Delayed Stress Response Research Articles

114 Effect of Timing of Dam Gestational Stress on Immune and Stress Responsiveness of the Progeny

Abstract Gestational stress may alter both the intrauterine environment and factors of passive immunity, which may affect the development of the immune system and the hypothalamic-pituitary-adrenal (HPA) axis of the progeny. Therefore, the objective was to determine if gestational stress and the stage of gestation at which stress occurred (mid vs. late) differentially affected the immune and stress variables of the offspring. First, parity gilts received either hydrocortisone acetate (HCA) or a placebo for 21 days at mid (d 51 to 72) or late (d 81 to 102) gestation to create a chronic psychological stress model. After farrowing, four piglets were tagged from each mid (M-HCA; n = 12), late (L-HCA; n = 12), and control (CON; n = 12) dam and followed through a 21-day lactation and 28-day nursery phase. Samples were obtained at birth, 7-, 14- and 21-days post birth (PB), and 24 hours, 7-, 14-, 21- and 28-days post-weaning (PW). A subset of piglets, balanced for dam treatment, body weight, and sex, were subjected to an ACTH challenge on day 21 PW consisting of an injection of ACTH (n = 12) or saline (n = 12). Data were analyzed utilizing the MIXED procedure of SAS with repeated measures. A treatment*day effect occurred for neutrophil (P < 0.0001) and lymphocyte (P < 0.0001) percentages and neutrophil-to-lymphocyte ratio (N:L; P < 0.0001). At birth, M-HCA piglets exhibited significantly less neutrophil and greater lymphocyte percentages than L-HCA or CON piglets. By day 14 PB, L-HCA piglets exhibited decreased neutrophil percentages. They tended to have greater lymphocyte percentages than M-HCA or CON piglets. On day 14PB, L-HCA piglets had the greatest N:L. Other immune measures like IgG and IgA plasma concentrations were also affected (P < 0.0001 for both; treatment*day); M-HCA piglets had less IgG on 7 PB than their counterparts and tended to have decreased IgA concentrations at birth and 21 PB in than CON piglets. Stress responsiveness of the progeny may have been affected by dam stress during gestation. For example, when challenged with ACTH, a significant treatment*injection*time effect was found (P = 0.0004). The ACTH-injected M-HCA piglets exhibited significantly greater plasma cortisol 1-h post-injection than ACTH-injected L-HCA or CON piglets and saline-injected M-HCA piglets. Notably, L-HCA was the only group not found to have a significant difference between ACTH and saline cortisol at 1 h. At 4-h post-injection, ACTH M-HCA piglets exhibited significantly less cortisol concentrations than their saline counterparts, while ACTH L-HCA piglets were still significantly greater at 24-h post-injection than their saline counterparts. Overall, these data suggest that stress during mid-gestation may have more of an effect on immune measures. In contrast, stress during late gestation may cause a diminished or delayed stress response in the progeny. Research is ongoing to characterize these immune and stress phenotypes further.

Delta Smelt stress responses during fish salvage at the John E. Skinner Delta Fish Protective Facility, California

The John E. Skinner Delta Fish Protective Facility (Skinner Fish Facility) diverts entrained fish from the State Water Project’s pumping facilities in the southern Sacramento-San Joaquin Delta (the Delta) and transports them via tanker trucks away from the immediate influence of the export pumps. During this process, the fish are counted and released back into the Delta, generally known as fish salvage. Since fish are caught and released back into the Delta, this whole process involves various points that can be stressful to fish, such as the Delta Smelt (Hypomesus transpacificus), a state and federally listed species. To understand this process and improve fish facilities function, an investigation was conducted in 2005–2006, in which we evaluated sublethal stress associated with the terminal portion of the fish salvage process. This study included fish collection, handling, transportation, and release (CHTR) away from the export facilities. Physiological stress parameters for Delta Smelt were measured in the Skinner Fish Facility. We inserted wild and cultured adult Delta Smelt into the CHTR process and later sampled for plasma cortisol, glucose, and lactate, which typically respond to acute and cumulative stress in fish. To help identify the source of overall stress response, we partitioned CHTR into three test phases: collection and handling, trucking and release, and uninterrupted CHTR. Differences in the delayed stress response between the different phases of CHTR were evaluated. Delta Smelt experienced stress in all phases of the CHTR process and in experimental handling controls indicated by higher plasma cortisol concentrations compared to their pre-experiment levels. Wild Delta Smelt experienced higher levels of cortisol response and took longer to recover than did cultured Delta Smelt.

