Eric Strachan

Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells

Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.

Terror Mismanagement: Evidence That Mortality Salience Exacerbates Phobic and Compulsive Behaviors

Terror management theory (TMT) posits that cultural worldviews and self-esteem function to buffer humans from mortality-related anxiety. TMT research has shown that important behaviors are influenced by mortality salience (MS) even when they have no obvious connection to death. However, there has been no attempt to investigate TMT processes in anxious responding. The present research examines that question. In Study 1, compared to a control condition, MS increased anxious responding to spider-related stimuli, but only for participants who met criteria for specific phobia. In Study 2, compared to an aversive control condition, MS increased time spent washing hands, but only for those scoring high on a measure of compulsive hand washing (CHW). In Study 3, compared to a different aversive control condition, MS increased avoidance of a social interaction, but only for those scoring high on a measure of social interaction anxiety. The relevance of TMT in anxious responding is discussed.

Disclosure of HIV status and sexual orientation independently predicts increased absolute CD4 cell counts over time for psychiatric patients

Objective: The objective of this study was to replicate the relationship between disclosure of sexual orientation and immune functioning in HIV-positive persons and to extend those findings to a different type of disclosure (HIV status) and a different population (psychiatric outpatients in a publicly funded HIV/AIDS clinic). Methods: A sample of psychiatric outpatients (N = 373) from a large, urban HIV clinic was assessed for level of sexual orientation and HIV status disclosure as well as absolute CD4 cell counts over time. Mixed-effects random regression analysis was used to build a predictor model that included biobehavioral covariates. Results: Consistent disclosure of both sexual orientation and HIV status independently predicted increased CD4 cell counts over time controlling for important biobehavioral covariates. The only other significant effects in the model were baseline CD4 cell count and number of days between assessment of disclosure and assessment of CD4 cell count. Conclusions: Relieving potential psychological distress by disclosing sexual orientation and HIV status has a positive impact on CD4 cell counts over time even among outpatients stressed by psychiatric illness and economic disadvantage. Additional research is needed to understand whether and under what conditions disclosure should be part of HIV disease management. AIDS = acquired immune deficiency syndrome; BASIS-32 = Behavior and Symptom Identification Scale; HAART = highly active antiretroviral therapy; HIV = human immunodeficiency virus; MCS = Mental Component Summary; PCS = Physical Component Summary; RSO = Relationship to Self and Others; SO = sexual orientation.

Preliminary Findings Concerning the Use of Prazosin for the Treatment of Posttraumatic Nightmares in a Refugee Population

Prazosin, a centrally active alpha-1 adrenergic receptor antagonist, has reduced nightmares and sleep disturbances in placebo-controlled studies involving patients with combat and civilian related posttraumatic stress disorder (PTSD). In this retrospective chart review, we analyzed data from 23 refugees diagnosed with chronic PTSD who were treated with prazosin. The recurrent distressing dreams item of the Clinician Administered PTSD Scale (CAPS) was used to quantify nightmare severity. A Clinical Global Impressions-Change (CGI-C) score assessed change in overall PTSD severity exclusive of nightmares. Using a paired-samples t-test, we found that CAPS scores decreased significantly (p <0.0005) from baseline after 8 weeks of treatment with a stable dose of prazosin. Overall PTSD severity was “markedly improved” in 6 patients, “moderately improved” in 11 patients, and “minimally improved” in 6 patients. These data provide preliminary support for the use of prazosin in targeting reduction of trauma-related nightmares and promoting improvement of global clinical status within an international sample of severely traumatized refugee patients. (Journal of Psychiatric Practice 2009;15:454–459)

Heritability of Pain Catastrophizing and Associations with Experimental Pain Outcomes: A Twin Study

Abstract This study used a twin paradigm to examine genetic and environmental contributions to pain catastrophizing and the observed association between pain catastrophizing and cold-pressor task (CPT) outcomes. Male and female monozygotic (n = 206) and dizygotic twins (n = 194) from the University of Washington Twin Registry completed a measure of pain catastrophizing and performed a CPT challenge. As expected, pain catastrophizing emerged as a significant predictor of several CPT outcomes, including cold-pressor Immersion Tolerance, Pain Tolerance, and Delayed Pain Rating. The heritability estimate for pain catastrophizing was found to be 37% with the remaining 63% of variance attributable to unique environmental influence. Additionally, the observed associations between pain catastrophizing and CPT outcomes were not found attributable to shared genetics or environmental exposure, which suggests a direct relationship between catastrophizing and experimental pain outcomes. This study is the first to examine the heritability of pain catastrophizing and potential processes by which pain catastrophizing is related to experimental pain response.

The effects of daily distress and personality on genital HSV shedding and lesions in a randomized, double-blind, placebo-controlled, crossover trial of acyclovir in HSV-2 seropositive women

Herpes simplex virus (HSV) infections are ubiquitous in humans, but the determinants of clinical and virologic severity are not completely understood. Prior research has suggested that psychological distress can be a co-factor in reactivation of latent HSV infection. Personality traits such as extraversion and neuroticism influence stress attributions and may inform the relationship between psychological distress and health outcomes. Earlier studies in this area have primarily focused on subjective reports of HSV lesion recurrence, but such reports may be influenced by both personality traits and distress. We report results from a randomized, double-blind, placebo-controlled, crossover trial of acyclovir in 19 women for whom personality was assessed at baseline and daily assessments of genital lesions, stress, anxiety, and depression levels were collected for 22 weeks. In addition, daily swabs of the genital mucosa were collected to assess HSV-2 viral reactivation. We found that daily stress predicted genital lesion frequency, and that daily stress, anxiety, and depression predicted genital lesion onset approximately 5 days before onset. Anxiety was also associated with genital lesions 3 days after onset. Distress and viral reactivation were not associated; and no personality traits were associated with any of the outcomes. These results support the hypothesis that psychological distress is both a cause and a consequence of genital lesion episodes.

