Cytomegalovirus induces abnormal chondrogenesis and osteogenesis during embryonic mandibular development

<p>Abstract</p> <p>Background</p> <p>Human clinical studies and mouse models clearly demonstrate that cytomegalovirus (CMV) disrupts normal organ and tissue development. Although CMV is one of the most common causes of major birth defects in humans, little is presently known about the mechanism(s) underlying CMV-induced congenital malformations. Our prior studies have demonstrated that CMV infection of first branchial arch derivatives (salivary glands and teeth) induced severely abnormal phenotypes and that CMV has a particular tropism for neural crest-derived mesenchyme (NCM). Since early embryos are barely susceptible to CMV infection, and the extant evidence suggests that the differentiation program needs to be well underway for embryonic tissues to be susceptible to viral infection and viral-induced pathology, the aim of this study was to determine if first branchial arch NCM cells are susceptible to mCMV infection prior to differentiation of NCM derivatives.</p> <p>Results</p> <p>E11 mouse mandibular processes (MANs) were infected with mouse CMV (mCMV) for up to 16 days <it>in vitr</it>o. mCMV infection of undifferentiated embryonic mouse MANs induced micrognathia consequent to decreased Meckel's cartilage chondrogenesis and mandibular osteogenesis. Specifically, mCMV infection resulted in aberrant stromal cellularity, a smaller, misshapen Meckel's cartilage, and mandibular bone and condylar dysmorphogenesis. Analysis of viral distribution indicates that mCMV primarily infects NCM cells and derivatives. Initial localization studies indicate that mCMV infection changed the cell-specific expression of FN, NF-κB2, RelA, RelB, and Shh and Smad7 proteins.</p> <p>Conclusion</p> <p>Our results indicate that mCMV dysregulation of key signaling pathways in primarily NCM cells and their derivatives severely disrupts mandibular morphogenesis and skeletogenesis. The pathogenesis appears to be centered around the canonical and noncanonical NF-κB pathways, and there is unusual juxtaposition of abnormal stromal cells and surrounding matrix. Moreover, since it is critically important that signaling molecules are expressed in appropriate cell populations during development, the aberrant localization of components of relevant signaling pathways may reveal the pathogenic mechanism underlying mandibular malformations.</p

Epstein-Barr Virus-Encoded LMP2A Induces an Epithelial–Mesenchymal Transition and Increases the Number of Side Population Stem-like Cancer Cells in Nasopharyngeal Carcinoma

It has been recently reported that a side population of cells in nasopharyngeal carcinoma (NPC) displayed characteristics of stem-like cancer cells. However, the molecular mechanisms underlying the modulation of such stem-like cell populations in NPC remain unclear. Epstein-Barr virus was the first identified human tumor virus to be associated with various malignancies, most notably NPC. LMP2A, the Epstein-Barr virus encoded latent protein, has been reported to play roles in oncogenic processes. We report by immunostaining in our current study that LMP2A is overexpressed in 57.6% of the nasopharyngeal carcinoma tumors sampled and is mainly localized at the tumor invasive front. We found also in NPC cells that the exogenous expression of LMP2A greatly increases their invasive/migratory ability, induces epithelial–mesenchymal transition (EMT)-like cellular marker alterations, and stimulates stem cell side populations and the expression of stem cell markers. In addition, LMP2A enhances the transforming ability of cancer cells in both colony formation and soft agar assays, as well as the self-renewal ability of stem-like cancer cells in a spherical culture assay. Additionally, LMP2A increases the number of cancer initiating cells in a xenograft tumor formation assay. More importantly, the endogenous expression of LMP2A positively correlates with the expression of ABCG2 in NPC samples. Finally, we demonstrate that Akt inhibitor (V) greatly decreases the size of the stem cell side populations in LMP2A-expressing cells. Taken together, our data indicate that LMP2A induces EMT and stem-like cell self-renewal in NPC, suggesting a novel mechanism by which Epstein-Barr virus induces the initiation, metastasis and recurrence of NPC

