Robert M. Rose

Social regulation of gene expression in human leukocytes

BackgroundSocial environmental influences on human health are well established in the epidemiology literature, but their functional genomic mechanisms are unclear. The present study analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates.ResultsDNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-κB/Rel transcription factors (p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways.ConclusionThese data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.

Localization of distinct monoamine oxidase a and monoamine oxidase b cell populations in human brainstem

Monoclonal antibodies, specific for either monoamine oxidases A or B, were used to determine the localization of monoamine oxidase in the human brain. Two distinct populations of neurons were detected by immunocytochemical staining. Neurons in regions rich in catecholamines were positive for monoamine oxidase A, including the nucleus locus coeruleus, the nucleus subcoeruleus and the medullary reticular formation. In these regions, monoamine oxidase A could be co-localized with the synthetic enzyme, dopamine-beta-hydroxylase. Neurons in the substantia nigra and the periventricular region of the hypothalamus, areas rich in dopamine neurons, stained for monoamine oxidase A but with much less frequency and intensity. The major accumulation of monoamine oxidase B-positive neurons was observed in the same regions in which monoamine oxidase B is found to co-localize with serotonin in monkey tissues, including the nucleus raphe dorsalis and the nucleus centralis superior. In addition, both monoamine oxidase A and B were localized in distinct populations of neurons in the lateral and tuberal regions of the hypothalamus, a region shown recently to contain histamine neurons in rats. Some glial cells were stained throughout the brain for monoamine oxidase A or B suggesting that glia are capable of either expression or uptake of these proteins.

Consequences of social conflict on plasma testosterone levels in rhesus monkeys.

&NA; Four adult male rhesus monkeys formed a new social group with 13 adult females. The male who became dominant [alpha] showed a progressive increase in plasma testosterone. The male who became subordinate to the other three males showed an 80% fall in testosterone from baseline levels. After 7 weeks, this group was introduced to a well‐established breeding group, and all four males became subordinate to all members of the breeding group. All four males evidenced a fall in testosterone during the first week after introduction, and within 6 weeks their levels were approximately—80% of pre‐introduction values. The alpha male of the breeding group showed a large increase in testosterone [238%] 24 hr after he successfully defended his group and became the dominant animal of the larger, newly‐formed group. Thus, plasma testosterone levels appear to be significantly influenced by the outcome of conflict attendant to alterations in status of rhesus monkeys living in social groups.

assessment of Aggressive Behavior and Plasma Testosterone in a Young Criminal Population

&NA; Plasma testosterone, levels of fighting and verbal aggression in prison and past criminal behavior were studied in 21 young prisoners. In addition, several psychologic tests were administered. Analysis of plasma testosterone showed considerable stability of an individuals values over the 2‐week study period, with highly significant differences observed between individuals. Plasma testosterone levels did not differ in fighting and nonfighting individuals. Although there were significant correlations between psychologic tests, the test scales did not correlate either with plasma testosterone or with fighting behavior. The 10 prisoners with histories of more violent and aggressive crimes in adolescence had a significantly higher level of testosterone than the 11 prisoners without such a history. An hypothesis is presented that within a population that is predisposed by virtue of social factors to develop antisocial behaviors, levels of testosterone may be an important additional factor in placing individuals at risk to commit more aggressive crimes in adolescence.

Depression and work productivity : The comparative costs of treatment versus nontreatment

This article discusses the impact of depression on work productivity and the potential for improved work performance associated with effective treatment. We undertook a review of the literature by means of a computer search using the following key terms: cost of illness, work loss, sickness absence, productivity, performance, and disability. Published works were considered in four categories: (1) naturalistic cross-sectional studies that found greater self-reported work impairment among depressed workers; (2) naturalistic longitudinal studies that found a synchrony of change between depression and work impairment; (3) uncontrolled treatment studies that found reduced work impairment with successful treatment; and (4) controlled trials that usually, but not always, found greater reduction in work impairment among treated patients. Observational data suggest that productivity gains following effective depression treatment could far exceed direct treatment costs. Randomized effectiveness trials are needed before we can conclude definitively that depression treatment results in productivity improvements sufficient to offset direct treatment costs.

