Perceived ethnic discrimination and persecutory paranoia in individuals at ultra-high risk for psychosis.

Despite a consensus that psychosocial adversity plays a role in the onset of psychosis, the nature of this role in relation to persecutory paranoia remains unclear. This study examined the complex relationship between perceived ethnic discrimination and paranoid ideation in individuals at Ultra High Risk (UHR) for psychosis using a virtual reality paradigm to objectively measure paranoia. Data from 64 UHR participants and 43 healthy volunteers were analysed to investigate the relationship between perceived ethnic discrimination and persecutory ideation in a virtual reality environment. Perceived ethnic discrimination was higher in young adults at UHR in comparison to healthy controls. A positive correlation was observed between perceived ethnic discrimination and paranoid persecutory ideation in the whole sample. Perceived ethnic discrimination was not a significant predictor of paranoid persecutory ideation in the VR environment. Elevated levels of perceived ethnic discrimination are present in individuals at UHR and are consistent with current biopsychosocial models in which psychosocial adversity plays a key role in the development of psychosis and attenuated symptomatology.

The Phenomenology and Generation of Positive Mental Imagery in Early Psychosis.

BACKGROUND: Theoretical models of depression and bipolar disorder emphasise the importance of positive mental imagery in mood and behaviour. Distressing, intrusive images are common in psychosis; however, little is known about positive imagery experiences or their association with clinical symptoms. The aim of the current study was to examine the phenomenology of positive imagery in early psychosis and the relationship between the characteristics of positive, future-oriented imagery and symptom severity. METHOD: Characteristics, thematic content and appraisals of recent self-reported images were examined in 31 people with early psychosis. The vividness and perceived likelihood of deliberately generated, future-oriented images were investigated in relation to clinical symptoms. RESULTS: Eighty-four percent of participants reported experiencing a recent positive image. Themes included the achievement of personal goals, spending enjoyable time with peers and family, loving, intimate relationships and escape from current circumstances. The vividness and perceived likelihood of generated prospective imagery were negatively correlated with levels of depression and social anxiety. CONCLUSIONS: The relationship between emotional problems and the ability to imagine positive, future events may have implications for motivation, mood and goal-directed behaviour in psychosis. Everyday experiences of positive imagery may represent the simulation of future goals, attempts to cope or avoid aversive experiences or idealised fantasy. Copyright © 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: The majority of participants experienced a recent positive image with themes related to goal attainment and social relationships. Depression and social anxiety levels were correlated with the vividness of intentionally generated positive future-oriented images and their perceived likelihood. The assessment of positive imagery in early psychosis appears warranted and may provide insights regarding individual coping strategies, values and goals.

Cognitive emotion regulation strategies, alexithymia and dissociation in schizophrenia, a review and meta-analysis.

AIMS: Many individuals with schizophrenia are reported to have maladaptive expression and processing of emotion. This may take the form of conscious and implicit processes. Potential regulatory processes underlying schizophrenia are reviewed. We aimed to estimate effect sizes, potential heterogeneity and publication bias across three areas of measurement: a range of cognitive emotion regulation strategies(1) (CERS), alexithymia and dissociation. METHOD: Data were pooled from 47 case-control studies involving measures of experiential avoidance, attentional deployment, cognitive reappraisal, emotion management, dissociation and alexithymia. All studies were rated for quality, risk of bias and publication bias. RESULTS: The following effect sizes (g) were observed: emotion management: 0.96 [0.77, 1.14] and cognitive reappraisal: 0.49 [0.32, 0.66] were negatively associated with schizophrenia. Experiential avoidance: -0.44 [-0.59, -0.29], attentional deployment -0.96 [-1.18, -0.75], dissociation: -0.86 [-1.13, -0.60] and alexithymia: -1.05 [-1.45, -0.65] were positively associated with schizophrenia. Subgroups of dissociation and attentional deployment were also analysed. Meta-analyses revealed potential publication bias and heterogeneity in the study of CERS in schizophrenia. CONCLUSIONS: A marked difference in the implementation of CERS is associated with schizophrenia compared to controls. Dissociation variables and alexithymia are also indicated and may be implicated in adaptive cognitive emotional regulation. Theoretical and research implications are discussed.

