Human Stress Response Research Articles

Acute psycho-social stress does not disrupt item-method directed forgetting, emotional stimulus content does

It has been shown that stress affects episodic memory in general, but knowledge about stress effects on memory control processes such as directed forgetting is sparse. Whereas in previous studies item-method directed forgetting was found to be altered in post-traumatic stress disorder patients and abolished for highly arousing negative pictorial stimuli in students, no study so far has investigated the effects of experimentally induced psycho-social stress on this task or examined the role of positive picture stimuli. In the present study, 41 participants performed an item-method directed forgetting experiment while being exposed either to a psychosocial laboratory stressor, the Trier Social Stress Test (TSST), or a cognitively challenging but non-stressful control condition. Neutral and positive pictures were presented as stimuli. As predicted, salivary cortisol level as a biological marker of the human stress response increased only in the TSST group. Still, both groups showed directed forgetting. However, emotional content of the employed stimuli affected memory control: Directed forgetting was intact for neutral pictures whereas it was attenuated for positive ones. This attenuation was primarily due to selective rehearsal improving discrimination accuracy for neutral, but not positive, to-be-remembered items. Results suggest that acute experimentally induced stress does not alter item-method directed forgetting while emotional stimulus content does.

Variant in oxytocin receptor gene is associated with amygdala volume

The oxytocin system plays a significant role in modulating stress responses in animals and humans; perturbations in this system may contribute to the pathogenesis of psychiatric disorder. Attempts to identify clinically relevant genetic variants in the oxytocin system have yielded associations between polymorphisms of the oxytocin receptor (OXTR) gene and both autism and major depression. To date, however, little is known about how such variants affect brain structures implicated in these disorders. Applying a manual tracing procedure to high-resolution structural magnetic resonance images, amygdala volumes were measured in 51 girls genotyped on OXTR rs2254298(G>A), a single nucleotide polymorphism associated with psychopathology. Results of this study indicate that despite having greater gray matter volume, participants homozygous for the G allele were characterized by smaller volumes of both left and right amygdala than were carriers of the A allele. A subsequent whole-brain voxel-based morphometry analysis revealed additional genotype-mediated volumetric group differences in the posterior brain stem and dorsomedial anterior cingulate cortex. These findings highlight one neurobiological pathway by which oxytocin gene variants may increase risk for psychopathology. Further research is needed to characterize the mechanism by which this polymorphism contributes to anatomical variability and to identify functional correlates of these alterations in regional brain volume.

Helplessness and perceived pain intensity: relations to cortisol concentrations after electrocutaneous stimulation in healthy young men

BackgroundUncontrollable aversive events are associated with feelings of helplessness and cortisol elevation and are suitable as a model of depression. The high comorbidity of depression and pain symptoms and the importance of controllability in both conditions are clinically well-known but empirical studies are scarce. The study investigated the relationship of pain experience, helplessness, and cortisol secretion after controllable vs. uncontrollable electric skin stimulation in healthy male individuals.MethodsSixty-four male volunteers were randomly assigned to receive 30 controllable (self-administered) or uncontrollable (experimenter-administered) painful electric skin stimuli. Perceived pain intensity (PPI), subjective helplessness ratings, and salivary cortisol concentrations were assessed. PPI was assessed after stress exposure. For salivary cortisol concentrations and subjective helplessness ratings, areas under the response curve (AUC) were calculated.ResultsAfter uncontrollable vs. controllable stress exposure significantly higher PPI ratings (P = 0.023), higher subjective helplessness AUC (P < 0.0005) and higher salivary cortisol AUC (P = 0.004, t-tests) were found. Correlation analyses revealed a significant correlation between subjective helplessness AUC and PPI (r = 0.500, P < 0.0005), subjective helplessness AUC and salivary cortisol AUC (r = 0.304, P = 0.015) and between PPI and salivary cortisol AUC (r = 0.298, P = 0.017).ConclusionsThe results confirm the impact of uncontrollability on stress responses in humans; the relationship of PPI with subjective helplessness and salivary cortisol suggests a cognitive-affective sensitization of pain perception, particularly under uncontrollable conditions.

