Alterations in leukocyte transcriptional control pathway activity associated with major depressive disorder and antidepressant treatment.

Major depressive disorder (MDD) is associated with a significantly elevated risk of developing serious medical illnesses such as cardiovascular disease, immune impairments, infection, dementia and premature death. Previous work has demonstrated immune dysregulation in subjects with MDD. Using genome-wide transcriptional profiling and promoter-based bioinformatic strategies, we assessed leukocyte transcription factor (TF) activity in leukocytes from 20 unmedicated MDD subjects versus 20 age-, sex- and ethnicity-matched healthy controls, before initiation of antidepressant therapy, and in 17 of the MDD subjects after 8 weeks of sertraline treatment. In leukocytes from unmedicated MDD subjects, bioinformatic analysis of transcription control pathway activity indicated an increased transcriptional activity of cAMP response element-binding/activating TF (CREB/ATF) and increased activity of TFs associated with cellular responses to oxidative stress (nuclear factor erythroid-derived 2-like 2, NFE2l2 or NRF2). Eight weeks of antidepressant therapy was associated with significant reductions in Hamilton Depression Rating Scale scores and reduced activity of NRF2, but not in CREB/ATF activity. Several other transcriptional regulation pathways, including the glucocorticoid receptor (GR), nuclear factor kappa-B cells (NF-κB), early growth response proteins 1-4 (EGR1-4) and interferon-responsive TFs, showed either no significant differences as a function of disease or treatment, or activities that were opposite to those previously hypothesized to be involved in the etiology of MDD or effective treatment. Our results suggest that CREB/ATF and NRF2 signaling may contribute to MDD by activating immune cell transcriptome dynamics that ultimately influence central nervous system (CNS) motivational and affective processes via circulating mediators.

Dysregulated relationship of inflammation and oxidative stress in major depression.

Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.

Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response.

Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication-free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness.

Clinical decision guidelines for NHS cosmetic surgery: analysis of current limitations and recommendations for future development.

Because of increasing demand for publicly funded elective cosmetic surgery, clinical decision guidelines have been developed to select those patients who should receive it. The aims of this study were to identify: the main characteristics of such guidelines; whether and how they influence clinical decision making; and ways in which they should be improved. UK health authorities were asked for their current guidelines for elective cosmetic surgery and, in a single plastic surgery unit, we examined the impact of its guidelines by observing consultations and interviewing surgeons and managers. Of 115 authorities approached, 32 reported using guidelines and provided sufficient information for analysis. Guidelines mostly concerned arbitrary sets of cosmetic procedures and lacked reference to an evidence base. They allowed surgery for specified anatomical, functional or symptomatic reasons, but these indications varied between guidelines. Most guidelines also permitted surgery 'exceptionally' for psychological reasons. The guidelines that were studied in detail did not appreciably influence surgeons' decisions, which reflected criteria that were not cited in the guidelines, including cost of the procedure and whether patients sought restoration or improvement of their appearance. Decision guidelines in this area have several limitations. Future guidelines should: include all cosmetic procedures; be informed by a broad range of evidence; and, arguably, include several nonclinical criteria that currently inform surgeons' decision-making.

Complex formation among rat pancreatic secretory proteins under mild alkaline pH conditions.

Previous in vitro studies have demonstrated that enzyme proteins liberated from isolated zymogen granules of the rat pancreas aggregate already at neutral or slightly basic pH and form small particles which in the acidic pH range progressively condense into dense cores of about the size of zymogen granules. To characterize the protein composition of the original particles in more detail non-denaturing agarose gel electrophoresis was employed. Five major protein complexes were identified which upon separation of individual complexes in 1-D or 2-D gel electrophoresis were shown to be composed of a distinct set of known enzymes and several unknown proteins. Complexes 1-4 quickly dissociated when enzyme activation was induced by enterokinase, but complex 5 was resistant even to this treatment. All 5 complexes revealed a distinct fine structure when eluted from the gels and studied in negative staining electron microscopy. These findings suggest that pancreatic zymogens form complexes already in the lumen of the rough endoplasmic reticulum and are transported as such to the Golgi complex where they aggregate into granule cores due to the internal acidic pH. Complex formation may thus facilitate zymogen sorting within the rough endoplasmic reticulum and may prevent premature enzyme activation within cellular compartments.