H11/HspB8 and Its Herpes Simplex Virus Type 2 Homologue ICP10PK Share Functions That Regulate Cell Life/Death Decisions and Human Disease.

Small heat shock proteins (sHsp) also known as HspB are a large family of widely expressed proteins that contain a 90 residues domain known as α-crystallin. Here, we focus on the family member H11/HspB8 and its herpes simplex virus type 2 (HSV-2) homologue ICP10PK, and discuss the possible impact of this relationship on human disease. H11/HspB8 and ICP10PK are atypical protein kinases. They share multi-functional activity that encompasses signaling, unfolded protein response (UPR) and the regulation of life cycle potential. In melanocytes H11/HspB8 causes growth arrest. It is silenced in a high proportion of melanoma prostate cancer, Ewing's sarcoma and hematologic malignancies through aberrant DNA methylation. Its restored expression induces cell death and inhibits tumor growth in xenograft models, identifying H11/HspB8 as a tumor suppressor. This function involves the activation of multiple and distinct death pathways, all of which initiate with H11/HspB8-mediated phosphorylation of transforming growth factor ß-activated kinase 1 (TAK1). Both ICP10PK and H11/HspB8 were implicated in inflammatory processes that involve dendritic cells activation through Toll-like receptor-dependent pathways and may contribute to the onset of autoimmunity. The potential evolutionary relationship of H11/HspB8 to ICP10PK, its impact on human disorders and the development of therapeutic strategies are discussed.

Tourism partnerships in protected areas: exploring contributions to sustainability.

Partnerships between natural-area managers and the tourism industry have been suggested to contribute to sustainability in protected areas. This article explores how important sustainability outcomes of partnerships are to their members, how well they are realised and the features of partnerships leading to their achievement. In 21 case studies in Australia, interviews (n = 97) and surveys (n = 100) showed that of 14 sustainability outcomes, improved understanding of protected areas values and improved biodiversity conservation were the most important. Other highly ranked outcomes were greater respect for culture, heritage, and/or traditions; improved quality of environmental conditions; social benefits to local communities; and improved economic viability of the protected area. Scores for satisfaction with outcomes were, like those for importance, all high but were less than those for importance for the majority, with improvement in quality of environmental conditions showing the largest gap. The satisfaction score exceeded that for importance only for increased competitiveness of the protected area as a tourist destination. "Brown" aspects of sustainability, i.e., decreased waste or energy use, were among the lowest-scoring outcomes for both importance and satisfaction. The most important factor enabling sustainability outcomes was provision of benefits to partnership members. Others were increased financial support, inclusiveness, supportive organisational and administrative arrangements, direct involvement of decision makers, partnership maturity, creation of new relationships, decreased conflict, and stimulation of innovation. Improving sustainability outcomes, therefore, requires maintaining these partnership attributes and also increasing emphasis on reducing waste and resource use.

Multi-targeted neuroprotection by the HSV-2 gene ICP10PK includes robust bystander activity through PI3-K/Akt and/or MEK/ERK-dependent neuronal release of vascular endothelial growth factor and fractalkine.

Hippocampal cultures infected with the DeltaRR vector for the HSV-2 anti-apoptotic gene ICP10PK survive cell death triggered by a wide variety of insults. Survival includes robust protection of uninfected neurons, but the mechanism of this bystander activity is still unclear. Here we report that ICP10PK+ neurons release soluble factors that protect uninfected neurons from NMDA and MPP+-induced apoptosis. Release depends on ICP10PK-mediated activation of the Ras signaling pathways MEK/ERK and PI3-K/Akt, and it was not seen for cultures infected with the ICP10PK negative vector DeltaPK. The released neuroprotective factors include vascular endothelial growth factor (VEGF) and fractalkine, the levels of which were significantly higher in conditioned media from hippocampal cultures infected with DeltaRR (NCM(DeltaRR)) than DeltaPK or phosphate-buffered saline (mock infection). VEGF neutralization inhibited the neuroprotective activity of NCM(DeltaRR), indicating that the VEGF protective function is through neuron-neuron cross-talk. NCM(DeltaRR) also stimulated microglia to release increased levels of IL-10 and decreased levels of TNF-alpha that were protective for uninfected neurons. These release patterns were not seen for microglia given NCM(DeltaRR) in which fractalkine was neutralized, indicating that the fractalkine protective function is through bidirectional neuron-microglia communication. Collectively, the data indicate that DeltaRR is a multiple target strategy to rescue neurons from excitotoxic injury.

