PIO Systematic Review Paper: Psychological Assessors and Coping Strategies for Injured Athletes during Recovery

Due to the large number of athletes participating in sports who sustain injuries there are common negative psychological responses presented such as the loss of athletic identity, low self-esteem, depression, anxiety, and fear1,4,13,15,18. According to the National Athletic Trainers’ Association (NATA) and the National Collegiate Athletic Association (NCAA), nearly one in three adolescents in the United States (31.9 %) will have an anxiety disorder18 and around 10% will have depression18,19. The objective of this paper is to determine if there are psychological assessors and coping strategies to best determine psychological preparedness and evaluate these negative psychological effects of athletic injury for return to sport in athletes. The systematic review included 21 articles about the negative psychological responses associated with athletic injury and ways to identify and cope with them. The articles were reviewed from a retrospective database search, narrowed down by reading the titles, then abstracts, and lastly the articles. Search criteria included English language publications between 1996 and 2016, with a subject population of adolescents and young adults presenting with an injury from athletics. After review of the literature, the CES-D, BDI, and POMS were validated and utilized the most along with HRQOL and stated to have high reliability and sensitivity3,8,10,14,18,19. In regards to coping, when athletes were satisfied with social support, they reported fewer symptoms of depression (p \u3c 0.0001) or anxiety (p \u3c 0.0001) at return to play compared with athletes who were dissatisfied with the social support20,21. Thus, it is recommended to use a mixed methods approach with multiple assessors, such as the ERAIQ and the POMS scale to accurately obtain patient-rated measures from an injured athlete4,14, as well as various coping strategies specific for the individual athlete, with social support emphasis throughout recovery1,11,13,17,20,21

Effect of the R1 Element on Expression of the US3 and US6 Immune Evasion Genes of Human Cytomegalovirus

AbstractHuman cytomegalovirus (HCMV) has several gene products that are important for escape from immune surveillance. These viral gene products downregulate the expression of HLA molecules on the cell surface. The viral US3 and US6 gene products are expressed at immediate-early and early times after infection, respectively. There are two regulatory regions between the US3 and the US6 transcription units. The first region is an NF-κB responsive enhancer that promotes the immediate-early expression of the US3 gene and is designated the R2 enhancer. Upstream of the R2 enhancer is a region designated the R1 element that in transient transfection assays behaves as a silencer by repressing the effect of the enhancer on downstream gene expression (A. R. Thrower et al., J. Virol. 1996, 70, 91; Y.-J. Chan et al., J. Virol. 1996, 70, 5312). We constructed recombinant viruses with wild-type or mutated R1 elements. The expression of the US3 gene at 6 h after infection and the US6 gene at 24 h was higher when the R1 element was present. The R1 element in the context of the viral genome is not a silencer of US3 or US6 gene expression. The R1 element has multiple effects on the US3 and US6 RNAs. It enhances the level of US3 and US6 mRNA; it determines the 3′-end cleavage and polyadenylation of US6 RNA, and it stabilizes read-through viral RNAs. The potential mechanisms of R1 enhancement of US3 and US6 gene expression are discussed

Cytomegalovirus is associated with depression and anxiety in older adults

Infection with cytomegalovirus (CMV), a β-herpesvirus, is common within the population. Although asymptomatic, infection is associated with increased serum concentrations of cytokines such as TNFα and IL-6, which are also related to mood and wellbeing. The present study examined whether infection with CMV was associated with mood in a community-based sample of olderadults. Blood samples and scores on the General Health Questionnaire were available for 137 participants. Serum was analysed for the presence of CMV-specific IgG and the antibody titre was used as an indirect measure of viral load. The majority of the participants (66%) were CMV-seropositive and seropositive status was not associated with psychological morbidity. However, within the CMV-positive group, individuals with higher CMV-specific antibody titres were more likely to be depressed, anxious, and suffer more overall psychological morbidity. This association could be mediated by the impact of affect-moderating cytokines secreted through the CMV-specific immune response.\ud \u

The Human Cytomegalovirus Major Immediate-Early Proteins as Antagonists of Intrinsic and Innate Antiviral Host Responses

The major immediate-early (IE) gene of human cytomegalovirus (CMV) is believed to have a decisive role in acute infection and its activity is an important indicator of viral reactivation from latency. Although a variety of gene products are expressed from this region, the 72-kDa IE1 and the 86-kDa IE2 nuclear phosphoproteins are the most abundant and important. Both proteins have long been recognized as promiscuous transcriptional regulators. More recently, a critical role of the IE1 and IE2 proteins in counteracting non-adaptive host cell defense mechanisms has been revealed. In this review we will briefly summarize the available literature on IE1- and IE2-dependent mechanisms contributing to CMV evasion from intrinsic and innate immune responses