Circulating ghrelin changes as a biomarker of the stress response and craving in abstinent smokers

RationaleThere has been growing interest in the role of ghrelin in stress and addiction. Ghrelin regulates central reward mechanisms by mediating the mesolimbic dopaminergic system. Stress also induces neurophysiological activations related to drug reward. However, the extent to which psychosocial stress is associated with changes in ghrelin levels has not been tested in individuals with nicotine dependency undergoing withdrawal, a condition known to induce stress-like symptoms. ObjectivesWe investigated the association of stress-induced ghrelin, craving, and smoking lapse. MethodsThirty-six smokers attended a laboratory session that included acute stress tasks during the initial phase of quitting. Self-report measures and biochemical samples were collected for the assessment of smoking status. Blood samples for the measurement of ghrelin and self-report measures of craving were collected multiple times throughout the session ResultsMultivariate analysis of variance controlling for gender found a significant main effect of sampling time and lapse group (p < 0.05). Ghrelin levels significantly increased over the pre-stress and post-stress periods (ps < 0.001), suggesting a delayed stress response. Those who lapsed during the study had higher ghrelin levels than those who were able to successfully abstain. A ghrelin stress response was calculated and a significant association was found between this response and craving, which changed across time points (ps < 0.008). ConclusionsThe results of this study demonstrate that ghrelin is sensitive to acute manipulation of stress and that there is potential usefulness for ghrelin as a marker of stress, craving, and smoking lapse.

Numerical prediction of dynamic tensile failure in concrete by a corrected strain-rate dependent nonlocal material model

Dynamic tensile failure (e.g. spall) is frequently observed when concrete structures are subjected to blast and impact loadings, which is accompanied by the increase of tensile strength with increase of loading rate. Accurate prediction of dynamic tensile failure in concrete material is a challenging problem, in which the strain-rate effect should be properly considered. In the present study, a new corrected strain-rate enhancement model is proposed by introducing a time scale to control the evolution of strain-rate, as to capture the delayed stress response under variations of strain-rate. This corrected strain-rate enhancement model is then combined with the damage-based nonlocal model recently proposed by Kong et al. [18] to investigate the influence of strain-rate effect on numerical predictions of dynamic tensile failure. Numerical examples of a 1D spalling test demonstrate that the introduction of a time scale in the corrected strain-rate captures the delayed stress response and has a weak regularization effect. Three sets of experiments, namely, the Split-Hopkinson Tensile Bar (SHTB) test, the Modified Split-Hopkinson bar (spalling) test and the Compact Tension test, are numerically simulated using the proposed corrected strain-rate enhancement model and the frequently-used instantaneous strain-rate enhancement model. It is found that, considering the instantaneous strain-rate enhancement in the material model, the multiple cracks and crack branching cannot be well predicted, and the capability of energy absorption of concrete structures is overestimated, which may lead to an unsafe design. Promising predictions of dynamic tensile failures in concrete, including multiple cracks, crack branching and the structural resistance are obtained by the damage-based nonlocal model incorporating with the corrected strain-rate enhancement model.

Induced aneuploidy in neural stem cells triggers a delayed stress response and impairs adult life span in flies.

Studying aneuploidy during organism development has strong limitations because chronic mitotic perturbations used to generate aneuploidy usually result in lethality. We developed a genetic tool to induce aneuploidy in an acute and time-controlled manner during Drosophila development. This is achieved by reversible depletion of cohesin, a key molecule controlling mitotic fidelity. Larvae challenged with aneuploidy hatch into adults with severe motor defects shortening their life span. Neural stem cells, despite being aneuploid, display a delayed stress response and continue proliferating, resulting in the rapid appearance of chromosomal instability, a complex array of karyotypes, and cellular abnormalities. Notably, when other brain-cell lineages are forced to self-renew, aneuploidy-associated stress response is significantly delayed. Protecting only the developing brain from induced aneuploidy is sufficient to rescue motor defects and adult life span, suggesting that neural tissue is the most ill-equipped to deal with developmental aneuploidy.

