the Chukchi Sea have been observed, with strong implications for our understanding of the production regimes in the Arctic Ocean. Using a combination of satellite remote sensing of phytoplankton biomass, in situ observations under sea ice from an autonomous underwater vehicle (AUV), and in vivo photophysiology, we examined the composition, magnitude and origin of a bloom detected beneath the sea ice Northwest of Svalbard (Southern Yermak Plateau) in May 2010. In situ concentration of up to 20 mg chlorophyll a [Chl a] m-3, were dominated by the northern planktonic spring species of diatoms, Thalassiosira nordenskioeldii, T. antarctica var. borealis, Chaetoceros socialis species complex and Fragilariopsis oceanica. These species were also found south of the marginal ice zone (MIZ). Cells in the water column under the sea ice were typically high-light acclimated, with a mean light saturation index (E k ) of 138 µmol photons m-2 s-1 and a ratio between photoprotective carotenoids (PPC) and Chl a (w:w) of 0.2. Remotely sensed data of [Chl a] showed a 32,000 km2 bloom developing south of the MIZ. In effect, our data suggest that the observed under-ice bloom was in fact a bloom developed in open waters south of the ice edge, and that a combination of northward-flowing water masses and southward drifting sea ice effectively positioned the bloom under the sea ice. This have implications for our general understanding of under-ice blooms, suggesting that their origin and connection with open water may be different in different regions of the Arctic.

Posttraumatic growth is related to subjective well-being of aid workers exposed to cumulative trauma in Palestine.

The present study examined how stress reactions after traumatic events influence subjective well-being (SWB) via the indirect effect of posttraumatic growth (PTG) in two samples of Palestinian professional helpers from the Gaza Strip and West Bank ( n = 201). Using the General Health Questionnaire (GHQ-12) as a dependent measure of well-being, and PTGI-10, PANAS-20, WHO-5 BREF, and IES-13 questionnaires as independent variables, structural equation modelling (SEM) was used to examine whether: (a) cumulative trauma was negatively and directly related to subjective well-being; (b) levels of trauma were positively and directly related to posttraumatic growth; and (c) PTG was positively and directly related to subjective well-being. The findings suggest that posttraumatic growth contributes to mitigating and buffering (on the order of approximately 10%) the effect of trauma on subjective well-being. PTG seems to be a resource that can help aid workers deal with the consequences of stressful life events. Clinical implications and directions for supervision and training are discussed.

Local RNA target structure influences siRNA efficacy: a systematic global analysis.

The efficiency with which small interfering RNAs (siRNAs) down-regulate specific gene expression in living cells is variable and a number of sequence-governed, biochemical parameters of the siRNA duplex have been proposed for the design of an efficient siRNA. Some of these parameters have been clearly identified to influence the assembly of the RNA-induced silencing complex (RISC), or to favour the sequence preferences of the RISC endonuclease. For other parameters, it is difficult to ascertain whether the influence is a determinant of the siRNA per se, or a determinant of the target RNA, especially its local structural characteristics. In order to gain an insight into the effects of local target structure on the biological activity of siRNA, we have used large sets of siRNAs directed against local targets of the mRNAs of ICAM-1 and survivin. Target structures were classified as accessible or inaccessible using an original, iterative computational approach and by experimental RNase H mapping. The effectiveness of siRNA was characterized by measuring the IC50 values in cell culture and the maximal extent of target suppression. Mean IC50 values were tenfold lower for accessible local target sites, with respect to inaccessible ones. Mean maximal target suppression was improved. These data illustrate that local target structure does, indeed, influence the activity of siRNA. We suggest that local target screening can significantly improve the hit rate in the design of biologically active siRNAs.

Counterfactual thinking and posttraumatic stress reactions.

Preoccupation with alternative outcomes (counterfactual thinking) is a central component of the ruminations of trauma victims. The questions investigated were whether such thinking should be distinguished from general rumination and whether elements of counterfactual thinking might relate to the process of adjustment. A sample of assault victims was interviewed. They completed a battery of self-report scales and thought-listing procedures. Frequency of counterfactual thinking was closely associated with continuing levels of posttraumatic distress. However, high availability of counterfactuals (as indexed by verbal fluency) was related to potentially adaptive outcomes, such as the generation of behavioral plans. In addition, as expected, levels of different aspects of counterfactual thinking were moderated by metacognitive control strategies as a function of time since the trauma.

Cationic phosphoramidate alpha-oligonucleotides efficiently target single-stranded DNA and RNA and inhibit hepatitis C virus IRES-mediated translation.

