Elevated Levels Of Stress Hormones Research Articles

Chronic stress boosts systemic inflammation and compromises antiviral innate immunity in Carassius gibel.

It is generally considered that stress causes decreased immune function and render fish vulnerable to infection and diseases. However, the molecular mechanisms between stress responses and susceptibility to infections, especially viral diseases, in fish remain unknown. Understanding and monitoring the biological consequences and mechanisms underlying stress responses in fish may contribute to the improvement of animal welfare and production efficiency. In this study, long-term exposure to a variety of stressors, including chasing, overcrowding, restraint stress, and air exposure mimicking chronic stresses, in aquaculture practices was conducted in Carassius gibel to investigate the consequences of chronic stress on inflammation and antiviral capability. With the continuation of stimulation, experimental fish gradually became insensitive to the stress of net chasing and feeding with the accompaniment of upregulated gene expressed in the HPI axis and elevated levels of stress hormones. As expected, stress-induced hyperglycaemia with a decrease in the insulin signaling pathway and altered gene expression in glycolysis and gluconeogenesis, suggesting the disturbance of glycometabolism. Importantly, a link between intestinal homoeostasis and systemic low-grade inflammation in stressed C. gibel was observed, implying crosstalk among the brain, intestine, and other organs. Furthermore, the compromised antiviral capability with impaired antiviral innate immunity in stressed fish was confirmed by RNA sequencing and infection with Cyprinid herpesvirus 2 (CyHV-2), promoting the understanding of enhanced susceptibility to viral infection in stressed fish.

Green tea consumption and the management of adrenal stress hormones in adolescents who stutter.

Green tea and its polyphenolic compounds have been shown to exert positive effects in individuals with psychological disorders. The protective role of green tea against stuttering or its related consequences, depression, anxiety and stress, were evaluated in adolescents with moderate stuttering (MS). A total of 60 adolescents aged (12-18) years old were enrolled in this study. Patients were classified according to standardized test material Stuttering Severity Instrument, 4th Edition was used to estimate the severity of stuttering; participants were classified into two groups: a normal healthy group (n=30) and a MS group (n=30). The Depression Anxiety Stress Scale and General Health Questionnaire were used to estimate the degree of depression, anxiety and stress as well as general mental health. The physiological profile of stress hormones, as a measure of the response to green tea response, was also measured amongst participants. Adrenal stress hormones cortisol, dehydroepiandrosterone (DHEA), acetylcholine (ACTH), corticosterone and the cortisol:DHEA ratio were assayed. In addition, the constituent green tea polyphenols and their quantities were determined using liquid chromatography analysis. Decaffeinated green tea was administered six cups/day for 6 weeks, and this significantly improved the depression, anxiety, stress and mental health consequences associated with stuttering in adolescents. In addition, increased consumption of green tea significantly reduced elevated levels of adrenal stress hormones; cortisol, DHEA, ACTH and corticosterone, and increased the cortisol:DHEA ratio in the control and adolescents who stuttered. The data showed that drinking six cups of decaffeinated green tea, which is enriched in catechins (1,580 mg) and other related polyphenols, was sufficient to improve the consequences of mental health associated with stuttering in younger aged individuals.

How do red deer react to increased visitor numbers? A case study on human-deer encounter probability and its effect on cortisol stress responses

The numbers of visitors to greenspaces in the United Kingdom has increased over the last few years as the health benefits of spending time in greenspaces have become better known. This has led to problems for conservation ecologists due to increased numbers of reported human-wildlife encounters. Deer are often found in public spaces and are of particular concern. Previous research suggests elevated levels of stress hormones (e.g., cortisol) in deer is a result of increased human activity. This has been linked to several negative effects on the deer’s health. From a practitioner’s point of view, it is therefore important to implement effective management strategies that are based on scientific evidence to help ensure the welfare of managed deer populations. In an effort to identify the impact of visitor numbers on faecal cortisol concentrations, samples from 2 red deer (Cervus elaphus) herds in Lyme Park (Cheshire), United Kingdom, were collected and analysed. A predictive spatial model was developed based on logistic regression to identify areas within the park of low and high human-deer encounter probability. The faecal cortisol levels were found to be significantly higher on days with a high number of visitors. In addition, landscape features such as buildings and roads increased the probability of human-deer encounters, whereas woodland and scrub decreased the probability. However, human-deer encounter probability changed with distance to the features. By providing local park managers with this scientific data, these findings can directly inform current management efforts to reduce deer stress levels in Lyme Park. In addition, the spatial modelling method has the capacity to be implemented in other parks across the country with minimal cost and effort.

