The complexity of p53 stabilization and activation

A number of proteins are activated by stress stimuli but none so spectacularly or with the degree of complexity as the tumour suppressor p53 (human p53 gene or protein). Once stabilized, p53 is responsible for the transcriptional activation of a series of proteins involved in cell cycle control, apoptosis and senescence. This protein is present at low levels in resting cells but after exposure to DNA-damaging agents and other stress stimuli it is stabilized and activated by a series of post-translational modifications that free it from MDM2 (mouse double minute 2 but used interchangeably to denote human also), a ubiquination ligase that ubiquitinates it prior to proteasome degradation. The stability of p53 is also influenced by a series of other interacting proteins. In this review, we discuss the post-translational modifications to p53 in response to different stresses and the consequences of these changes.

Post-traumatic stress disorder: Findings from the Australian National Survey of Mental Health and Well-being

Background. We report on the epidemiology of post-traumatic stress disorder (PTSD) in the Australian community, including information on lifetime exposure to trauma, 12-month prevalence of PTSD, sociodemographic correlates and co-morbidity. Methods. Data were obtained from a stratified sample of 10641 participants as part of the Australian National Survey of Mental Health and Well-being. A modified version of the Composite International Diagnostic Interview was used to determine the presence of PTSD, as well as other DSM-IV anxiety, affective and substance use disorders. Results. The estimated 12-month prevalence of PTSD was 1.33%, which is considerably lower than that found in comparable North American studies. Although females were at greater risk than males within the subsample of those who had experienced trauma, the large gender differences noted in some recent epidemiological research were not replicated. Prevalence was elevated among the never married and previously married respondents, and was lower among those aged over 55. For both men and women, rape and sexual molestation were the traumatic events most likely to be associated with PTSD. A high level of Axis I co-morbidity was found among those persons with PTSD Conclusions. PTSD is a highly prevalent disorder in the Australian community and is routinely associated with high rates of anxiety, depression and substance disorders. Future research is needed to investigate rates among other populations outside the North American continent.

Eye-movements and visual imagery: A working memory approach to the treatment of post-traumatic stress disorder

It has been claimed that the symptoms of post-traumatic stress disorder (PTSD) can be ameliorated by eye-movement desensitization-reprocessing therapy (EMD-R), a procedure that involves the individual making saccadic eye-movements while imagining the traumatic event. We hypothesized that these eye-movements reduce the vividness of distressing images by disrupting the function of the visuospatial sketchpad (VSSP) of working memory, and that by doing so they reduce the intensity of the emotion associated with the image. This hypothesis was tested by asking non-PTSD participants to form images of neutral and negative pictures under dual task conditions. Their images were less vivid with concurrent eye-movements and with a concurrent spatial tapping task that did not involve eye-movements. In the first three experiments, these secondary tasks did not consistently affect participants' emotional responses to the images. However, Expt 4 used personal recollections as stimuli for the imagery task, and demonstrated a significant reduction in emotional response under the same dual task conditions. These results suggest that, if EMD-R works, it does so by reducing the vividness and emotiveness of traumatic images via the VSSP of working memory. Other visuospatial tasks may also be of therapeutic value.

GABAA receptor β3 subunit gene and psychiatric morbidity in a post-traumatic stress disorder population

GABAergic systems have been implicated in the pathogenesis of anxiety, depression and insomnia. These symptoms are part of the core and comorbid psychiatric disturbances in post-traumatic stress disorder (PTSD) In a sample of Caucasian male PTSD patients, dinucleotide repeat polymorphisms of the GABAA receptor beta3 subunit gene were compared to scores on the General Health Questionnaire-28 (GHQ). As the major allele at this gene locus (GABRB3) was GI, the alleles were divided into GI and non-GI groups. On the total score of the GHQ, which comprises the somatic symptoms, anxiety/insomnia, social dysfunction and depression subscales, patients with the GI non-GI genotype had a significantly higher score when compared to either the G1G1 genotype (alpha = 0.01) or the non-GI non-GI genotype (alpha = 0.05). No significant difference was found between the G1G1 and non-Gl non-G1 genotypes. When the GI non-G1 heterozygotes were compared to the combined G1G1 and non-GI non-GI homozygotes, a significantly higher total GHQ score was found in the heterozygotes (P = 0.002). These observations suggest a heterosis effect. Further analysis of GHQ subscale scores showed that heterozygotes compared to the combined homozygotes had higher scores on the somatic symptoms (P = 0.006), anxiety/insomnia (P = 0.003), social dysfunction (P = 0.054) and depression (P = 0.004) subscales. In conclusion, the present study indicates that in a population of PTSD patients, heterozygosity of the GABRB3 major (GI) allele confers higher levels of somatic symptoms, anxiety/insomnia, social dysfunction and depression than found in homozygosity. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Harmful drinking in military veterans with post-traumatic stress disorder: Association with the D2 dopamine receptor A1 allele

Aims: The frequency of the Taq I A alleles (A1 and A2) of the D2 dopamine receptor (DRD2) gene was examined in Caucasian post-traumatic stress disorder (PTSD) patients and controls. Results: In 91 PTSD patients, the frequency of the A1 allele was higher (P = 6.12 x 10(-3)) than in the 51 controls. In the 38 PTSD harmful drinkers (greater than or equal to60 g alcohol/day), A1 allelic frequency was higher (P = 3.91 x 10(-2)) than in the 53 non-harmful drinkers (