Acute skin eruptions that are positive for herpes simplex virus DNA polymerase in patients with stem cell transplantation: a new manifestation within the erythema multiforme reactive dermatoses.

BACKGROUND: Patients with stem cell transplantation (SCT) develop erythematous eruptions (SCTE) that are often misdiagnosed and poorly treated. Latent herpes simplex virus (HSV) is likely to be reactivated by SCT-associated immunosuppression. Therefore, one of the differential diagnostic possibilities for SCTE is HSV-associated erythema multiforme (HAEM) in which HSV genetic fragments localize in stem cells that deliver them to the skin on differentiation. OBSERVATIONS: Lesional skin from patients with SCTE, HAEM, HSV, or drug-induced erythema (DIEM) was stained with antibodies to the HSV antigen DNA polymerase (Pol) and the major capsid protein, virion protein 5 (VP5). The HSV DNA polymerase Pol was expressed in 79% of patients with SCTE and 75% of those with HAEM. The protein VP5 was not expressed in these patients, indicative of the absence of virus replication. Findings in patients with DIEM were negative for both antigens, and those with HSV lesions were positive for both antigens. CONCLUSIONS: There is a growing problem with SCTE, related to the increasing numbers of performed SCT. The greater frequency of SCT-generated circulating stem cells in patients with hematological malignant neoplasms (who have latent HSV infection) may result in a widespread SCTE characterized by skin deposition of HSV DNA fragments, notably those expressing Pol antigen. This HAEM-like presentation should be considered in the differential diagnosis of SCTE. Prolonged high-dosage antiviral chemotherapy during and after hospitalization may be warranted.

DeltaRR vaccination protects from KA-induced seizures and neuronal loss through ICP10PK-mediated modulation of the neuronal-microglial axis.

Ischemic brain injury and epilepsy are common neurodegenerative diseases caused by excitotoxicity. Their pathogenesis includes microglial production of inflammatory cytokines. Our studies were designed to examine whether a growth compromised HSV-2 mutant (Delta RR) prevents excitotoxic injury through modulation of microglial responses by the anti-apoptotic HSV-2 protein ICP10PK. EOC2 and EOC20 microglial cells, which are differentially activated, were infected with Delta RR or the ICP10PK deleted virus (Delta PK) and examined for virus-induced neuroprotective activity. Both cell lines were non-permissive for virus growth, but expressed ICP10PK (Delta RR) or the PK deleted ICP10 protein p95 (Delta PK). Conditioned medium (CM) from Delta RR-, but not Delta PK-infected cells prevented N-methyl-D-aspartate (NMDA)-induced apoptosis of primary hippocampal cultures, as determined by TUNEL and caspase-3 activation (76.9 +/- 5.3% neuroprotection). Neuroprotection was associated with inhibition of TNF-alpha and RANTES and production of IL-10. The CM from Delta PK-infected EOC2 and EOC20 cells did not contain IL-10, but it contained TNF-alpha and RANTES. IL-10 neutralization significantly (p < 0.01) decreased, but did not abrogate, the neuroprotective activity of the CM from Delta RR-infected microglial cultures indicating that ICP10PK modulates the neuronal-microglial axis, also through induction of various microglial neuroprotective factors. Rats given Delta RR (but not Delta PK) by intranasal inoculation were protected from kainic acid (KA)-induced seizures and neuronal loss in the CA1 hippocampal fields. Protection was associated with a significant (p < 0.001) increase in the numbers of IL-10+ microglia (CD11b+) as compared to Delta PK-treated animals. Delta RR is a promising vaccination/therapy platform for neurodegeneration through its pro-survival functions in neurons as well as microglia modulation.

Growth-compromised HSV-2 vector Delta RR protects from N-methyl-D-aspartate-induced neuronal degeneration through redundant activation of the MEK/ERK and PI3-K/Akt survival pathways, either one of which overrides apoptotic cascades.

