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Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2.

Epitope-tagged glutaredoxin (GRX) was utilized to determine the role of GRX in oxidative stress-induced signaling and cytotoxicity in glucose-deprived human cancer cells (MCF-7/ADR and DU-145). GRX-overexpressing cells demonstrated resistance to glucose deprivation-induced cytotoxicity and decreased activation of c-Jun N-terminal kinase (JNK1). Deletion mutants showed the C-terminal portion of apoptosis signal-regulating kinase 1 (ASK1) bound GRX, and glucose deprivation disrupted binding. Treatment with l-buthionine-(S,R)-sulfoximine reduced glutathione content by 99% and prevented glucose deprivation-induced dissociation of GRX from ASK1. A thiol antioxidant, N-acetyl-l-cysteine, or overexpression of an H(2)O(2) scavenger, catalase, inhibited glucose deprivation-induced dissociation of GRX from ASK1. GRX active site cysteine residues (Cys(22) and Cys(25)) were required for dissociation of GRX from ASK1 during glucose deprivation. Kinase assays revealed that SEK1 and JNK1 were regulated in an ASK1-dependent fashion during glucose deprivation. Overexpression of GRX or catalase inhibited activation of ASK1-SEK1-JNK1 signaling during glucose deprivation. These results demonstrate that GRX is a negative regulator of ASK1 and dissociation of GRX from ASK1 activates ASK1-SEK1-JNK1 signaling leading to cytotoxicity during glucose deprivation. These results support the hypothesis that the GRX-ASK1 interaction is redox sensitive and regulated in a glutathione-dependent fashion by H(2)O(2).

Acetylcysteine↗

Parental posttraumatic stress symptoms as a moderator of child's acute biological response and subsequent posttraumatic stress symptoms in pediatric injury patients.

OBJECTIVE: To examine how parental responses following pediatric injury may influence their child's posttraumatic stress symptoms (PTSS). METHODS: Heart rate (HR) from 82 pediatric injury patients was measured during emergency medical services (EMSs) transport and following hospital admission. Twelve-hour urinary cortisol levels were assessed upon admission. Child PTSS and parental PTSS and general distress were assessed 6 weeks and 6 months after trauma. RESULTS: Six-week parental PTSS predicted 6-month child PTSS even after controlling for demographics and general parent distress (DeltaR(2) = .08, p = .03). Parental PTSS moderated the relationship between (a) child cortisol levels and 6-month child PTSS (DeltaR2 = .08, p = .03) and between (b) hospital HR and 6-month child PTSS (DeltaR2 = .09, p = .03). CONCLUSION: The present findings suggest that parental response to trauma may interact with child acute physiological responses to predict persistent child PTSS.

Acute Disease↗

Effect of chronic stress associated with unemployment on salivary cortisol: overall cortisol levels, diurnal rhythm, and acute stress reactivity.

This study examined the effect of chronic stress associated with unemployment on the magnitude of salivary cortisol excretion, on the diurnal rhythm of cortisol, and on cortisol reactivity to acute naturalistic stressors using Experience Sampling Methodology (ESM). Employed (N = 60) and unemployed (N = 60) subjects were studied for 2 days. Subjects were beeped 6 times per day by a preprogrammed wristwatch to assess acute stressors; 25 minutes after each ESM-beep, subjects were beeped a second time for saliva samples. The groups did not differ in their overall cortisol excretion or in cortisol reactivity to acute daily stressors. Compared to employed subjects, unemployed subjects had a diurnal pattern of cortisol excretion with relatively higher morning and lower evening levels. Subjects' daily activities and their locations were associated with diurnal rhythm differences.

Adult↗

Baseline plasma N-terminal pro-B-type natriuretic peptide is associated with the extent of stress-induced myocardial ischemia during dobutamine stress echocardiography.