Book Review: Healing Spaces: The Science of Place and Well-Being

Healing Spaces: The Science of Place and Well- Being. (2009). Esther Sternberg, MD. Cambridge, MA: Belknap Press of Harvard University Press. Hardcover, 352 pages. ISBN-13: 978-0-674- 03336-8. Paperback: $12.53; hardcover: $34.34.Ancient civilizations understood the power of the mind to heal or harm the body. This was largely forgotten when science began to demand empirical proof as the standard of scientific evidence. Esther Sternberg's Healing Spaces: The Science of Place and Well-Being takes us back to the earliest understanding that emotions and health are intertwined, this time revealing the scientific method within. Dr. Sternberg positions this scientific understanding in the context of place, showing how the environment can contribute to wellbeing and health. She does this by investigating the body's sensual perceptions and physiological response to the physical environment.Sternberg frames the scientific investigation of the links between the healing process and the environment by asking a simple question: Can the spaces around us help us heal? (2009, p. 1). She articulates how physical space affects and transforms the healing process. Sternberg is a physician who has extensively studied the interaction between the brain and the functioning of the immune system, as well as the psychophysiological effects of stress on health. Fortunately for designers, she has dedicated this book to exploring the role of the physical environment on these issues.Dr. Sternberg takes us on a journey through the senses of sight, sound, touch, smell, and spirit. She discusses the effect of the environment on the continuum of illness and health and how throughout our lifetime the environment can produce changes in our health. Healing Spaces offers fascinating case studies woven together to form a more holistic understanding of oneself and one's environment, always returning to the ideas of health, healing, and often healthcare. She creates this broad understanding by introducing the reader first to the macro-scale, and then delving into the micro-scale to create a more dynamic and complete understanding of the subject.Although many of us believe in the healing powers of the environment, few understand the psychophysiological mechanisms that bring about this healing effect. This phenomenon is tied to the human stress response, in which chronic stress leads to suppression of the immune system, stifling the body's ability to heal. While developing the polio vaccine, immunologist Jonas Salk began feeling a sense of chronic stress and fatigue. Exhausted, he took a sabbatical to Assisi, Italy, where he was transformed by the beauty and spirit of the place, and he returned home to create the vaccine. Moved by his experience, Salk created a facility that would impart the same spirit, light, and nature as Assisi. Because of this moving experience, we now have the Salk Institute in La Jolla, California, one of the top centers for innovative scientific research.Just as Salk was inspired by the beauty of Assisi, people are affected emotionally by sound and music. Sound perception is connected to different regions of the brain that are associated with reward, emotion, memory, and movement. These associations give music its power to thrill, delight, and elicit the memory of the night one first danced to its rhythms. …

Salivary Hsp72 does not track exercise stress and caffeine-stimulated plasma Hsp72 responses in humans

Heat shock protein 72 (Hsp72) has been detected within saliva, and its presence may contribute to oral defence. It is currently unknown how physiological stress affects salivary Hsp72 or if salivary Hsp72 concentrations reflect plasma Hsp72 concentrations. We studied the effect of exercise upon salivary Hsp72 expression, and using caffeine administration, investigated the role of sympathetic stimulation upon salivary Hsp72 expression. Six healthy males performed two treadmill running exercise bouts in hot conditions (30°C) separated by 1week in a randomized cross-over design, one with caffeine supplementation (CAF) the other with placebo (PLA). Plasma and saliva samples were collected prior to, during and post-exercise and assayed for Hsp72 concentration by ELISA. Exercise significantly increased plasma Hsp72, but not salivary Hsp72 concentration. Mean salivary Hsp72 concentration (5.1 ± 0.8ng/ml) was significantly greater than plasma Hsp72 concentration (1.8 ± 0.1ng/ml), and concentrations of salivary and plasma Hsp72 were unrelated. Caffeine supplementation and exercise increased the concentration of catecholamines, salivary α-amylase and total protein, whilst the salivary Hsp72:α-amylase ratio was lower in CAF. Salivary Hsp72 was not altered by exercise stress nor caffeine supplementation, and concentrations did not track plasma Hsp72 concentration.

Study of coastal water zone ecosystem health in Zhejiang Province based on remote sensing data and GIS

The coastal ecosystem health assessment is a field of increasing importance. In this paper, a preliminary assessment of ecosystem health in Zhejiang coastal water zone was made, mainly based on remote sensing data and GIS technique. Its spatial and quantitative evaluation was facilitated by the progress of remote sensing and GIS technique development. Firstly, human activities, hydrology and ecosystem problems in the study area were discussed and analyzed. Secondly, from 4 aspects of human stress, physical, chemical and biological responses to anthropogenic activities and natural stress, several indicators such as water transparency (Secchi Disk Depth, SDD), suspended substance concentration, dissolved inorganic nitrogen, active phosphate, chlorophyll, harmful algae bloom, as well as distribution of sewage, sea lanes and port were employed. Thirdly, the Analytic Hierarchical Process was used for indicator weight calculation, and the ecosystem health criteria were established according to the integrative analysis of national water quality criteria, similar coastal ecosystem health research in other places or data inherent properties. The results indicated that from 2005 to 2007 the coastal water ecosystem health value in Zhejiang Province was unhealthy and needs ecological restoration by human intervention.