Affected other interventions: a systematic review and meta-analysis across addictions

BACKGROUND AND AIMS: Individuals impacted by someone else's alcohol, illicit drug, gambling and gaming problems (affected others) experience extensive harms. To our knowledge, this is the first systematic review and meta-analysis to determine the effectiveness of psychosocial interventions delivered to affected others across addictions. METHODS: This review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. An electronic database search (PsycInfo, Medline, Cinahl and EMBASE) of randomized controlled trials (RCTs) published until August 2021 was conducted. RCTs with passive control groups, evaluating psychosocial tertiary interventions delivered to affected others of people with addictions (problematic alcohol use, substance use, gambling or gaming) that did not require the involvement of the addicted person, were included. RESULTS: Twenty included studies, published in 22 articles, mainly evaluated interventions for alcohol use, followed by gambling and illicit drugs, with none investigating gaming interventions. The interventions mainly targeted partners/spouses and focused upon improving affected other outcomes, addicted person outcomes or both. Meta-analyses revealed beneficial intervention effects over control groups on some affected other (depressive symptomatology, life satisfaction and coping style, addicted person [treatment entry] and relationship functioning outcomes (marital discord) at post-intervention. No beneficial intervention effects were identified at short-term follow-up (4-11 months post-treatment). The beneficial intervention effects identified at post-treatment remained when limiting to studies of alcohol use and therapist-delivered interventions. CONCLUSIONS: Psychosocial interventions delivered to affected others of people with addictions (problematic alcohol use, substance use, gambling or gaming) may be effective in improving some, but not all, affected other (depression, life satisfaction, coping), addicted person (treatment) and relationship functioning (marital discord) outcomes for affected others across the addictions, but the conclusion remains tentative due to limited studies and methodological limitations

Improved outcomes following contact with a gambling helpline: The impact of gender on barriers and facilitators

Gambling helplines were developed at a time when evidence for help-seeking was almost entirely based on male gamblers and there is limited evidence that helplines have changed in response to the exponential increase in female gamblers over the past 20 years. The current study aimed to explore the impact of gender on calls to Australian helplines, including caller characteristics, barriers and facilitators to contact as well as call outcomes. We surveyed 170 callers (94% problem gamblers, 61% male) approximately 1 month following their helpline call and found gender differences in terms of age, preferred gambling type, employment and source of referral. Males reported barriers related to pride and problem denial more frequently than females did, and also reported more frequent problems associated with the welfare of others and/or their living arrangements that facilitated their calling. Males and females were equally likely to seek further help from formal, informal and self-help resources. With only 10% of callers not accessing further help, these findings highlight the importance of helplines as a key support for both men and women with gambling problems. © 2014 Taylor & Francis

The efficacy of Personalized Normative Feedback interventions across addictions: A systematic review and meta-analysis

Personalized Normative Feedback (PNF) may help address addictive disorders. PNF highlights discrepancies between perceived and actual peer norms, juxtaposed against self-reported behavior. PNF can be self-directed and cost-efficient. Our study estimates the efficacy of PNF alone, and in combination with other self-directed interventions, to address frequency and symptom severity of hazardous alcohol use, problem gambling, illicit drug and tobacco use. We searched electronic databases, grey literature, and reference lists of included articles, for randomized controlled trials published in English (January 2000-August 2019). We assessed study quality using the Cochrane Risk of Bias tool. Thirty-four studies met inclusion criteria (k = 28 alcohol, k = 3 gambling, k = 3 cannabis, k = 0 tobacco). Thirty studies provided suitable data for meta-analyses. PNF alone, and with additional interventions, reduced short-term alcohol frequency and symptom severity. PNF with additional interventions reduced short-term gambling symptom severity. Effect sizes were small. PNF did not alter illicit drug use. Findings highlight the efficacy of PNF to address alcohol frequency and symptom severity. The limited number of studies suggest further research is needed to ascertain the efficacy of PNF for gambling and illicit drug use. Cost-effectiveness analyses are required to determine the scale of PNF needed to justify its use in various settings.</jats:p