Antepartum Depression and Preterm Birth: Pathophysiology, Epidemiology, and Disparities due to structural racism.

Informed by the evidence of links between physiology of stress and parturition, we review recent epidemiologic evidence (2015-2020) of antenatal depression as a risk factor for preterm birth (PTB). We also explain racial/ethnic disparities in depression and preterm birth as a consequence of structural racism. Epidemiologic evidence is consistent in linking antepartum depression with an elevated risk of PTB. Antidepressant usage has been linked with an elevated risk of PTB. However, recent evidence suggests that severity of depression is the underlying driver of the elevated risk attributed to antidepressant usage. The number of depressive symptoms, as a proxy for severity of maternal stress, may be a more informative predictor of PTB than criterion based predictors. Across various study designs, measurement modalities, and populations, antenatal depression predicts an elevated risk of delivering preterm. The physiology of stress provides a plausible explanation for this observation. Excessive stress-induced elevations in maternal and then fetal HPA hormones can alter maternal and fetal homeostasis and hasten the timing of parturition. Antenatal depression and exposure to structural racism are two stressors that can trigger the maternal stress response. Chronically elevated levels of stress hormones among women of color in the USA provide a likely physiologic explanation for Black-White disparities in the risk of PTB. Focusing on the number of depressive symptoms as the more informative predictor of PTB raises several questions. We consider these questions as well as directions for future research in the context of recent advances in the field.

A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks.

Stress activates a complex network of hormones known as the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone‐secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland‐mass dynamics may play an important role in the pathophysiology of stress‐related disorders.

Locus Coeruleus Norepinephrine Drives Stress-Induced Increases in Basolateral Amygdala Firing and Impairs Extinction Learning.

Stress impairs extinction learning, and these deficits depend, in part, on stress-induced norepinephrine (NE) release in the basolateral amygdala (BLA). For example, systemic or intra-BLA administration of propranolol reduces the immediate extinction deficit (IED), an impairment in extinction learning that occurs when extinction trials are administered soon after fear conditioning. Here, we explored whether locus coeruleus (LC)-NE regulates stress-induced changes in spike firing in the BLA and consequent extinction learning impairments. Rats were implanted with recording arrays in the BLA and, after recovery from surgery, underwent a standard auditory fear conditioning procedure. Fear conditioning produced an immediate and dramatic increase in the spontaneous firing of BLA neurons that persisted (and in some units, increased further) up to an hour after conditioning. This stress-induced increase in BLA firing was prevented by systemic administration of propranolol. Conditioning with a weaker footshock caused smaller increases in BLA firing rate, but this could be augmented by chemogenetic activation of the LC. Conditioned freezing in response to a tone paired with a weak footshock was immune to the IED, but chemogenetic activation of the LC before the weak conditioning protocol increased conditioned freezing behavior and induced an IED; this effect was blocked with intra-BLA infusions of propranolol. These data suggest that stress-induced activation of the LC increases BLA spike firing and causes impairments in extinction learning. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with stress- and trauma-related disorders.SIGNIFICANCE STATEMENT Patients with post-traumatic stress disorder (PTSD) show heightened amygdala activity; elevated levels of stress hormones, including norepinephrine; and are resistant to the extinction of fear memories. Here, we show that stress increases basolateral amygdala (BLA) spike firing. This could be attenuated by systemic propranolol and mimicked by chemogenetic activation of the locus coeruleus (LC), the source of forebrain norepinephrine (NE). Finally, we show that LC-NE activation is sufficient to produce extinction deficits, and this is blocked by intra-BLA propranolol. Stress-induced increases in BLA activity mediated by LC-NE may be a viable therapeutic target for individuals with PTSD and related disorders.