Corticotropin-Releasing Factor Regulates TLR4 Expression in the Colon and Protects Mice From Colitis

Defects in the colonic innate immune response have been associated with inflammatory bowel disease (IBD). Corticotropin-releasing hormone (CRH, or corticotropin-releasing factor [CRF]) is a neuropeptide that mediates the stress response in humans, is an immunomodulatory factor with proinflammatory effects, and regulates transcription of Toll-like receptors (TLR)-2 and TLR4. We investigated the role of CRF in an innate immunity-dependent mouse model of IBD. Crh(-/-) and wild-type (Crh(+/+)) mice, which are glucocorticoid insufficient, were given dextran sodium sulfate in their drinking water to induce colitis; in some experiments, mice were also given glucocorticoids. Phenotypes of mice were compared; tissues were analyzed by histology and for expression of immune mediators. Crh(-/-) mice had more colonic inflammation than Crh(+/+) mice, characterized by reduced numbers of crypts and severe epithelial damage and ulcerations. Colonic tissue levels of the proinflammatory factors interleukin-12 and prostaglandin E(2) were increased in the Crh(-/-) mice. Colons of Crh(-/-) mice expressed lower levels of Tlr4 than wild-type mice before, but not after, colitis was induced. Administration of glucocorticoid at low levels did not prevent Crh(-/-) mice from developing severe colitis. Crh(-/-) mice were unable to recover from acute colitis, as indicated by their increased death rate. Mice deficient in CRF down-regulate TLR4 and are more susceptible to dextran sodium sulfate-induced colitis. CRF has anti-inflammatory effects in innate immunity-dependent colitis and its recovery phase; these are independent of glucocorticoid administration. CRF might therefore be developed as a therapeutic target for patients with IBD.

Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits

Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity...

Comparative Human Cell Toxicogenomic Analysis of Monohaloacetic Acid Drinking Water Disinfection Byproducts

The monohaloacetic acids (monoHAAs), iodoacetic, bromoacetic and chloroacetic acids are toxic disinfection byproducts. In vitro toxicological end points were integrated with DNA damage and repair pathway-focused toxicogenomic analyses to evaluate monoHAA-induced alterations of gene expression in normal nontransformed human cells. When compared to concurrent control transcriptome profiles, metabolic pathways involved in the cellular responses to toxic agents were identified and provided insight into the biological mechanisms of toxicity. Using the Database for Annotation, Visualization and Integrated Discovery to analyze the gene array data, the majority of the altered transcriptome profiles were associated with genes responding to DNA damage or those regulating cell cycle or apoptosis. The major pathways involved with altered gene expression were ATM, MAPK, p53, BRCA1, BRCA2, and ATR. These latter pathways highlight the involvement of DNA repair, especially the repair of double strand DNA breaks. All of the resolved pathways are involved in human cell stress response to DNA damage and regulate different stages in cell cycle progression or apoptosis.

Glucagon-like peptide-1 receptor gene polymorphism ( Leu260Phe) is associated with morning cortisol in preschoolers

Glucagon-like peptide-1 (GLP-1) has been shown to be a potent stress-regulating neuropeptide in animal models, but little is known about whether genetic polymorphisms that influence this peptide influence stress responses in humans. We therefore explored whether a missense mutation (rs1042044) in the GLP-1 receptor was associated with morning and evening salivary cortisol levels in preschool aged children. Morning and evening saliva samples and individual buccal swabs for DNA extraction were collected from seventy-seven preschool aged children. Salivary cortisol was assayed using a time-resolved fluorescence immunoassay with fluorometric end-point detection (DELFIA), and the rs1042044 single nucleotide polymorphism (SNP) was genotyped using allele specific TaqMan probes. Children homozygous for the phenylalanine (C) substitution in the GLP-1R gene had significantly higher morning salivary cortisol levels than children with other GLP-1R genotypes ( p = 0.029). Additionally, children with one or two copies of the phenylalanine (C) allele had significantly higher morning cortisol levels compared to children homozygous for the leucine (A) allele ( p = 0.008). Our results identify associations between a novel genetic variant of GLP-1R and hypothalamus–pituitary–adrenal (HPA) axis regulation. This polymorphism may have functional significance in stress-related psychiatric disorders.