Presentation of CMV immediate-early antigen to cytolytic T lymphocytes is selectively prevented by viral genes expressed in the early phase

The regulation of antigen processing and presentation to MHC class I-restricted cytolytic T lymphocytes was studied in cells infected with murine cytomegalovirus. Recognition by cytolytic T lymphocytes of the phosphoprotein pp89, the immunodominant viral antigen expressed in the immediate-early phase of infection, was selectively prevented during the subsequent expression of viral early genes. The surface expression of MHC class I glycoproteins and their capacity to present externally added pp89-derived antigenic peptides were not affected. Because recognition of several other antigens occurred during the early phase, a general failure in processing and presentation was excluded. Since neither rate of synthesis, amount, stability, nor nuclear transport of pp89 was modified, the failure in recognition indicates a selective interference with pp89 antigen processing and presentation

Significance of herpesvirus immediate early gene expression in cellular immunity to cytomegalovirus infection

Interstitial pneumonia linked with reactivation of latent human cytomegalovirus due to iatrogenic immunosuppression can be a serious complication of bone marrow transplantation therapy of aplastic anaemia and acute leukaemia1. Cellular immunity plays a critical role in the immune surveillance of inapparent cytomegalovirus infections in man and the mouse1−7. The molecular basis of latency, however, and the interaction between latently or recurrently infected cells and the immune system of the host are poorfy understood. We have detected a so far unknown antigen in the mouse model. This antigen is found in infected cells in association with the expression of the herpesvirus 'immediate early' genes and is recognized by cytolytic T lymphocytes (CTL)8. We now demonstrate that an unexpectedly high proportion of the CTL precursors generated in vivo during acute murine cytomegalovirus infection are specific for cells that selectively synthesize immediate early proteins, indicating an immunodominant role of viral non-structural proteins

The Human Cytomegalovirus UL76 Gene Regulates the Level of Expression of the UL77 Gene

Human cytomegalovirus (HCMV) can be reactivated under immunosuppressive conditions causing several fatal pneumonitis, hepatitis, retinitis, and gastrointestinal diseases. HCMV also causes deafness and mental retardation in neonates when primary infection has occurred during pregnancy. In the genome of HCMV at least 194 known open reading frames (ORFs) have been predicted, and approximately one-quarter, or 41 ORFs, are required for viral replication in cell culture. In contrast, the majority of the predicted ORFs are nonessential for viral replication in cell culture. However, it is also possible that these ORFs are required for the efficient viral replication in the host. The UL77 gene of HCMV is essential for viral replication and has a role in viral DNA packaging. The function of the upstream UL76 gene in the HCMV-infected cells is not understood. UL76 and UL77 are cistons on the same viral mRNA and a conventional 5' mRNA for UL77 has not been detected. The vast majority of eukaryotic mRNAs are monocistronic, i.e., they encode only a single protein.To determine whether the UL76 ORF affects UL77 gene expression, we mutated UL76 by ORF frame-shifts, stop codons or deletion of the viral gene. The effect on UL77 protein expression was determined by either transfection of expression plasmids or infection with recombinant viruses. Mutation of UL76 ORF significantly increased the level of UL77 protein expression. However, deletion of UL76 upstream of the UL77 ORF had only marginal effects on viral growth.While UL76 is not essential for viral replication, the UL76 ORF is involved in regulation of the level of UL77 protein expression in a manner dependent on the translation re-initiation. UL76 may fine-tune the UL77 expression for the efficient viral replication in the HCMV- infected cells

Modular cell-based platform for high throughput identification of compounds that inhibit a viral interferon antagonist of choice