Bridging psychology and biology: The analysis of individuals in groups

Biological systems are particularly prone to variation, and the authors argue that such variation must be regarded as important data in its own right. The authors describe a method in which individual differences are studied within the framework of a general theory of the population as a whole and illustrate how this method can be used to address three types of issues: the nature of the mechanisms that give rise to a specific ability, such as mental imagery; the role of psychological or biological mediators of environmental challenges, such as the biological bases for differences in dispositional mood; and the existence of processes that have nonadditive effects with behavioral and physiological variables, such as factors that modulate the response to stress and its effects on the immune response.

Altering expectancy dampens neural response to aversive taste in primary taste cortex

The primary taste cortex consists of the insula and operculum. Previous work has indicated that neurons in the primary taste cortex respond solely to sensory input from taste receptors and lingual somatosensory receptors. Using functional magnetic resonance imaging, we show here that expectancy modulates these neural responses in humans. When subjects were led to believe that a highly aversive bitter taste would be less distasteful than it actually was, they reported it to be less aversive than when they had accurate information about the taste and, moreover, the primary taste cortex was less strongly activated. In addition, the activation of the right insula and operculum tracked online ratings of the aversiveness for each taste. Such expectancy-driven modulation of primary sensory cortex may affect perceptions of external events.

Aggression and social controls in rhesus monkey (Macaca mulatta) groups revealed in group formation studies.

Agonistic responses were the primary form of social interaction during five rhesus group formations. Males showed the most extreme forms of aggression initially, but as formative processes progressed, females became more active and aggression less severe. Initial agonistic interactions serve to establish the social order of an emerging group. As a group becomes organized, extreme forms of aggression disappear and aggressive frequencies decline.

Cortisol and growth hormone responses to psychological stress during the menstrual cycle.

&NA; Twenty‐one healthy women were studied during one menstrual cycle in order to determine whether cortisol and growth hormone responsivity to psychological stress was related to estrogen levels. Blood was drawn approximately three times per week for analysis of estradiol, progesterone, cortisol, and human growth hormone. During either the menstrual or intermenstrual phase, each subject participated in an interview that was designed to be mildly stressful. State and trait anxiety were assessed using the Spielberger State‐Trait Anxiety Inventory. Anxiety state was measured prior to and immediately following exposure to the psychological stress; trait anxiety was assessed at the end of the study. Cortisol and growth hormone responses to the psychological stress were not related to menstrual cycle phase. Anxiety levels were also independent of menstrual cycle phase. Subjects who displayed significant cortisol and/or growth hormone responsivity to the interview had significantly higher anxiety levels post stress than did nonresponders, although anxiety level prior to the interview was not different for the two groups.

Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia.

Experimental and clinical data suggest that GABA-ergic drugs such as valproate may have a potential role in the treatment of schizophrenia. The authors designed a 21-day prospective, double-blind, randomized, placebo-controlled pilot study of divalproex sodium as add-on treatment to haloperidol in 12 hospitalized patients with acute exacerbations of chronic schizophrenia. All patients received haloperidol 10 mg/day for 3 days and 15 mg/day for the remaining 18 days. In addition, five patients were randomly assigned to receive divalproex augmentation and seven to receive placebo. The divalproex dose was adjusted to a target serum concentration of 75 microg/mL for 2 weeks; placebo replaced divalproex during the third and last weeks to determine any carryover effect. Psychiatric rating scales were administered at baseline and on days 7, 14, and 21. Although the placebo group improved with haloperidol treatment, the divalproex group demonstrated greater improvement. On day 21, the divalproex group had greater improvement from baseline on the Clinical Global Impression Scale (p < or = 0.04), Brief Psychiatric Rating Scale (p < or = 0.13), and Schedule for Assessment of Negative Symptoms scores (p < or = 0.007). After divalproex withdrawal on day 15, a carryover effect was observed during week 3. The authors concluded that the addition of divalproex sodium to standard antipsychotic drugs may prove effective in relieving the symptoms of acute schizophrenia. Future studies may benefit from the design of this pilot study. However, it is premature to apply this augmentation strategy in the clinical setting just yet because of the small sample size and the likely heterogeneity of the disorder.