A prospective study of changes in negative mood states of women undergoing surgical hysterectomy: the relationship to cognitive predisposition and familial support.

Levels of anxiety and depression were documented by questionnaire response from a sample of 89 women who were to undergo surgical hysterectomy 3 weeks later. Fifty-four per cent (n = 48) of the sample reported anxiety and 26% (n = 23) reported depression at clinical levels during the preoperative period, with an additional number (n = 16 anxiety; n = 19 depression) at borderline status. Despite an overall significant postoperative reduction of negative mood states, clinical levels of anxiety were found in a substantial minority of women both 2 (24%) and 6 months (31%) after surgery. Levels of depression at these times were respectively 13% and 11% of the sample which provided postoperative information. These data confirm previous reports of high levels of negative mood states in patients referred for surgical hysterectomy. However, analyses of individual profiles of change confirm that there was a beneficial outcome for the large majority of the women, with 83% of those with clinical levels of anxiety showing improved status. Regression analyses indicated that postoperative outcomes with respect to negative affect could be predicted from preoperative status, and the data provide some support for the hypothesis that for a minority of women, negative mood states co-presented with gynecological symptoms may not be attenuated by surgery. Both dispositional resilience and familial cohesiveness were entered as significant variables in regression models examining postoperative status, although they provided only a limited increase to the postoperative variance prediction from measure of preoperative levels of affect. Preoperative mood status was found to be inversely related to an intrapersonal dimension of 'dispositional resilience' and to 'family cohesiveness'. It is suggested that measurement of preoperative mood status to family cohesiveness and dispositional resilience may provide useful adjunctive measures in attempts to identify women at risk of reporting an unsatisfactory surgical outcome.

Functional aspects of recollective experience in face recognition.

This article describes two experiments on awareness in recognition memory for novel faces. Two kinds of awareness, recollective experience and feelings of familiarity in the absence of recollective experience, were measured by "remember" and "know" responses. Experiment 1 showed that "remember" but not "know" responses were reduced by divided attention at study. Experiment 2 showed that massed versus spaced repetition of faces in the study list had opposite effects on "remember" and "know" responses. Massed repetition increased "know" responses and reduced "remember" responses. Spaced repetition increased "remember" responses and reduced "know" responses. The results of both experiments replicate previous findings from the verbal domain in the domain of face recognition, and hence they increase the ecological validity of this experimental approach to memory and awareness and the generality of its database. These findings are discussed from a rehearsal perspective on factors influencing the two states of awareness and in relation to the alternative "process dissociation" procedure.

The Kings Cross fire: psychological reactions.

The psychological reactions of 50 survivors of the King's Cross fire, which hit London's underground railway system on the 18th day of November 1987, are described. Results are presented for the Impact of Event scale, the General Health Questionnaire (28-item version), the Eysenck Personality Questionnaire and a King's Cross Event Schedule. These are investigated in relation to (a) validity measures, (b) relationships between exposure and personality, and (c) spontaneous de-briefing. Two thirds of the sample had significant levels of psychological distress (meeting the "caseness" criterion on the GHQ). Both personality (neuroticism and L-scale) and degree of trauma exposure were related to subsequent reaction. Spontaneous debriefing was associated with subjective benefit. Transportation disasters present particular problems in relation to research and service delivery.

Eliciting EuroQol descriptive data and utility scale values from inpatients. A feasibility study.

We conducted a microstudy to elicit health state descriptions and utility values, using the EuroQol instrument, from a sample of acutely ill inpatients on 5 wards at University College London Medical School. Most current work to date has elicited such descriptive and valuation data from random surveys of the general population. One problem with this is that most responders from the general population have not actually experienced the states being valued. Our goal was to ascertain whether there were any differences between the values given by inpatients and those of the general population. However, the small sample size of patients included in our feasibility study means our conclusions must remain tentative. Nevertheless, the results suggest that patients give higher values than the general population. We suggest that more research needs to be done eliciting values from patients.

The Marchioness disaster: preliminary report on psychological effects.

The psychological after-effects on 27 survivors of the Marchioness riverboat disaster of 20 August 1989 are described. On measures of intrusive memories and psychological difficulties these subjects are significantly higher than population norms, and somewhat higher than psychiatric in-patient populations. Personality measures taken after the disaster show that neuroticism scores are very much higher than population norms, but personality measures were not correlated with distress.