Fathers and sons: Physiological stress in male Zaisan mole voles, Ellobius tancrei

The social environment can be stressful for at least some group members, resulting in elevated levels of glucocorticoid stress hormones (GC). Patterns of the relationships between social rank and GC levels vary between species. In carnivores, primates and birds that live in permanent cooperative groups, helpers do not usually display physiological indicators of stress. Very little is known about status-related GC differences within cooperative groups of rodents. In this laboratory study, we compared GC concentrations in dominant (fathers) and subordinate (natal sons) males of a cooperative subterranean vole, Ellobius tancrei. The assessment of adrenocortical activity by measuring urine glucocorticoid metabolites (UGM) was previously validated for this species through an ACTH challenge test. We observed clear peaks of UGM in the second or third urine samples taken after the administration of ACTH (lag time equal to 2.5–3 h). Thus, UGM is suitable to estimate physiological stress in Ellobius. Postpubertal sons living in natal groups had significantly higher UGM concentrations than their fathers. The average UGM levels of sons were positively associated with their ages and paternal body masses, and negatively associated with paternal ages. Hence, son-father interactions rather than just younger ages of sons appear to contribute to GC differences. The revealed pattern was not consistent with that reported for most cooperative species from other taxa, highlighting the importance of comparative studies.

Cardiac Sequelae of Severe Burn Injury

Research Article| March 01 2018 Cardiac Sequelae of Severe Burn Injury AAP Grand Rounds (2018) 39 (3): 34. https://doi.org/10.1542/gr.39-3-34 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Cardiac Sequelae of Severe Burn Injury. AAP Grand Rounds March 2018; 39 (3): 34. https://doi.org/10.1542/gr.39-3-34 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: burns, cardiac complications Source: Hundeshagen G, Herndon DN, Clayton RP, et al. Long-term effect of critical illness after severe paediatric burn injury on cardiac function in adolescent survivors: an observational study. Lancet Child Adolesc Health 2017; 1: 293– 301; doi. https://doi.org/10.1016/S2352-4642(17)30122-0Google Scholar Investigators from multiple institutions conducted a prospective observational study to assess the long-term cardiac sequelae of adolescent survivors of severe pediatric burn injury. Participants were eligible if they had a history of severe burn affecting at least 30% of the total body surface area at least 5 years before the study period, were treated acutely for the burn at the study institution, and were receiving follow-up care at the study institution. A convenience sample of healthy controls was also enrolled as age-matched controls. All study participants had demographic and medical information collected at enrollment, and all underwent transthoracic echocardiography to measure ejection fraction, diastolic function, ventricular compliance, and myocardial fibrosis. Exercise testing was also performed to assess peak oxygen consumption (VO2). Symptoms of heart failure were assessed among burn participants using the New York Heart Association (NYHA) classification (class I: no symptoms or limitation, class II: mild symptoms, class III: marked limitation in activity due to symptoms, and class IV: severe limitations). Investigators compared the cardiac characteristics among burn participants and healthy controls. Data on 40 burn participants and 25 healthy controls were included in analysis. Compared to healthy controls, burn participants had significantly lower ejection fractions (52% vs 61%, P=.004), worse diastolic function, and more myocardial fibrosis. Burn participants also had significantly lower absolute VO2 during exercise testing compared to healthy controls. Overall, most burn participants were classified as NYHA class I (65%), with 33% class II, 3% class III, and none as class IV. The investigators conclude that adolescent survivors of severe burns have long-term reductions in ejection fraction, diastolic function, and exercise tolerance. Dr Spar has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Significant burn injuries can lead to systemic responses affecting every organ system, including the heart and circulatory system. Acutely, cardiac stress secondary to increased catecholamine response is marked by tachycardia, increased myocardial oxygen consumption, and increased cardiac output. There are also elevated levels of catecholamines and stress hormones that persist for many years.1 Though the short-term activation of the stress response is important for survival, the prolonged duration leads to deleterious effects on metabolism, immune function, and cardiovascular function.2 Duke et al3 performed a population-based longitudinal study reviewing children with burn injuries and found that children with burns had 1.3 times as many admissions and 2.3 times the number of days in hospital for circulatory diseases. In a separate population-based longitudinal study, the same authors demonstrated that burn patients had increased hospital admission rates, prolonged length of hospital stay, and increased long-term mortality related to circulatory system diseases.1 The results of... You do not currently have access to this content.