An Examination of Clinician Responses to Problem Gambling in Community Mental Health Services

Gambling problems commonly co-occur with other mental health problems. However, screening for problem gambling (PG) rarely takes place within mental health treatment settings. The aim of the current study was to examine the way in which mental health clinicians respond to PG issues. Participants (n = 281) were recruited from a range of mental health services in Victoria, Australia. The majority of clinicians reported that at least some of their caseload was affected by gambling problems. Clinicians displayed moderate levels of knowledge about the reciprocal impact of gambling problems and mental health but had limited knowledge of screening tools to detect PG. Whilst 77% reported that they screened for PG, only 16% did so &ldquo;often&rdquo; or &ldquo;always&rdquo; and few expressed confidence in their ability to treat PG. However, only 12.5% reported receiving previous training in PG, and those that had, reported higher levels of knowledge about gambling in the context of mental illness, more positive attitudes about responding to gambling issues, and more confidence in detecting/screening for PG. In conclusion, the findings highlight the need to upskill mental health clinicians so they can better identify and manage PG and point towards opportunities for enhanced integrated working with gambling services.</jats:p

Behaviour change strategies for problem gambling: An analysis of online posts

Hing, N ORCiD: 0000-0002-2150-9784Reducing or quitting problematic gambling often requires implementing a variety of behaviour change strategies, but there is limited evidence regarding the breadth of specific strategies that gamblers use to control or limit gambling behaviours. This study aimed to identify the range of change strategies reported by gamblers in a naturalistic setting (i.e. two online forums for problem gambling). A total of 2937 change strategies were extracted from online posts (N = 1370). Content analysis identified 27 discrete change strategies that were pre-decisional (i.e. barriers–behavioural and psychological, decisional balance, realization–behaviour and cognitions, set reasons to change, seek knowledge and information, self-assessment), pre-actional (i.e. action planning, commitment, goal setting), actional (i.e. alternative activity, behavioural substitution, avoidance–abstinence, environment and financial, consumption control, maintain readiness, reinforcement, urge management, cognitive restructuring, seek inspiration, self-monitoring and spiritual) and multi-phased (i.e. external support, social support and well-being). This study suggests the breadth and depth of change strategies are far more complex than previously reported. Future research with a broader population needs to determine which change strategies are most effective for those experiencing different levels of gambling problems. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.Associated Grant:Funding for this study was provided by Gambling Research Australia (GRA)

Affected Others Responsivity to Gambling Harm: An International Taxonomy of Consumer-Derived Behaviour Change Techniques

Affected others impacted by someone else&rsquo;s gambling utilise numerous behaviour change strategies to minimise gambling-related harm but knowledge on what these strategies are and how they are implemented is limited. This study aimed to develop a comprehensive data-driven taxonomy of the types of self-help strategies used by affected others, and to categorize these into high-level behaviour change techniques (BCTs). Two taxonomies were developed using an inductive and deductive approach which was applied to a dataset of online sources and organised into the Rubicon model of action phases. These taxonomies were family-focused (how to reduce the impact of gambling harm on families) and gambler-focused (how to support the gambler in behaviour change). In total, 329 online sources containing 3536 different strategies were identified. The family-focused classification contained 16 BCTs, and the most frequent were professional support, financial management and planned consequences. The gambler-focused classification contained 11 BCTs, and the most frequent were feedback on behaviours, professional support and financial management. The majority of family- and gambler-focused BCTs fell under the actional phase of the Rubicon model. Grounded in lived experience, the findings highlight the need for intervention and resource development that includes a wide range of specific techniques that affected others can utilise.</jats:p