OBJECTIVE: To determine the relationship between baseline plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the presence and extent of myocardial ischemia during dobutamine stress echocardiography (DSE). METHODS: NT-proBNP was measured in 170 consecutive patients prior to DSE. Rest wall motion abnormalities (RWMAs) and new wall motion abnormalities (NWMAs) were scored using a 5-point, 17-segment model. Kruskal-Wallis tests were applied to study differences in NT-proBNP levels between patients with normal DSE, RWMAs but no NWMAs, and NWMAs, and (in patients with NWMAs) between those with 1-2, 3-4 and >4 ischemic segments. Univariate and multivariate regression analyses were used to determine the value of NT-proBNP in predicting NWMAs. RESULTS: The median NT-proBNP level was 110 ng/l (interquartile range: 42-389 ng/l). Median NT-proBNP was 59, 321 and 440 ng/l in patients with normal DSE, with RWMAs but no NWMAs, and with NWMAs, respectively (P<0001). Among patients with NWMAs, median NT-proBNP was associated with the number of ischemic segments: 364, 710 and 2376 ng/l in patients with 1-2, 3-4 and >4 ischemic segments, respectively (P<0.001). Elevated NT-proBNP levels were significantly associated with NWMAs (odds ratio per 100 ng/l increase: 1.14, 95% confidence interval: 1.1-1.2) in a multivariate analysis of clinical baseline variables and RWMAs. CONCLUSION: Elevated baseline levels of NT-proBNP are associated with the presence and extent of myocardial ischemia during DSE, independent of the presence of RWMAs.

Adult↗

Parent-child agreement regarding children's acute stress: the role of parent acute stress reactions.

OBJECTIVE: We examined parent-child agreement regarding child acute stress disorder (ASD) and the relationship between parent ASD symptoms and parent ratings of child ASD. METHOD: Parent-child dyads (N = 219; child age 8-17 years) were assessed within 1 month of child injury. Parent-child agreement was examined regarding child ASD presence, severity, and specific symptoms. Relationships among parent ASD and parent- and child-reported child ASD were examined using regression analysis and generalized estimating equations (GEE). RESULTS: Parent-child agreement was low for presence of child ASD (kappa = 0.22) and for individual symptoms. Parent and child ratings of child ASD severity were moderately correlated (r = 0.35). Parent ASD was independently associated with parent-rated child ASD, after accounting for child self-rating (beta =.65). Generalized estimating equations indicated that parents with ASD overestimated child ASD and parents without ASD underestimated child ASD, compared to the child's self-rating. CONCLUSIONS: Parents' own responses to a potentially traumatic event appear to influence their assessment of child symptoms. Clinicians should obtain child self-report of ASD whenever possible and take parent symptoms into account when interpreting parent reports. Helping parents to assess a child's needs following a potentially traumatic event may be a relevant target for clinical attention.

Adolescent↗

Stress, social avoidance and anxiolytics: a potential model of stress-induced anxiety.

We investigated the social behavioural effects of a single exposure to either social defeat or electric shocks, using the recently developed social avoidance test in rats. The testing apparatus consisted of two connected chambers, one of which contained an unfamiliar male confined in a sub-chamber by a perforated Plexiglas wall. The subjects were placed in the empty chamber and, after 3 min of habituation, were allowed to explore the apparatus for 5 min. The latency, frequency and duration of visits made to the opponent-containing chamber were recorded. Both stressors reduced the exploration of the opponent-containing chamber for more than 5 days. The effects of electric shocks were not affected by housing conditions, whereas group housing protected rats from the long-term effects of defeat. In addition, the effects of social defeat in isolated rats lasted longer than the effects of electric shocks. These differences suggest that the two stressors have qualitatively different effects and may model different behavioural states in humans. In a second experiment, social avoidance induced by electric shocks was readily abolished by both chlordiazepoxide and buspirone. We suggest that the shock-induced social avoidance paradigm may become a useful model of stress-induced anxiety.

Animals↗

Job stress and major coronary events: results from the Job Stress, Absenteeism and Coronary Heart Disease in Europe study.