Flight performance in the altricial zebra finch: Developmental effects and reproductive consequences.

The environmental conditions animals experience during development can have sustained effects on morphology, physiology, and behavior. Exposure to elevated levels of stress hormones (glucocorticoids, GCs) during development is one such condition that can have long‐term effects on animal phenotype. Many of the phenotypic effects of GC exposure during development (developmental stress) appear negative. However, there is increasing evidence that developmental stress can induce adaptive phenotypic changes. This hypothesis can be tested by examining the effect of developmental stress on fitness‐related traits. In birds, flight performance is an ideal metric to assess the fitness consequences of developmental stress. As fledglings, mastering takeoff is crucial to avoid bodily damage and escape predation. As adults, takeoff can contribute to mating and foraging success as well as escape and, thus, can affect both reproductive success and survival. We examined the effects of developmental stress on flight performance across life‐history stages in zebra finches (Taeniopygia guttata). Specifically, we examined the effects of oral administration of corticosterone (CORT, the dominant avian glucocorticoid) during development on ground‐reaction forces and velocity during takeoff. Additionally, we tested for associations between flight performance and reproductive success in adult male zebra finches. Developmental stress had no effect on flight performance at all ages. In contrast, brood size (an unmanipulated variable) had sustained, negative effects on takeoff performance across life‐history stages with birds from small broods performing better than birds from large broods. Flight performance at 100 days posthatching predicted future reproductive success in males; the best fliers had significantly higher reproductive success. Our results demonstrate that some environmental factors experienced during development (e.g. clutch size) have stronger, more sustained effects than others (e.g. GC exposure). Additionally, our data provide the first link between flight performance and a direct measure of reproductive success.

Social-Biological Interactions in Oral Disease: A 'Cells to Society' View.

Oral diseases constitute a major worldwide public health problem, with their burden concentrating in socially disadvantaged and less affluent groups of the population, resulting in significant oral health inequalities. Biomedical and behavioural approaches have proven relatively ineffective in reducing these inequalities, and have potentially increased the health gap between social groups. Some suggest this stems from a lack of understanding of how the social and psychosocial contexts in which behavioural and biological changes occur influence oral disease. To unravel the pathways through which social factors affect oral health outcomes, a better understanding is thus needed of how the social ‘gets under the skin,’ or becomes embodied, to alter the biological. In this paper, we present the current knowledge on the interplay between social and biological factors in oral disease. We first provide an overview of the process of embodiment in chronic disease and then evaluate the evidence on embodiment in oral disease by reviewing published studies in this area. Results show that, in periodontal disease, income, education and perceived stress are correlated with elevated levels of stress hormones, disrupted immune biomarkers and increased allostatic load. Similarly, socioeconomic position and increased financial stress are related to increased stress hormones and cariogenic bacterial counts in dental caries. Based on these results, we propose a dynamic model depicting social-biological interactions that illustrates potential interdependencies between social and biological factors that lead to poor oral health. This work and the proposed model may aid in developing a better understanding of the causes of oral health inequalities and implicate the importance of addressing the social determinants of oral health in innovating public health interventions.

Sex-specific ecophysiological responses to environmental fluctuations of free-ranging Hermann's tortoises: implication for conservation.