Clinical-psychopathological and dynamic features of socially-disadaptative post-combat syndrome in the military personnel of Ukraine in modern realities

The aim of the study was to establish the clinical features of the Socially-Disadaptative Post-Combat syndrome as one of the psychopathological states associated with participation in hostilities. To achieve this aim, 482 Ukrainian military personnel who took part in the anti-terrorist operation / Joint Force Operation and requested psychiatric assistance had examined. As part of the study, clinical, anamnestic, psychopathological, psychodiagnostic, follow-up, statistical research methods had used. In the course of the study, it was found that 15% of servicemen combined the presence of a certain group of symptoms, which, due to their clinical-psychopathological continuum, etiology and dynamics features, became possible to combine into a single syndrome, called the “Socially-Disadaptative Post-Combat syndrome”. With this syndrome, the explosiveness, the lability of emotions and moods, dysphorism, emotional stress, conflict, non-conformal, egocentrism, an increased sense of justice, which arose some time after the return of the combatant from the combat zone, prevail. The study found that the debut of this syndrome could be attributed to the group of delayed stress response disorders, but this does not allow the following fact: the main etiological factor of the pathological condition is maladjustment in the social environment, which is caused by alienation and disharmonious perception of civilian life and its associated information space of a person who is faced with the realities of the combat situation and has developed adaptation mechanisms to it. Another etiological component of this syndrome is the emotional stress that has remained after being in a combat zone, which affects the perception of the environment. Not the last etiological component of the Socially-Disadaptative Post-Combat syndrome is the informational component of the “hybrid war” and its consequences, reflected in the verbal and behavioral practices of the civilian population. The elimination of the Socially-Disadaptative Post-Combat syndrome took place on its own immediately upon the return of servicemen to the combat zone or, in the case of a long period of stay of servicemen in a civilian environment, extremely slowly and in the conditions of treatment. The identification and establishment of the clinical features of the Socially-Disadaptative Post-Combat syndrome has expanded the understanding of the psychopathological states from the Combat stress reaction group; however, this psychopathological condition requires further analysis and research.

Relation of urinary endothelin-1 to stress-induced pressure natriuresis in healthy adolescents

We hypothesize that delayed natriuresis during mental stress increases the risk of hypertension and other diseases. Our preclinical studies demonstrate an important role for renal endothelin-1 (ET-1) in regulating sodium excretion. Thus, we predict ET-1 may be linked to the delayed stress response in at-risk individuals. We hypothesize that reduced renal ET-1 accounts for derangements in sodium handling under stress, a link never explored in a large human cohort. We determined urinary ET-1 excretion in three observational studies of changes in sodium excretion during mental stress, in which 776 healthy youth (15–19 years) enrolled in a 5-hour protocol (2 hours of rest before and after 1 hour of mental stress). In all studies, 60-minute urine samples were obtained throughout the protocol. Subjects were grouped as retainers (reduced sodium excretion during stress relative to baseline) or excreters (increased sodium excretion during stress relative to baseline). In excreters, ET-1 excretion was significantly increased from baseline to stress (+0.02 pg/min; P < .001). In contrast, ET-1 excretion was significantly higher (P = .028) in retainers than excreters at baseline but significantly reduced in retainers under stress (−0.02 pg/min; P < .001). ET-1 excretion declined further in retainers during recovery but returned to prestress levels in excreters. Albumin excretion and albumin-to-creatinine ratio were significantly higher in retainers (P = .022, P < .001, respectively). Thus, loss of ET-1–dependent natriuresis may account for sodium retention during stress and may predispose retainers to renal diseases such as hypertension and kidney disease.

Singlet oxygen triggers chloroplast rupture and cell death in the zeaxanthin epoxidase defective mutant aba1 of Arabidopsis thaliana under high light stress

The two Arabidopsis thaliana mutants, aba1 and max4, were previously identified as sharing a number of co-regulated genes with both the flu mutant and Arabidopsis cell suspension cultures exposed to high light (HL). On this basis, we investigated whether aba1 and max4 were generating high amounts of singlet oxygen (1O2) and activating 1O2-mediated cell death. Thylakoids of aba1 produced twice as much 1O2 as thylakoids of max4 and wild type (WT) plants when illuminated with strong red light. 1O2 was measured using the spin probe 2,2,6,6-tetramethyl-4-piperidone hydrochloride. 77-K chlorophyll fluorescence emission spectra of thylakoids revealed lower aggregation of the light harvesting complex II in aba1. This was rationalized as a loss of connectivity between photosystem II (PSII) units and as the main cause for the high yield of 1O2 generation in aba1. Up-regulation of the 1O2 responsive gene AAA-ATPase was only observed with statistical significant in aba1 under HL. Two early jasmonate (JA)-responsive genes, JAZ1 and JAZ5, encoding for two repressor proteins involved in the negative feedback regulation of JA signalling, were not up-regulated to the WT plant levels. Chloroplast aggregation followed by chloroplast rupture and eventual cell death was observed by confocal imaging of the fluorescence emission of leaf cells of transgenic aba1 plants expressing the chimeric fusion protein SSU-GFP. Cell death was not associated with direct 1O2 cytotoxicity in aba1, but rather with a delayed stress response. In contrast, max4 did not show evidence of 1O2-mediated cell death. In conclusion, aba1 may serve as an alternative model to other 1O2-overproducing mutants of Arabidopsis for investigating 1O2-mediated cell death.