Hormonal Reactivity to Extreme Military Stress: Effect Of Psychological Skills Training

A better understanding of individual differences in the human stress response is needed for performance maintenance under stress as well as prevention and treatment of operational stress reactions. Military operations provide a unique opportunity to examine the influence of realistic physical and psychological stress on human health in an ecologically valid context. PURPOSE: We examined hormonal reactivity during stressful military survival training. A second purpose was to explore effects of a brief psychological skills training (PST) intervention. METHOD: Baseline salivary data were collected in 75 military subjects prior to stressful field exercises during survival training. Subjects were then randomized either to PST or a control group (C) that received no training beyond the normal survival training curriculum. PST received training in goal setting, mental imagery, arousal control, and positive self-talk in two separate sessions. Salivary samples were subsequently taken from all subjects during a stressful mock-captivity phase of training as well as 24 hours after the conclusion of training. Repeated-measures analyses of variance with follow-up paired t tests examined differences across time and conditions. RESULTS: Substantial increases were observed in response to military stress for interleukin-6 (p <.05) while decreases were observed for secretory immunoglobulin-A (p <.001), androstenedione (p <.001) and alpha amylase (p <.001). Inconsistent with prior research, substantial increases in testosterone were observed (p <.001). No differences were shown between PST and C, nor were there any interaction effects. CONCLUSIONS: Military survival training results in dramatic, analyte-specific shifts in hormone function. Brief PST does not appear to influence these effects.

Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits

Evidence of marked variability in response among people exposed to the same environmental risk implies that individual differences in genetic susceptibility might be at work. The study of such Gene-by-Environment (GxE) interactions has gained momentum. In this article, the authors review research about one of the most extensive areas of inquiry: variation in the promoter region of the serotonin transporter gene (SLC6A4; also known as 5-HTT) and its contribution to stress sensitivity. Research in this area has both advanced basic science and generated broader lessons for studying complex diseases and traits. The authors evaluate four lines of evidence about the 5-HTT stress-sensitivity hypothesis: 1) observational studies about the serotonin transporter linked polymorphic region (5-HTTLPR), stress sensitivity, and depression in humans; 2) experimental neuroscience studies about the 5-HTTLPR and biological phenotypes relevant to the human stress response; 3) studies of 5-HTT variation and stress sensitivity in nonhuman primates; and 4) studies of stress sensitivity and genetically engineered 5-HTT mutations in rodents. The authors then dispel some misconceptions and offer recommendations for GxE research. The authors discuss how GxE interaction hypotheses can be tested with large and small samples, how GxE research can be carried out before as well as after replicated gene discovery, the uses of GxE research as a tool for gene discovery, the importance of construct validation in evaluating GxE research, and the contribution of GxE research to the public understanding of genetic science.

The influence of percutaneous nephrolithotomy on human systemic stress response, SIRS and renal function

The objective of this study is to investigate the influences of percutaneous nephrolithotomy (PNL) and open surgery nephrolithotomy on the systemic stress response, SIRS and renal function. Forty patients with kidney calculi were enrolled in the study. Twenty cases were randomized to the PNL group and the other twenty cases to the open surgery group. Levels of C-reactive protein (CRP), interleukin-6(IL-6), β(2)-microglobulin (β(2)-MG), respiration rate, heart rate, body temperature and white blood cell counts were examined. CRP and IL-6 were measured in all patients pre-operatively and on post-operative days 1, 3 and 6, respectively. There was significant difference in their pre- and post-operation levels (P < 0.05), with the peak of CRP and IL-6 observed at post-operative days 3 and 1, respectively. There was significant difference in both CRP and IL-6 between the two groups (P < 0.05). At post-operative day 1, there were 5 cases of SIRS in PNL group and 12 cases in open surgery group; there was significant difference between the two groups (P < 0.05). Serum β(2)-MG levels were measured as the same time as CRP and no significant changes were observed within or between the groups (P > 0.05). Urine β(2)-MG levels were also measured. There was significant difference between pre- and the first day post-PNL (P < 0.05); there was no significant difference between pre- and the third and sixth day post-PNL (P > 0.05). There was significant difference between pre- and first and third day post-open surgery (P < 0.05); but there was no significant difference between pre- and the sixth day post-open surgery (P > 0.05). There was significant difference between two groups at the first, third and sixth days (P < 0.05). The systemic stress response is activated both in PNL group and open surgery group to some extent. The degree of stress response of PNL is lower than that of open surgery, proving the advantages of PNL with reference to serum immunology. There were cases in both the groups with SIRS, but the degree of SIRS in PNL group was lesser than the other group. Both the groups have no obvious effect on glomerular filtration function after operation and have effect on renal tubular reabsorption in the early stage after operation; but the recovery of the PNL group is faster than the open surgery group. It is thus shown that PNL is much safer and more feasible and has lesser effect on renal function.