We have previously shown that intrastriatal injection of Delta RR, the growth-compromised herpes simplex virus type 2 (HSV-2) vector for the antiapoptotic protein ICP10PK, prevents apoptosis caused by the excitotoxin N-methyl-D-aspartate (NMDA) in a mouse model of glutamatergic neuronal cell death (Golembewski et al. [2007] Exp. Neurol. 203:381-393). Because apoptosis regulation is stimulus and cell type specific, our studies were designed to examine the mechanism of Delta RR-mediated neuroprotection in striatal neurons. Organotypic striatal cultures (OSC) that retain much of the synaptic circuitry of the intact striatum were infected with Delta RR or a growth-compromised HSV-2 vector that lacks ICP10PK (Delta PK) and examined for neuroprotection-associated signaling. The mutated ICP10 proteins (p175 and p95) were expressed in 70-80% of neurons from Delta RR- and Delta PK-infected cultures, respectively, as determined by double-immunofluorescent staining with antibodies to ICP10 and NeuN or GAD65. Delta RR- but not Delta PK-treated OSC were protected from NMDA-induced apoptosis, as verified by ethidium homodimer staining, TUNEL, caspase-3 activation, and poly(AD-ribose) polymerase (PARP) cleavage. Neuroprotection was through ICP10PK-mediated activation of the survival pathways MEK/ERK and PI3-K/Akt, up-regulation of the antiapoptotic proteins Bag-1 and Bcl-2, and phosphorylation (inactivation) of the proapoptotic protein Bad. It was blocked by the MEK inhibitor U0126 or the PI3-K inhibitor LY294002, suggesting that either pathway can prevent NMDA-induced apoptosis. The data indicate that Delta RR-delivered ICP10PK stimulates redundant survival pathways that override proapoptotic cascades. Delta RR is a promising gene therapy platform against glutamatergic cell death.

The herpes simplex virus type 2 gene ICP10PK protects from apoptosis caused by nerve growth factor deprivation through inhibition of caspase-3 activation and XIAP up-regulation.

The herpes simplex virus type 2 (HSV-2) protein ICP10PK has anti-apoptotic activity in virus-infected hippocampal cultures through activation of the Ras/Raf-1/MEK/ERK pathway. To exclude the possible contribution of other viral proteins to cell fate determination, we examined the survival of primary hippocampal cultures and neuronally differentiated PC12 cells transfected with ICP10PK from apoptosis caused by nerve growth factor (NGF) withdrawal. NGF deprivation caused apoptosis in cultures mock-transfected or transfected with the kinase-negative ICP10 mutant p139(TM), but not in ICP10PK-transfected cultures. In one clone (PC47), ICP10PK inhibited caspase-3 activation through up-regulation/stabilization of adenylate cyclase (AC), activation of PKA and MEK, and the convergence of the two pathways on extracellular signal-regulated kinase activation. The anti-apoptotic proteins Bag-1 and Bcl-2 were stabilized and the pro-apoptotic protein Bad was phosphorylated (inactivated). In another clone (PC70), ICP10PK inhibited apoptosis through MEK-dependent up-regulation of the anti-apoptotic protein XIAP (that inhibits the activity of processed caspase-3) and down-regulation of the apoptogenic protein Smac/DIABLO. This may be cell-type specific, but the baculovirus p35 protein did not potentiate the neuroprotective activity of ICP10PK in PC12 cells, suggesting that ICP10PK inhibits both caspase activation and activity. The data indicate that ICP10PK inhibits apoptosis independent of other viral proteins and is a promising neuronal gene therapy platform.

The Herpes simplex virus gene Pol expressed in herpes-associated erythema multiforme lesions upregulates/activates SP1 and inflammatory cytokines.

BACKGROUND/AIMS: Herpes-simplex-virus-associated erythema multiforme (HAEM) is characterized by lesional skin expression of the viral protein Pol and localized inflammation. The objective of this study is to examine the mechanism whereby Pol induces localized inflammation. METHODS: A431 cells transfected with Pol or an empty vector and lesional skin from HAEM or drug-induced erythema multiforme patients were examined for expression of the transcription factor SP1 and SP1-regulated genes by immunoblotting, immunohistochemistry and immunofluorescence. RESULTS: SP1, TGF-beta, p21(waf1) and Hsp27 were upregulated in A431 cells transfected with Pol but not the empty vector. Expression was further increased by exposure to IFN-gamma. Pol+ HAEM lesional skin expressed SP1, Hsp27, TGF-beta and p21(waf1). Normal skin and drug-induced erythema multiforme lesional skin were negative. CONCLUSION: The data indicate that Pol activates SP1, causing upregulation of SP1 target genes (notably TGF-beta) involved in localized inflammation. Upregulation is potentiated by IFN-gamma.