Blunted growth hormone response to clonidine in post-traumatic stress disorder

Hyperactivity of the sympathetic and noradrenergic systems is thought to be a feature of post-traumatic stress disorder (PTSD). Assessment of noradrenergic receptor function can be undertaken by measuring the growth hormone (GH) response to the alpha(2)-agonist clonidine. The aim of this study was to examine whether subjects with combat-related PTSD (with or without co-morbid depression) have a blunted growth hormone response to clonidine, compared to a combat-exposed control group. Twenty-three Vietnam veterans suffering from PTSD alone, 27 suffering from PTSD and co-morbid depression, and 32 veteran controls with no psychiatric illness were administered 1.5 mug/kg clonidine i.v. Plasma growth hormone was measured every 20 min for 120 min. The growth hormone response to clonidine was significantly blunted in the non-depressed PTSD group compared to both the depressed PTSD group and the control group as measured by peak growth hormone, delta growth hormone and AUC growth hormone. Subjects with PTSD and no co-morbid depressive illness show a blunted growth hormone response to clonidine. This suggests that post-synaptic alpha(2)-receptors are subsensitive. This finding is consistent with other studies showing increased noradrenergic activity in PTSD. (C) 2003 Elsevier Ltd. All rights reserved.

Glucocorticoid receptor polymorphisms and post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is reported in some studies to be associated with increased glucocorticoid (GC) sensitivity. Two common glucocorticoid receptor (GR) potymorphisms (N363S and 8cll) appear to contribute to the population variance in GC sensitivity. There is some evidence that there may be a genetic predisposition to PTSD. Hence we studied 118 Vietnam war veterans with PTSD for (i) GR polymorphisms, particularly the N363S and the Bcll polymorphisms which are thought to be GC sensitising, and (ii) two measures of GC sensitivity, the tow-dose 0.25 mg dexamethasone suppression test (LD-DST) and the dermal vasoconstrictor assay (DVVA). The DST and GR polymorphisms were also performed in 42 combat exposed Vietnam war veterans without PTSD. Basal plasma cortisol levels were not significantly different in PTSD (399.5 +/- 19.2 nmol/L, N=75) and controls (348.6 +/- 23.0 nmol/L, N = 33) and the LD-DST resulted in similar cortisol suppression in both groups (45.6 +/- 3.2 vs. 40.8 +/- 4.1%). The cortisol suppression in PTSD patients does not correlate with Clinician Administered PTSD Scores (CAPS), however there was a significant association between the Bcll GG genotype and low basal cortisol levels in PTSD (P=0.048). The response to the DVVA was similar to controls (945 +/- 122, N = 106 vs. 730 +/- 236, N = 28, P = 0.42). PTSD patients with the GG genotype, however, tended to be more responsive to DVVA and in this group the DVVA correlated with higher CAPS scores. The only exon 2 GR polymorphisms detected were the R23K and N363S. Heterozygosity for the N363S variant in PTSD, at 5.1% was not more prevalent than in other population studies of the N363S polymorphism in Caucasians (6.0-14.8%). The GG genotype of the Bcll polymorphism found to be associated with increased GC sensitivity in many studies showed a tendency towards increased response with DVVA and correlated with higher CAPS scores. In conclusion, the N363S and Bcll GR polymorphisms were not more frequent in PTSD patients than controls and reported population frequencies. Our PTSD group did not display GC hypersensitivity, as measured by the LD-DST and DVVA. In a subset of PTSD patients with the Bcll GG genotype, CAPS scores and basal cortisol Levels were negatively correlated. (C) 2004 Elsevier Ltd. All rights reserved.

Psychosocial sequelae of the 1989 Newcastle earthquake .2. Exposure and morbidity profiles during the first 2 years post-disaster

Background. A sample of 1089 Australian adults was selected for the longitudinal component of the Quake Impact Study, a 2-year, four-phase investigation of the psychosocial effects of the 1989 Newcastle earthquake. Of these, 845 (78%) completed a survey 6 months post-disaster as well as one or more of the three follow-up surveys. Methods. The phase I survey was used to construct dimensional indices of self-reported exposure to threat the disruption and also to classify subjects by their membership of five 'at risk' groups (the injured; the displaced; owners of damaged small businesses; helpers in threat and non-threat situations). Psychological morbidity was assessed at each phase using the 12-item General Health Questionnaire (GHQ-12) and the Impact of Event Scale (IES). Results. Psychological morbidity declined over time but tended to stabilize at about 12 months post-disaster for general morbidity (GHQ-12) and at about 18 months for trauma-related (IES) morbidity. Initial exposure to threat and/or disruption were significant predictors of psychological morbidity throughout the study and had superior predictive power to membership of the targeted 'at risk' groups. The degree of ongoing disruption and other life events since the earthquake were also significant predictors of morbidity. The injured reported the highest levels of distress, but there was a relative absence of morbidity among the helpers. Conclusions. Future disaster research should carefully assess the threat and disruption experiences of the survivors at the time of the event and monitor ongoing disruptions in the aftermath in order to target interventions more effectively.