Neurobiological adaptations to violence across development.

Developmental adaptations to violent environments involve a multitude of cascading effects spanning many levels of analysis from genes to behavior. In this review, we (a) examine the potentiating effects of violence on genetic vulnerabilities and the functioning of neurotransmitter systems in producing both internalizing and externalizing psychopathology; (b) describe implications of violence exposure for brain development, particularly within the hippocampus and prefrontal cortex; and (c) consider the effects of violence on developing human stress and startle responses. This review integrates literatures on the developmental effects of violence among rodents, nonhuman primates, and humans. Many neurobiological changes that are adaptive for survival in violent contexts become maladaptive in other environments, conferring life-long risk for psychopathology.

Examining infants' cortisol responses to laboratory tasks among children varying in attachment disorganization: Stress reactivity or return to baseline?

Cortisol is a hormone involved in mounting a stress response in humans. The evidence of stress reactivity among young children has been mixed, however. In the present study, the order of two laboratory tasks (i.e., Strange Situation and play) was counterbalanced, and home saliva samples were obtained. Saliva samples were also collected upon the children's arrival at the laboratory and at 40, 65, and 80 min after arrival. The authors examined changes in cortisol using piecewise hierarchical linear modeling, testing whether observed increases reflected a return to baseline or stress reactivity. An interaction between attachment disorganization and task emerged, such that disorganized infants showed increases in cortisol in response to the stressor compared with play, whereas organized infants did not show cortisol reactivity to either task. Implications for the buffering effects of maternal care on stress reactivity are discussed.

Brain-Body Interactions: The Physiological Impact of Mental Processes — The Neurobiology of the Stress Response

CME Educational Objectives 1. Cite the neurobiological basis of the human stress response. 2. Review the mechanisms by which psychosocial stressors and psychiatric illness activate stress responses and cause physiological alterations that can aggravate medical conditions. 3. Explain the biological basis of inflammatory responses and how they can be triggered by stress and psychiatric illness.

Thioredoxin Interacting Protein (TXNIP) Correlates with Production of Reactive Oxygen Species (ROS) and Underlines Differences in Stress Response Gene Profile in Patients with Chronic Lymphocytic Leukemia (CLL).