Physiological parameters provide indicators to evaluate how organisms respond to conservation actions. For example, individuals translocated during reinforcement programmes may not adapt to their novel host environment and may exhibit elevated chronic levels of stress hormones and/or decreasing body condition. Conversely, successful conservation actions should be associated with a lack of detrimental physiological perturbation. However, physiological references fluctuate over time and are influenced by various factors (e.g. sex, age, reproductive status). It is therefore necessary to determine the range of natural variations of the selected physiological metrics to establish useful baselines. This study focuses on endangered free-ranging Hermann's tortoises (Testudo hermanni hermanni), where conservation actions have been preconized to prevent extinction of French mainland populations. The influence of sex and of environmental factors (site, year and season) on eight physiological parameters (e.g. body condition, corticosterone concentrations) was assessed in 82 individuals from two populations living in different habitats. Daily displacements were monitored by radio-tracking. Most parameters varied between years and seasons and exhibited contrasting sex patterns but with no or limited effect of site. By combining behavioural and physiological traits, this study provides sex-specific seasonal baselines that can be used to monitor the health status of Hermann's tortoises facing environmental threats (e.g. habitat changes) or during conservation actions (e.g. translocation). These results might also assist in selection of the appropriate season for translocation.

Long-term Effects of Pediatric Burns on the Circulatory System.

The systemic responses to burns (in particular, elevated levels of catecholamines and stress hormones) have been shown to have an impact on cardiac function for at least 3 years in children with burns. However, it is not clear if these changes lead to long-term effects on the heart. The aim of this study was to assess whether pediatric burn injury is associated with increased long-term hospital use for circulatory diseases. A population-based longitudinal study was undertaken using linked hospital and death data from Western Australia for children younger than 15 years when hospitalized for a first burn injury (n = 10 436) in 1980-2012 and a frequency matched noninjury comparison cohort, randomly selected from Western Australia's birth registrations (n = 40 819). Crude admission rates and cumulative length of stay for circulatory diseases were calculated. Negative binomial and Cox proportional hazards regression modeling were used to generate incidence rate ratios and hazard ratios, respectively. After adjustment for demographic factors and preexisting health status, the burn cohort had 1.33 (incidence rate ratio) times (95% confidence interval [CI]: 1.08-1.64) as many circulatory system hospitalizations, 2.26 times the number of days in hospital with a diagnosis of a circulatory disease (2.26, 95% CI: 1.06-4.81), and were at a higher risk of incident admissions (hazard ratio 1.22, 95% CI: 1.03-1.46), compared with the uninjured cohort. Children who sustain burn injury experience elevated hospital admission rates and increased length of hospital stay for diseases of the circulatory system for a prolonged period of time after burn discharge.

High cytokinin levels induce a hypersensitive-like response in tobacco

Cytokinins are positive regulators of shoot development. However, it has previously been demonstrated that efficient activation of the cytokinin biosynthesis gene ipt can cause necrotic lesions and wilting in tobacco leaves. Some plant pathogens reportedly use their ability to produce cytokinins in disease development. In response to pathogen attacks, plants can trigger a hypersensitive response that rapidly kills cells near the infection site, depriving the pathogen of nutrients and preventing its spread. In this study, a diverse set of processes that link ipt activation to necrotic lesion formation were investigated in order to evaluate the potential of cytokinins as signals and/or mediators in plant defence against pathogens. The binary pOp-ipt/LhGR system for dexamethasone-inducible ipt expression was used to increase endogenous cytokinin levels in transgenic tobacco. Changes in the levels of cytokinins and the stress hormones salicylic, jasmonic and abscisic acid following ipt activation were determined by ultra-performance liquid chromatography-electrospray tandem mass spectrometry (UPLC-MS/MS). Trends in hydrogen peroxide content and lipid peroxidation were monitored using the potassium iodide and malondialdehyde assays. The subcellular distribution of hydrogen peroxide was investigated using 3,3'-diaminobenzidine staining. The dynamics of transcripts related to photosynthesis and pathogen response were analysed by reverse transcription followed by quantitative PCR. The effects of cytokinins on photosynthesis were deciphered by analysing changes in chlorophyll fluorescence and leaf gas exchange. Plants can produce sufficiently high levels of cytokinins to trigger fast cell death without any intervening chlorosis - a hallmark of the hypersensitive response. The results suggest that chloroplastic hydrogen peroxide orchestrates the molecular responses underpinning the hypersensitive-like response, including the inhibition of photosynthesis, elevated levels of stress hormones, oxidative membrane damage and stomatal closure. Necrotic lesion formation triggered by ipt activation closely resembles the hypersensitive response. Cytokinins may thus act as signals and/or mediators in plant defence against pathogen attack.