A potential means to improve the efficacy of steric-blocking antisense oligonucleotides (ON) is to increase their affinity for a target RNA. The grafting of cationic amino groups to the backbone of the ON is one way to achieve this, as it reduces the electrostatic repulsion between the ON and its target. We have examined the duplex stabilising effects of introducing cationic phosphoramidate internucleoside linkages into ON with a non-natural alpha-anomeric configuration. Cationic alpha-ON bound with high affinity to single-stranded DNA and RNA targets. Duplex stabilisation was proportional to the number of cationic modifications, with fully cationic ON having particularly high thermal stability. The average stabilisation was greatly increased at low ionic strength. The duplex formed between cationic alpha-ON and their RNA targets were not substrates for RNase H. The penalty in T(m) inflicted by a single mismatch, however, was high; suggesting that they are well suited as sequence-specific, steric-blocking, antisense agents. Using a well-described target sequence in the internal ribosome entry site of the human hepatitis C virus, we have confirmed this potential in a cell-free translation assay as well as in a whole cell assay. Interestingly, no vectorisation was necessary for the cationic alpha-ON in cell culture.

Overseas nurses' experiences of equal opportunities in the NHS in England.

PURPOSE: To explore the experiences of overseas black and minority ethnic nurses in the National Health Service (NHS) in the south of England. METHODS: Semi-structured in-depth interviews were conducted with 12 overseas black and minority ethnic nurses. All interviews were taped, transcribed verbatim and analysed using thematic analysis. All transcripts were read and re-read to elicit general themes. FINDINGS: Qualitative data analysis was undertaken using Van Manen framework and this enabled a number of themes to be identified that were part of overseas black and minority ethnic nurses' experience, however, two main themes would be discussed in this study. Firstly, unequal opportunities in career advancement and secondly, unequal opportunities for skill development and training. Both themes affected overseas nurses chances of promotion in the NHS. RESEARCH LIMITATION/IMPLICATIONS: The study has identified a notably gap in the implementation of equal opportunity policies and suggests that a more transparent implementation of such policies is needed in the NHS in the UK where this study was conducted. Additionally, more research is needed to determine whether overseas nurses in other areas experience similar problems. PRACTICAL IMPLICATIONS: The findings of this study could encourage managers to re-examine their equal opportunity policies in the light of these findings. Although this study has explored overseas nurses experiences, the findings cannot be generalised to the wider population. ORIGINALITY VALUE: The differences experienced by overseas nurses in relation to career opportunities and skill development and training.

The regulated expression of c-IAP1 and c-IAP2 during the rat seminiferous epithelial cycle plays a role in the protection of germ cells from Fas-mediated apoptosis.

The inhibitor of apoptosis proteins, c-IAP1 and c-IAP2, are highly expressed in rat testis and potentially play a regulatory role in testicular apoptosis. To better understand their functions during spermatogenesis, we have analyzed their spatio-temporal distribution in rat testis, how their expression is controlled by the paracrine stem-cell factor (SCF) and how they affect Fas-mediated apoptosis. Both c-IAP1 and c-IAP2 showed cycles of transcriptional expression, throughout the seminiferous epithelial cycle. c-IAP1 protein showed a diffuse nuclear distribution in type B spermatogonia, preleptotene, leptotene, and zygotene spermatocytes. In pachytene spermatocytes, c-IAP1 colocalized with SUMO-1 in the XY-body. c-IAP2 protein was cytoplasmic in spermatocytes, from stage VI pachytene onwards, round spermatids, elongated spermatids and Leydig cells. Its expression was upregulated by SCF. Inhibition of IAP activity resulted in a greater sensitivity of germ cells to Fas-mediated apoptosis. These results suggest an important role for IAPs in the regulation of spermatogenic apoptosis.

Oligonucleotide-based strategies to inhibit human hepatitis C virus.

Hepatitis C virus (HCV) infection represents a worldwide problem, and current antiviral regimens are not satisfactory. The need to develop novel, specific, anti-HCV antiviral drugs is clear. Antisense oligonucleotides (AS-ON), ribozymes, and more recently, small interfering RNAs (siRNAs) have been widely used to control gene expression, and several clinical trials are in progress. The potential to use AS-ON as tools to control HCV infection, either by promoting an RNase H mediated cleavage of viral genomic RNA or by interfering with the assembly of a translation initiation complex on the internal ribosome entry site (IRES) is reviewed. Extensive knowledge of IRES structure and conservation among HCV genotypes have rendered the HCV IRES (and, in particular, its IIId loop) particularly attractive for antisense approaches. Encouraging data have been obtained with IRES-targeted RNase H-competent and incompetent ON analogs. We demonstrate here that very short steric blocking ONs can inhibit the formation of translation preinitiation complexes on the IRES and block IRES-mediated translation in a cell-free translation assay and in a transfected hepatoma cell line.

Survivin expression in rat testis is upregulated by stem-cell factor.