The work was supported by the Medical Research Council, U.K. (University of St Andrews Doctoral Training Grant to AV and CSA), Deutsche Forschungsgemeinschaft (PA 815/2-1) to CP, Tenovus Scotland (T15/38) to MN and Wellcome Trust to CP, MN (ISSF) and RER (101788/Z/13/Z)Viral interferon (IFN) antagonists are a diverse class of viral proteins that counteract the host IFN response, which is important for controlling viral infections. Viral IFN antagonists are often multifunctional proteins that perform vital roles in virus replication beyond IFN antagonism. The critical importance of viral IFN antagonists is highlighted by the fact that almost all viruses encode one of these proteins. Inhibition of viral IFN antagonists has the potential to exert pleiotropic antiviral effects and thus this important protein class represents a diverse plethora of novel therapeutic targets. To exploit this, we have successfully developed and executed a novel modular cell-based platform that facilitates the safe and rapid screening for inhibitors of a viral IFN antagonist of choice. The platform is based on two reporter cell-lines that provide a simple method to detect activation of IFN induction or signaling via an eGFP gene placed under the control of the IFNβ or an ISRE-containing promoter, respectively. Expression of a target IFN antagonist in the appropriate reporter cell-line will block the IFN response and hence eGFP expression. We hypothesized that addition of a compound that inhibits IFN antagonist function will release the block imposed on the IFN response and hence restore eGFP expression, providing a measurable parameter for high throughput screening (HTS). We demonstrate assay proof-of-concept by (i) exploiting hepatitis C virus (HCV) protease inhibitors to inhibit NS3-4A's capacity to block IFN induction and (ii) successfully executing two HTS targeting viral IFN antagonists that block IFN signaling; NS2 and IE1 from human respiratory syncytial virus (RSV) and cytomegalovirus (CMV) respectively, two clinically important viruses for which vaccine development has thus far been unsuccessful and new antivirals are required. Both screens performed robustly and Z′ Factor scores of >0.6 were achieved. We identified (i) four hit compounds that specifically inhibit RSV NS2's ability to block IFN signaling by mediating STAT2 degradation and exhibit modest antiviral activity and (ii) two hit compounds that interfere with IE1 transcription and significantly impair CMV replication. Overall, we demonstrate assay proof-of-concept as we target viral IFN antagonists from unrelated viruses and demonstrate its suitability for HTS.Publisher PDFPeer reviewe

Gene silencing induced by oxidative DNA base damage: association with local decrease of histone H4 acetylation in the promoter region

Oxidized DNA bases, particularly 7,8-dihydro-8-oxoguanine (8-oxoG), are endogenously generated in cells, being a cause of carcinogenic mutations and possibly interfering with gene expression. We found that expression of an oxidatively damaged plasmid DNA is impaired after delivery into human host cells not only due to decreased retention in the transfected cells, but also due to selective silencing of the damaged reporter gene. To test whether the gene silencing was associated with a specific change of the chromatin structure, we determined the levels of histone modifications related to transcriptional activation (acetylated histones H3 and H4) or repression (methylated K9 and K27 of the histone H3, and histone H1) in the promoter region and in the downstream transcribed DNA. Acetylation of histone H4 was found to be specifically decreased by 25% in the proximal promoter region of the damaged gene, while minor quantitative changes in other tested chromatin components could not be proven as significant. Treatment with an inhibitor of histone deacetylases, trichostatin A, partially restored expression of the damaged DNA, suggesting a causal connection between the changes of histone acetylation and persistent gene repression. Based on these findings, we propose that silencing of the oxidatively damaged DNA may occur in a chromatin-mediated mechanism

Human cytomegalovirus infection of langerhans-type dendritic cells does not require the presence of the gH/gL/UL128-131A complex and is blocked after nuclear deposition of viral genomes in immature cells

Human cytomegalovirus (CMV) enters its host via the oral and genital mucosae. Langerhans-type dendritic cells (LC) are the most abundant innate immune cells at these sites, where they constitute a first line of defense against a variety of pathogens. We previously showed that immature LC (iLC) are remarkably resistant to CMV infection, while mature LC (mLC) are more permissive, particularly when exposed to clinical-strain-like strains of CMV, which display a pentameric complex consisting of the viral glycoproteins gH, gL, UL128, UL130, and UL131A on their envelope. This complex was recently shown to be required for the infection of immature monocyte-derived dendritic cells. We thus sought to establish if the presence of this complex is also necessary for virion penetration of LC and if defects in entry might be the source of iLC resistance to CMV. Here we report that the efficiency of LC infection is reduced, but not completely abolished, in the absence of the pentameric complex. While virion penetration and nuclear deposition of viral genomes are not impaired in iLC, the transcription of the viral immediate early genes UL122 and UL123 and of the delayed early gene UL50 is substantially lower than that in mLC. Together, these data show that the UL128, UL130, and UL131A proteins are dispensable for CMV entry into LC and that progression of the viral cycle in iLC is restricted at the step of viral gene expression