Prenatal exposure to chronic mild stress increases corticosterone levels in the amniotic fluid and induces cognitive deficits in female offspring, improved by treatment with the antidepressant drug amitriptyline

Prenatal stress and associated in utero exposure to elevated levels of stress hormones can adversely affect the development of the central nervous system, thereby increasing the risk of mental illnesses in later life. Here, we examined the impact of prenatal exposure to chronic mild stress (CMS) on locomotion, anxiety-related behaviour, cognition and hippocampal serotonergic neurotransmission in juvenile and adult B6D2F2 mice, and whether antidepressant treatment in adulthood could reverse the observed behavioural disturbances.Pregnant B6D2F1 female mice were either subjected to CMS or left undisturbed until parturition. Three-week and 7-week-old male and female offspring were assessed in the open-field, novel object recognition and contextual fear conditioning tests. Hippocampal levels of serotonin and its major metabolite were then quantified using high-performance liquid chromatography. Some prenatally-stressed adult females were treated with amitriptyline (20mg/kg/day in drinking water) for 10 days, from the day prior to onset of behavioural testing. In a separate experiment, amniotic fluid was collected from stressed and non-stressed dams on gestational (G) days 13 and 18 to quantify levels of corticosterone. We found that prenatal CMS specifically impaired learning and memory performance in adult females. Amitriptyline elevated hippocampal serotonin levels and attenuated these cognitive deficits. Corticosterone levels in the amniotic fluid were increased by CMS on G13 but by G18, the levels in non-stressed dams reached those of stressed dams.These results suggest that female mice are particularly vulnerable to the adverse developmental effects of prenatal stress which can be improved by appropriate treatment strategies including antidepressants.

Prenatal Programming of Human Neurological Function

The human placenta expresses the genes for proopiomelanocortin and the major stress hormone, corticotropin-releasing hormone (CRH), profoundly altering the “fight or flight” stress system in mother and fetus. As pregnancy progresses, the levels of these stress hormones, including maternal cortisol, increase dramatically. These endocrine changes are important for fetal maturation, but if the levels are altered (e.g., in response to stress), they influence (program) the fetal nervous system with long-term consequences. The evidence indicates that fetal exposure to elevated levels of stress hormones (i) delays fetal nervous system maturation, (ii) restricts the neuromuscular development and alters the stress response of the neonate, (iii) impairs mental development and increases fearful behavior in the infant, and (iv) may result in diminished gray matter volume in children. The studies reviewed indicate that fetal exposure to stress peptides and hormones exerts profound programming influences on the nervous system and may increase the risk for emotional and cognitive impairment.

Elevated levels of stress hormones in crop-raiding male elephants

Crop raiding is one of the most common forms of human–elephant conflict. Deterring elephants from raiding crops requires an understanding of the factors influencing the behavior of the individuals involved. We collected fecal samples from five group ranches in southern Kenya where crop-raiding incidents had occurred (n=10) and two protected areas, Amboseli National Park (n=24) and Maasai Mara National Reserve (n=20). We used molecular sexing to sex the individuals and radioimmunoassay kits to determine the level of glucocorticoid metabolites (i.e. stress hormones) in their dung. All crop-raiding individuals were male and had a significantly elevated concentration of glucocorticoid metabolites as compared with the Amboseli elephants (W=12, P=0.0005). We detected no significant difference between Maasai Mara elephants and either Amboseli or the crop-raiding elephants when just males were compared. Our results suggest that crop raiding may be related to stress in elephants.