The inhibitor of apoptosis protein BIRC-5/survivin plays roles in both apoptosis and the regulation of chromosome-segregation/cytokinesis during mitosis. As the population dynamics of male germ cells are regulated by both proliferation (mitosis and meiosis) and apoptotic culling, we hypothesized that BIRC-5/survivin could be central to the regulation of spermatogenesis. We have analyzed BIRC-5/survivin expression throughout the seminiferous epithelial cycle of the rat. BIRC-5/survivin RNA and protein exhibit rhythms of expression throughout the seminiferous epithelial cycle. The highest levels of expression were found, by immunohistochemistry and in situ hybridization, to occur during the long first meiotic prophase of spermatocytes. Cytoplasmic abundance declined at metaphase and reappeared at anaphase. Some BIRC-5/survivin expression was also found to occur in interstitial Leydig cells. BIRC-5/survivin protein levels were up-regulated in vitro by the paracrine, Stem-Cell Factor, that is known to regulate both proliferation and apoptosis of germ cells and Leydig cells.

Cellular uptake and intracellular fate of antisense oligonucleotides.

Antisense oligonucleotides and short interfering RNAs are routinely used for gene function analysis and are being developed for clinical applications. The mechanism underlying internalization of free oligonucleotides into cells is poorly understood and inefficient in most cases. Antisense oligonucleotide delivery into ex vivo cells is routinely improved by the addition of cationic lipids. New chemical modifications and vectors allowing improved cellular delivery in vivo are being developed.

An analysis of information available to relatives in intensive care.

The Comprehensive Critical Care Review published by the Government in 2000 acknowledges that patients are part of family units and critical illness has an extended impact. It outlines information that should be provided to relatives and suggests recommendations be implemented within 3-5 years. The aim of this study was to gauge an overall view of provisions available across general Intensive Care Units in England for relatives, by conducting an analysis of information available and unit policies, and to see the extent that government guidelines have been adhered to. Two hundred and ten units were approached for copies of policy documents and leaflets. There was a 56% response rate. Results were collated and analysed for basic descriptive statistics using software package SPSS version 11.5. The Gunning's Fog Index was performed on 20% of leaflets to measure readability. All leaflets measured above the recommended level. Sixteen percent of units do not have a leaflet and therefore do not comply with the Department of Health recommendations. Huge variation exists nationally over the amount and quality of information that relatives have access to and receive. Only 9% of units had an official policy on how to deal with relatives. The implications of this are discussed.

Differential role of autophagy in CD4 T cells and macrophages during X4 and R5 HIV-1 infection.

BACKGROUND: HIV-1 can infect and replicate in both CD4 T cells and macrophages. In these cell types, HIV-1 entry is mediated by the binding of envelope glycoproteins (gp120 and gp41, Env) to the receptor CD4 and a coreceptor, principally CCR5 or CXCR4, depending on the viral strain (R5 or X4, respectively). Uninfected CD4 T cells undergo X4 Env-mediated autophagy, leading to their apoptosis, a mechanism now recognized as central to immunodeficiency. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate here that autophagy and cell death are also induced in the uninfected CD4 T cells by HIV-1 R5 Env, while autophagy is inhibited in productively X4 or R5-infected CD4 T cells. In contrast, uninfected macrophages, a preserved cell population during HIV-1 infection, do not undergo X4 or R5 Env-mediated autophagy. Autophagosomes, however, are present in macrophages exposed to infectious HIV-1 particles, independently of coreceptor use. Interestingly, we observed two populations of autophagic cells: one highly autophagic and the other weakly autophagic. Surprisingly, viruses could be detected in the weakly autophagic cells but not in the highly autophagic cells. In addition, we show that the triggering of autophagy in macrophages is necessary for viral replication but addition of Bafilomycin A1, which blocks the final stages of autophagy, strongly increases productive infection. CONCLUSIONS/SIGNIFICANCE: Taken together, our data suggest that autophagy plays a complex, but essential, role in HIV pathology by regulating both viral replication and the fate of the target cells.

OLIGONUCLEOTIDE PRIMERS FOR THE DETECTION OF BIOLUMINESCENT DINOFLAGELLATES REVEAL NOVEL LUCIFERASE SEQUENCES AND INFORMATION ON THE MOLECULAR EVOLUTION OF THIS GENE(1).

Bioluminescence is reported in members of 18 dinoflagellate genera. Species of dinoflagellates are known to have different bioluminescent signatures, making it difficult to assess the presence of particular species in the water column using optical tools, particularly when bioluminescent populations are in nonbloom conditions. A "universal" oligonucleotide primer set, along with species and genus-specific primers specific to the luciferase gene were developed for the detection of bioluminescent dinoflagellates. These primers amplified luciferase sequences from bioluminescent dinoflagellate cultures and from environmental samples containing bioluminescent dinoflagellate populations. Novel luciferase sequences were obtained for strains of Alexandrium cf. catenella (Whedon et Kof.) Balech and Alexandrium fundyense Balech, and also from a strain of Gonyaulax spinifera (Clap. et Whitting) Diesing, which produces bioluminescence undetectable to the naked eye. The phylogeny of partial luciferase sequences revealed five significant clades of the dinoflagellate luciferase gene, suggesting divergence among some species and providing clues on their molecular evolution. We propose that the primers developed in this study will allow further detection of low-light-emitting bioluminescent dinoflagellate species and will have applications as robust indicators of dinoflagellate bioluminescence in natural water samples.