A delayed antioxidant response in heat-stressed cells expressing a non-DNA binding HSF1 mutant

To assess the consequences of inactivation of heat shock factor 1 (HSF1) during aging, we analyzed the effect of HSF1 K80Q, a mutant unable to bind DNA, and of dnHSF1, a mutant lacking the activation domain, on the transcriptome of cells 6 and 24h after heat shock. The primary response to heat shock (6h recovery), of which 30% was HSF1-dependent, had decayed 24h after heat shock in control cells but was extended in HSF1 K80Q and dnHSF1 cells. Comparison with literature data showed that even the HSF1 dependent primary stress response is largely cell specific. HSF1 K80Q, but not HSF1 siRNA-treated, cells showed a delayed stress response: an increase in transcript levels of HSF1 target genes 24h after heat stress. Knockdown of NRF2, but not of ATF4, c-Fos or FosB, inhibited this delayed stress response. EEF1D_L siRNA inhibited both the delayed and the extended primary stress responses, but had off target effects. In control cells an antioxidant response (ARE binding, HMOX1 mRNA levels) was detected 6h after heat shock; in HSF1 K80Q cells this response was delayed to 24h and the ARE complex had a different mobility. Inactivation of HSF1 thus affects the timing and nature of the antioxidant response and NRF2 can activate at least some HSF1 target genes in the absence of HSF1 activity.

Establishing cellular stress response profiles as biomarkers of homeodynamics, health and hormesis

Aging is the progressive shrinkage of the homeodynamic space. A crucial component of the homeodynamic space is the stress response (SR), by virtue of which a living system senses disturbance and initiates a series of events for maintenance, repair, adaptation, remodeling and survival. Here we discuss the main intracellular SR pathways in human cells, and argue for the need to define and establish the immediate and delayed stress response profiles (SRP) during aging. Such SRP are required to be established at several age-points, which can be the molecular biomarkers of homeodynamic space and the health status of cells and organisms. SRP can also be useful for testing potential protectors and stimulators of homeodynamics, and can be a standard for monitoring the efficacy of potential pro-survival, health-promoting and aging-modulating conditions, food components and other compounds. An effective strategy, which makes use of SRP for achieving healthy aging and extending the healthspan, is that of strengthening the homeodynamics through repeated mild stress-induced hormesis by physical, biological and nutritional hormetins. Furthermore, SRP can also be the basis for defining health as a state of having adequate physical and mental independence of activities of daily living, by identifying a set of measurable parameters at the most fundamental level of biological organization.