Modulating Gene Expression through Psychotherapy: The Contribution of Noninvasive Somatic Interventions

Mapping the relationship between gene expression and psychopathology is proving to be among the most promising new frontiers for advancing the understanding, treatment, and prevention of mental disorders. Each cell in the human body contains some 23,688 genes, yet only a tiny fraction of a cell's genes are active or “expressed” at any given moment. The interactions of biochemical, psychological, and environmental factors influencing gene expression are complex yet relatively accessible technologies for assessing gene expression have allowed the identification of specific genes implicated in a range of psychiatric disorders, including depression, anxiety, and schizophrenia. Moreover, successful psychotherapeutic interventions have been shown to shift patterns of gene expression. Five areas of biological change in successful psychotherapy that are dependent upon precise shifts in gene expression are identified in this article. Psychotherapy ameliorates (a) exaggerated limbic system responses to innocuous stimuli, (b) distortions in learning and memory, (c) imbalances between sympathetic and parasympathetic nervous system activity, (d) elevated levels of cortisol and other stress hormones, and (e) impaired immune functioning. The thesis of this article is that psychotherapies that utilize noninvasive somatic interventions may yield greater precision and power in bringing about therapeutically beneficial shifts in gene expression that control these biological markers. The article examines the manual stimulation of acupuncture points during psychological exposure as an example of such a somatic intervention. For each of the five areas, a testable proposition is presented to encourage research that compares acupoint protocols with conventional therapies in catalyzing advantageous shifts in gene expression.

Further reflections on recent updates to perioperative beta-blocker guidelines

To the Editor, ‘‘For every complex problem, there is an answer that is clear, simple, and wrong.’’ H.L. Mencken. In a recent editorial on perioperative b-blockers, London noted that, ‘‘The current process (on guidelines for perioperative b-blockers) appears to be limited increasingly to the...few effective Class I practices..., leaving the majority of real world clinical controversy in the nebulous Class II category.’’ I write to provide several additional perspectives to this discussion. The foremost viewpoint, given the potential problems of guidelines, is that the issue is not about the guidelines per se, but about the often overlooked postoperative care on surgical wards. The pathogenesis of perioperative myocardial infarction (PMI) is complex. Coronary artery disease is a major factor in the pathogenesis of PMI, but PMI also occurs in patients without critical stenosis or any identifiable coronary lesions. Genetic predisposition, postoperative hypercoagulability, and elevated levels of perioperative stress hormones are additional factors. While much is known about preoperative risk factors in predicting PMI, little is known about the manner in which postoperative risk factors influence PMI. This is the reality, in spite of the knowledge that it is postoperative myocardial ischemia rather than preand intraoperative ischemia that has been identified as an independent predictor of adverse cardiac outcomes, suggesting that the postoperative period is more important. Some of the current controversies of the POISE study centre on the pharmacogenomics and the dose of b-blockers perioperatively. While CYP2D6 genotypes predict the plasma concentrations of metoprolol, plasma concentrations do not predict clinical effects of metoprolol. Pharmacokinetically, metoprolol succinate (extended release) has a greater first pass effect, hence, at least 25% less bioavailability compared with metoprolol tartrate (immediate release). Metoprolol succinate 200 mg is equivalent to metoprolol tartrate 65 mg q12hr. Furthermore, during the postoperative period in the POISE study, a titration protocol was used in order to avoid ‘‘toxicity’’. Thus, based on current evidence, it may be premature to focus on pharmacogenomics of b-blockers, and it is potentially misleading to equate dosages of the extended formulation to the immediate release formulation without recognizing the first pass effect. As alluded to above, the postoperative period may be more clinically important than either the preoperative or the intraoperative period in terms of temporal targeting of interventions to reduce PMI. In this context, one possible interpretation regarding some of the controversy related to the POISE study is that, in addition to the fact that perioperative b-blockers reduce the incidence of PMI, the study findings exposed an unanticipated interaction between b-blockers and other postoperative outcomes, including stroke. We recognize that patients being managed postoperatively on surgical wards have a limited number of assessments. Based on this fact, it is possible that a largescale trial, such the POISE study, involving thousands of postoperative evaluations in high-risk patients was able to unmask an interaction between perioperative b-blocker administration and postoperative risk factors, such as bleeding, anemia, or even sepsis, that were not easily predictable in the preoperative period. In the current debate, the adverse effects in the POISE study are difficult to reconcile. Many practitioners have suggested that these adverse events could be eliminated or reduced by further fine-tuning preoperative risk factors. If H. Yang, MD (&) University of Ottawa, Ottawa, ON, Canada e-mail: hyang@ottawahospital.on.ca