C-Reactive Protein and Pain Sensitivity: Findings from Female Twins

BackgroundSystemic inflammation and pain sensitivity may contribute to the development and maintenance of chronic pain conditions.PurposeWe examined the relationship between systemic inflammation as measured by C-reactive protein (CRP) and cold pain sensitivity in 198 female twins from the University of Washington Twin Registry. We also explored the potential role of familial factors in this relationship.MethodsLinear regression modeling with generalized estimating equations examined the overall and within-pair associations.ResultsHigher levels of CRP were associated with higher pain sensitivity ratings at pain threshold (p = 0.02) and tolerance (p = 0.03) after adjusting for age, body mass index, time to reach pain threshold or tolerance, and clinical pain status. The magnitude of the associations remained the same in within-pair analyses controlling for familial factors.ConclusionsThe link between CRP and pain sensitivity may be due to non-shared environmental factors. CRP and pain sensitivity can be examined as potential biomarkers for chronic pain and other inflammatory conditions.

Coping, self-efficacy and psychiatric history in patients with both chronic widespread pain and chronic fatigue.

OBJECTIVE To investigate the relationship of coping style and self-efficacy to functional impairment in a group of patients with both chronic widespread pain (CWP) and chronic fatigue, as well as the possible mediating role of psychiatric diagnosis. METHODS We identified 138 consecutive clinic patients who met criteria for CWP and chronic fatigue. We collected demographic and clinical characteristics, as well as measures of emotion-focused and problem-focused coping styles, fatigue-related self-efficacy and self-reported general health. Psychiatric diagnoses were determined with a structured interview. Short Form-36 subscales of pain-related and fatigue-related functioning were the dependent variables in ordinal multiple regression analyses to identify the best-fit model for each. RESULTS In the final model for pain, increased functional impairment was associated with increased emotion-focused coping as well as less education, lower general health scores and higher body mass index. Conversely, in the final model for fatigue, increased functional impairment was significantly associated with less emotion-focused coping, lower general health scores and lower self-efficacy. CONCLUSIONS The unexpected finding that emotion-focused coping was associated differently with chronic pain and fatigue among patients who experience both symptoms is discussed in the context of the research on the effects of self-efficacy and possible treatment approaches.

Current Smoking as a Predictor of Chronic Musculoskeletal Pain in Young Adult Twins

UNLABELLED Chronic pain is common during adolescence and young adulthood and is associated with poor quality of life, depression, and functional disability. Recognizing that chronic pain has significant consequences, it is important to identify modifiable health behaviors that may place young adults at risk for chronic pain. This study examines associations between chronic musculoskeletal pain and smoking in young adult twins (n = 1,588, ages 18-30) participating in a statewide twin registry. Twins completed questionnaires assessing smoking, mood (anxiety, depressive symptoms, and stress), and chronic musculoskeletal pain. Analyses examined associations between chronic pain and smoking, particularly the role of genetics/shared familial factors and psychological symptoms. As predicted, results revealed a near-2-fold increased risk for chronic musculoskeletal pain in twins who currently smoked compared to nonsmokers, even when accounting for psychological factors. Results of within-pair analyses were only minimally attenuated, suggesting that associations between smoking and chronic musculoskeletal pain are better accounted for by nonshared factors than by shared familial factors/genetic effects. Future twin research is needed to identify what nonshared factors (eg, attitudes, direct effects of smoking on pain) contribute to these associations to further understand comorbidity. Longitudinal studies and recruitment of participants prior to smoking initiation and chronic pain onset will better identify causal associations. PERSPECTIVE This article describes associations between musculoskeletal pain and smoking in young adult twins, taking into account psychological symptoms. Findings highlight the importance of nonshared factors in associations between pain and smoking and the need to explore the roles of lifestyle, individual attitudes, and direct effects of smoking on pain.

Chronic Fatigue and Personality: A Twin Study of Causal Pathways and Shared Liabilities

BackgroundThe etiology of chronic fatigue syndrome (CFS) remains unknown. Personality traits influence well-being and may play a role in CFS and unexplained chronic fatigue.PurposeThis study aimed to examine the association of emotional instability and extraversion with chronic fatigue and CFS in a genetically informative sample.MethodsWe evaluated 245 twin pairs for two definitions of chronic fatigue. They completed the Neuroticism and Extraversion subscales of the NEO Five Factor Inventory. Using a co-twin control design, we examined the association between personality and chronic fatigue.ResultsHigher emotional instability was associated with both definitions of chronic fatigue and was confounded by shared genetics. Lower extraversion was also associated with both definitions of fatigue, but was not confounded by familial factors.ConclusionsBoth emotional instability and extraversion are related to chronic fatigue and CFS. Whereas emotional instability and chronic fatigue are linked by shared genetic mechanisms, the relationship with extraversion may be causal and bidirectional.