Aberrant DNA methylation silences the novel heat shock protein H11 in melanoma but not benign melanocytic lesions.

BACKGROUND: The heat shock protein H11 is silenced in melanoma cell lines, where its forced expression by demethylation with Aza-C triggers apoptosis. OBJECTIVE: To examine whether H11 is silenced by aberrant DNA methylation in melanoma as compared to nevi and normal skin tissues. METHODS: Cell suspensions from benign intradermal nevi, atypical nevi and malignant melanoma tissues were used in reverse-transcriptase PCR and methylation-specific PCR. Paraffin-embedded tissues were stained with H11 antibody. RESULTS: H11 is methylated in 60-75% of melanoma and atypical nevi, but not in normal skin or most benign nevi. Methylation is inversely correlated with H11 expression. CONCLUSION: The heat shock protein H11 is silenced by aberrant DNA methylation in melanoma, but not benign melanocytic lesions or normal skin melanocytes. The data suggest that H11 is a promising target for the molecular therapy of melanoma.

The growth compromised HSV-2 mutant DeltaRR prevents kainic acid-induced apoptosis and loss of function in organotypic hippocampal cultures.

We have previously shown that the HSV-2 anti-apoptotic protein ICP10PK is delivered by the replication incompetent virus mutant DeltaRR and prevents kainic acid (KA)-induced epileptiform seizures and neuronal cell loss in the mouse and rat models of temporal lobe epilepsy. The present studies used DeltaRR and the ICP10PK deleted virus mutant DeltaPK to examine the mechanism of neuroprotection. DeltaRR-infected neuronal cells expressed a chimeric protein in which ICP10PK is fused in frame to LacZ (p175) while retaining ICP10PK kinase activity. DeltaPK-infected neuronal cells expressed a mutant ICP10 protein that is deleted in the PK domain and is kinase negative (p95). p175 and p95 were expressed in CA3 (86+/-3%) and CA1 (69+/-7%) cells from DeltaRR or DeltaPK-infected organotypic hippocampal cultures (OHC) and 80-85% of the ICP10 positive cells co-stained with antibody to beta(III) Tubulin (neuronal marker). DeltaRR, but not DeltaPK, inhibited KA-induced cell death and caspase-3 activation in CA3 neurons, an inhibition seen whether DeltaRR was delivered 2 days before or 2 days after KA administration (95% neuroprotection). Neuroprotection was associated with ERK and Akt activation and was abrogated by simultaneous treatment with the MEK (U0126) and PI3-K (LY294002) inhibitors. DeltaRR-mediated neuroprotection was associated with increased expression of the anti-apoptotic protein Bag-1 and decreased expression of the pro-apoptotic protein Bad. The surviving neurons retained normal synaptic function potentially related to increased expression of the transcription factor CREB. The data indicate that DeltaRR is a promising platform for neuroprotection from excitotoxic injury.

Intranasal administration of the growth-compromised HSV-2 vector DeltaRR prevents kainate-induced seizures and neuronal loss in rats and mice.

Identification of targets and delivery platforms for gene therapy of neurodegenerative disorders is a clinical challenge. We describe a novel paradigm in which the neuroprotective gene is the herpes simplex virus type 2 (HSV-2) antiapoptotic gene ICP10PK and the vector is the growth-compromised HSV-2 mutant DeltaRR. DeltaRR is delivered intranasally. It is not toxic in rats and mice. ICP10PK is expressed in the hippocampus of the DeltaRR-treated animals for at least 42 days in the absence of virus replication and late virus gene expression. Its expression is regulated by an AP-1 amplification loop. Intranasally delivered DeltaRR prevents kainic acid-induced seizures, neuronal loss, and inflammation, in both rats and mice. The data suggest that DeltaRR is a promising therapeutic platform for neurodegenerative diseases.