Effects of in vivo hyperthermia on natural killer cell activity, in vitro proliferative responses and blood mononuclear cell subpopulations

This work was designed to test the hypothesis that elevations in body temperature of humans induce immunostimulation. Eight healthy volunteers were immersed in a water bath (water temperature 39.5 degrees C) for 2 h, during which their rectal temperature rose to 39.5 degrees C. On a later day they served as their own controls, being immersed into thermoneutral water (34.5 degrees C) for 2 h. Blood samples were collected before immersion, at body temperatures of 38 degree C, 39 degree C and 39.5 degree C, and 2 h after water immersion. The interleukin-2 (IL-2) enhanced natural killer (NK) cell activity (lysis per fixed number of mononuclear cells), as well as the proportion and total number of NK cells (CD16+ cells), increased significantly during hyperthermia compared with control values. The lymphocyte proliferative responses did not differ significantly between hyperthermia and thermoneutral conditions. The proportion of pan-T (CD3+) cells was maximally depressed 2 h after water immersion. The decreased proportion of CD3+ cells was mainly due to a decreased percentage of CD4+ cells (not significant). The proportion of B cells (CD19+ cells) did not fluctuate significantly, while a marked and significant increase in monocyte proportion (CD14+ cells) was found 2 h after hyperthermia. Two hours after hot water immersion the lymphocyte concentration declined while the neutrophil and monocyte concentrations were augmented. Induced hyperthermia causes significantly increased serum cortisol, plasma norepinephrine and plasma epinephrine concentrations compared to controls. It is possible that the altered immune functions induced by elevated body temperature can be ascribed to altered composition and function of blood mononuclear cells induced by elevated levels of stress hormones.

Endotoxin increases plasma leptin and ghrelin levels in dogs*

Evaluations of plasma leptin and ghrelin levels and their relations with circulating levels of proinflammatory mediators, stress hormones, and biochemical markers of hepatorenal injury during experimental endotoxemia in dogs. Uludag University. Placebo-controlled animal study. Adult mongrel dogs (n = 16). Intravenous injection of endotoxin (1 mg/kg) and blood sample withdrawal before and at 0.5-48 hrs posttreatment. Mean baseline plasma leptin and ghrelin levels were 2.4 +/- 0.1 ng/mL and 867 +/- 58 pg/mL, respectively. Plasma leptin and ghrelin increased significantly by 16% (p < .05) and 72% (p < .001) at 0.5 hr, and they remained elevated by 33-41% (p < .001) and 59-74% (p < .001) at 48 hrs after administration of endotoxin, respectively. There was positive correlation (r = .844; p < .001) between plasma leptin and ghrelin levels in endotoxin-treated dogs. Endotoxemia was associated with several-fold elevations in circulating levels of stress hormones, proinflammatory mediators, and hepatorenal injury markers. Plasma leptin and ghrelin levels in endotoxin-treated dogs were correlated with serum nitric oxide (r = .955 and r = .890; p < .001), procalcitonin (r = .825 and r = .716; p < .001), cortisol (r = .823 and r = .786; p < .001), and hepatorenal injury markers (r = .580 to .745 and r = .393 to .574; p < .05 to .01). Circulating leptin and ghrelin levels increase during endotoxemia, and these increases are associated with elevated levels of proinflammatory mediators, stress hormones, and serum biochemical markers for hepatorenal dysfunction.