Abstract 4375 IntroductionOur previous studies have focused on the role of TXNIP/ROS/TRX axis and hyperglycemia in breast cancer (Clin Cancer Res.13:3724-30, 2007). A main function of thioredoxin-interacting protein (TXNIP) is to bind and inactivate thioredoxin (TRX) leading to increased reactive oxygen species (ROS) production and apoptosis. While ROS and TRX have been examined in CLL, no studies have been performed on TXNIP levels. Based on the fact that CLL is known to have high levels of ROS compared to normal individuals and that TRX has been shown to have a protective function in CLL, we wanted to first determine if there was any correlation between TXNIP RNA and ROS production, and whether there was any relationship with TRX levels in patient plasma. MethodsVenous blood samples were obtained from the first ten consecutive patients with definite diagnosis of CLL during their routine clinic visits. Patients were selected without regard to demographics or stage or grade of disease. Prior treatment for CLL was not an exclusion criterion. Cells were purified using a Ficoll density gradient. ROS activity was measured using DCFDA by flow cytometry and reported as mean fluorescence intensity. TXNIP and TRX RNA levels were assessed by semi-quantitative PCR. Thioredoxin levels in plasma were measured using a thioredoxn-1 Elisa. Gene profiling of our patient extremes was accomplished using the Human Stress Response 96 StellARray plate and analyzed using Global Pattern Recognition software [Display omitted] ResultsOver a four week period, 10 CLL patients were seen in our clinic and participated in this study. Six out of the 10 patients were either actively being treated or had finished treatment for CLL. The rest were under observation. Three out of the 10 patients had trisomy 12 on FISH and the remaining had normal cytogenetics. We examined the levels of TXNIP RNA in our samples. The median level of TXNIP was 0.77 relative ratio (range: 0.45-1.01). The median ROS levels in our patient samples was 7108 (range 2340-10861). We found a statistically significant correlation between the level of TXNIP RNA and ROS (Fig. 1). TRX RNA levels did not significantly differ among the patients. We also measured TRX levels in the patient plasma and found a median level of 33 ng/ml (range: 18-46 ng/ml) not significantly correlating with TXNIP, TRX RNA levels or ROS levels (R2 = 0.48). Based on the correlation between TXNIP and ROS, 2 patients at either end of our spectrum (see Fig. 1, circled squares) were chosen for further analysis by targeted microarray. Patient (PT009) with the low TXNIP/ROS (currently undergoing treatment) was set as our baseline and the patient (PT005) with high TXNIP/ROS (observation only) was used as test comparison. The microarray has 96 genes involved in cellular stress response pathways. Comparing PT005 to PT009 we found of the 96 genes, 15 genes were up-regulated greater than 2-fold and 21 genes were down-regulated. Among the up-regulated genes were superoxide dismutase (SOD1), FOXO1 transcription factor, catalase (CAT) and members of the catenin family of proteins. Down-regulated genes included BAX and BCL2L1, GSK3-B, and thioredoxin reductase.In conclusion, we measured the expression of TXNIP in CLL patient samples. We found a range of TXNIP expression that robustly correlates with the level of ROS production, and is associated with differences in the stress response signature the clinical or biological relevance of which deserves further investigation. Disclosures:Turturro:Celgene: Speakers Bureau; Genentech: Speakers Bureau; Merck & Co: Research Funding.

Anger Expression and Stress Responses in Military Men

A better understanding of individual differences in the human stress response may enhance prevention and treatment of operational stress reactions. In this study, we examined the relationships of anger experience and expression to stress indices during daily living and in response to military survival training in 45 men. Prior to participation in survival training, subjects completed self-report measures of perceived stress and anger. The revised Impact of Event Scale was then administered 24 h after the conclusion of training. As expected, outward anger expression was positively associated with perceived stress during free living (P < 0.0125). Outward anger expression, inward anger expression, and angry temperament then combined to account for 25% of the variance in psychological impact of a stressful mock-captivity challenge. Anger characteristics are associated with human stress endpoints, both during daily living and in response to an ecologically valid stressor. These findings may assist in the prevention and treatment of operational stress reactions.

Effects of Exposure to Intermittent Hypoxia on Oxidative Stress and Acute Hypoxic Ventilatory Response in Humans

Periodic occlusion of the upper airway in patients with obstructive sleep apnea leads to chronic intermittent hypoxia, which increases the acute hypoxic ventilatory response (AHVR). Animal studies suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans. To determine whether 4 days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress and to determine the strength of the association between oxidative stress and AHVR. After two normoxic control days (Day -4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1-4) of intermittent hypoxia for 6 hours per day. AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring alpha-tocopherol, total vitamin C, and antioxidant enzymatic activities. Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid, and vitamin C, whereas antioxidant enzymatic activities and alpha-tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r = 0.88; P = 0.002). Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.

Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells

Stress response gene ATF3 plays a pleiotropic role in determining cell fate in response to mitogenic or stress stimuli. An alternate promoter of the human ATF3 gene (designated P1 in this study) has recently been reported, which is located ∼43.5 kb upstream of the previously reported P2 promoter. We showed here that the P1 promoter is highly conserved between human and mouse and is functional in response to various stimuli, whereas the P1 promoter was dominantly induced by serum and the P2 promoter was more efficiently activated in response to TGF-β and oncogenic HRAS. The P1 promoter contains multiple transcriptional start sites, and the different 5′-UTRs markedly affected their translation in response to stress. In human prostate and Hodgkin Reed–Sternberg cancer cells with elevated expression of ATF3, the P1 promoter was constitutively activated and its chromatin structure was modified into active configuration. The differential usage of alternate promoters of the ATF3 gene at both transcriptional and translational level and the modification of chromatin structure may provide a novel mechanism for expressing ATF3 in determining cell fate during stress response and cancer.