Primary Biliary Cirrhosis: Bad Genes, Bad Luck

Primary biliary cirrhosis (PBC) is considered a model for autoimmune disease based upon its hallmark autoantibodies serologic response, the focused target destruction of biliary epithelial cells (BEC), and the clinical homogeneity among patients [1]. PBC is also overwhelmingly a disease of middle-aged and older females, being virtually absent in the pediatric or adolescent population. True pediatric PBC is indeed highly rare, and likely represents an etiopathogenesis that is extremely atypical compared to the classical PBC in adults. PBC also has one of the latest ages of onset out of all autoimmune diseases [2]. The etiology remains enigmatic, although various genetic and environmental factors have been implicated in the disease development and progression, many of which also provide insight as to why females are more prone to PBC [3, 4]. Both genetic and environmental factors may well contribute to the decline of an already ageing immune system, a phenomenon termed immunosenescence [5], through recurrent infections and inflammation, as well as oxidative damage. Immunosenescence is known to begin in approximately the fifth decade of life, and is characterized by a progressive decline in immunological functioning [5–8]. It is likely that the immune system may then reach a critical stage where tolerance to self is lost, thus contributing to the development of autoimmune diseases. A number of studies showing immunosenescence have provided additional evidence as to why middle age presentation often occurs in PBC. For example, changes in T cell signaling such as the decreased expression of the co-stimulatory receptor CD28, have been largely described [7, 11]. In PBC, an age-related progressive increase number of immune-related circulating cells carrying only one X chromosome, that is with monosomy X, was reported [9, 10]. Again, several phenotypical and functional changes have been also noted in the CD4 and CD8 T lymphocytes of PBC patients [1]. Of interest is for example the increased CD127 (marker of effector cells), reduced CD39 (marker of normal Treg function) expression of the CD8 Treg, and that CD8?CD28-cells from PBC patients failed to display a regulatory immune response after incubation with IL-10 [12]. A growing number of evidences suggest that not only immunosenescence but also senescence of the target organ, that is of BEC, has a role in the development of PBC. Senescence is a well-known delayed stress response induced by factors such as oxidative stress, telomere shortening, DNA damage, and autophagy [13]. First, several studies have demonstrated that oxidative stress is an inducer of cell senescence in the BEC of PBC patients [14– 16]. Sasaki et al. [14] notes that cellular senescence in early-stage PBC was associated with an infiltration of myeloperoxidase-positive inflammatory cells, indicating oxidative stress. Another study by the same group showed that Bmi1 (a suppressor of oxidative stress) was significantly reduced in damaged BEC of PBC patients [16]. Second, shortened telomere length with associated cellular senescence has been demonstrated in a study by Sasaki and colleagues [17]. In particular, they examined telomere length using quantitative fluorescent in situ hybridization of 13 patients with PBC and 13 controls and showed a significant decrease in telomere length in damaged BEC from PBC patients, in comparison to histologically normal P. Invernizzi Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano, Italy

Effect of Escapable and Inescapable Stress on Levels of Catecholamines in Adrenals and Corticosterone in Blood Plasma in Young and Aged Rats

Effect of escapable and inescapable electrical stress (ES, IS) on the catecholaminergic system was studied in young (3 months) and aged (25 months) male Wistar rats on the day 3 after stress, using radioimmune analysis and high-pressure liquid chromatography. Catecholamine concentration in adrenals and corticosterone level in blood of control aged rats was lower than in young animals. On the third day after the electrical stimulation in cages with current-conducting floor, production of hormones of adrenal cortical and medullar layers rose significantly in aged rats, with a more pronounced increase of noradrenaline after IS, while of blood adrenaline and corticosterone, after ES. In young rats no significant changes in catecholamines were revealed, whereas the blood corticosterone level was increased after IS. Thus, in aged rats, a low basal level of catecholamines and corticosterone and a delayed stress response can be established. In old animals after ES, a long post-action was observed, which was quite comparable with the results obtained after IS in the both age groups.

Treatment for delayed stress response

Treatment for delayed stress response

Treatment for delayed stress response

A husband dies unexpectedly. His wife makes funeral arrangements, receives comfort from family and friends, and apparently accepts the tragedy. Then one day she realizes she feels emotionally numb, the shock sets in, and she can no longer cope. A man suffers serious injuries when his car collides with another. He recuperates from his physical injuries after extended hospitalization. Then the psychological trauma strikes; coping is impossible. In both cases, the emotional stress response is similar. Patients with such stress response syndromes now are being treated with a modified, brief psychotherapy approach by Mardi Horowitz, MD, and associates at the Langley Porter Institute of the University of California at San Francisco. The goal is to restore psychosocial homeostasis with (if possible) only 12 hours of therapy. In each case the patient is assigned to an interviewer and a therapist. Interviews are audiotaped and videotaped to provide the therapist with insight

Delayed Stress Response Syndrome: Family Therapy Indications*

The paper draws upon the work of Mardi Horowitz and his colleagues in the explication of the delayed stress response syndrome. The syndrome is a form of chronic catastrophic stress disorder to be discussed in the new “Diagnostic and Statistical Manual.” The theoretical nature of the syndrome and its most characteristic symptoms are delineated within the context of treating Vietnam combat veterans. The paper outlines treatment implications within a family therapy program. Specific issues and procedures discussed include (a) diagnosis of the syndrome and the family pathology within which it is embedded, (b) identification of the particular family characteristics which tend to affect and be affected by the syndrome, and (c) the use of both the spouse and another survivor of the catastrophic event in the treatment program.

A Prediction of Delayed Stress Response Syndromes in Vietnam Veterans

It is posited that over the next years civilian mental health professionals will encounter stress response syndromes in Vietnam veterans, will misread etiological factors, and will be unable to treat such persons effectively. This paper attempts to describe the types of problems which may be expected and suggests special approaches which will be required and may assist the treatment process.