AIMS: The intention of this study is to investigate the relationship of the demands/control/strain model with hard coronary events in an epidemiological, prospective, multicenter, European study. METHODS AND RESULTS: Six cohorts (Brussels, Ghent, Lille, Barcelona, Göteborg and Malmö) from four European countries (Belgium, France, Spain and Sweden) consisting of 21 111 middle-aged male subjects participated between 1993 and 1996 in the baseline survey of the Job Stress, Absenteeism and Coronary Heart Disease in Europe (JACE) study. The Karasek strain model of psychological demands (five items)/control (nine items) was used. During a mean follow-up of 40 months 185 acute coronary events or coronary deaths were observed. Age-adjusted hazard ratios (HRs) for developing an acute coronary event were 1.46 [CI 95% confidence interval (1.08-1.97)] for high against low psychological demands and 1.53 (95% CI 1.0-2.35) for strained (high demands plus low control) against relaxed (low demands plus high control) groups. After adjustment for standard cardiovascular risk factors the HR for developing a coronary event for those above or equal to the median against those below the median of psychological demands was 1.46 (95% CI 1.08-1.97) whereas the HR for strained against relaxed groups is 1.46 (95% CI 0.96-2.25). Sensitivity analyses confirmed the robustness of the results. CONCLUSION: In this European, multicenter, prospective, epidemiological study the Karasek job strain model was an independent predictor of acute coronary events, with the psychological demands scale emerging as the important component.

Absenteeism↗

Chronicity in posttraumatic stress disorder and predictors of the course of posttraumatic stress disorder among primary care patients.

The present study examined the course of posttraumatic stress disorder (PTSD) in a sample of 84 primary care patients. More specifically, this study investigated the role of Axis I comorbidity, psychosocial impairment, and treatment participation in the maintenance of an episode of chronic PTSD and whether patients at follow-up met criteria for PTSD (full remission) or continued to exhibit residual PTSD symptoms and impairment (partial PTSD). Diagnostic structured interviews established all clinical diagnoses and information on the course of anxiety disorder symptoms, psychosocial functioning, and treatment status. Using a prospective, longitudinal design, this study found that during the first 2 years of follow-up, the probability of no longer meeting full DSM-IV criteria for PTSD was .69, and .18 for full remission from PTSD. The number of comorbid anxiety disorders and degree of psychosocial impairment at intake were significantly related to remission status (i.e., full and partial PTSD). This study suggests that, in a primary care setting, PTSD is a persistent illness, and that many subjects who have recovered from PTSD continue to suffer from subthreshold symptoms of PTSD.

Adult↗

Measuring the negative mood component of stress experiences: description and psychometric properties of a short adjective check-list of stress responses.

Negative Mood (NM) is a 19-items adjective check-list developed to assess negative mood and stress responses. The items of the scale reflect dimensions such as depressed mood, anxiety, anger and time urgency. The data were collected from four different samples, two random population samples and two smaller selective samples. The psychometric properties of the NM showed high internal consistency (Cronbach's Alpha). When analysed with principal components analysis, three factors emerged, anxiety/depression, time pressure, and anger. The factors emerged in all four samples, within samples and between gender. The NM factors were tested for convergent and discriminative validity by correlating them with other more established measures of different aspects of negative mood. The results showed high convergent and discriminative validity for two of the NM factors, i.e., anxiety/depression, and anger, whereas the results for the third factor, time pressure, were more ambiguous. This scale has proven to be useful in capturing some vital dimensions of negative affect across different kinds of populations.

Adult↗

Initial urethral pressure increase during stress episodes in genuine stress incontinent women.

The urethral and bladder pressure increments registered during a cough were investigated in 30 woman with genuine stress incontinence (GSI) and compared with those from 30 previously investigated healthy women. The pressures were measured by means of a double microtip transducer catheter with the bladder sensor uncovered and the urethral sensor covered with a water-filled rubber cylinder and placed at the bladder neck, midurethrally, or distally in the urethra. In GSI women the pressure increment preceding the pressure spike produced by coughing was significantly higher in the bladder compared with the urethra, and the pressure increment seemed to be initiated in the bladder and all along the urethra simultaneously. In healthy women the pressure increment preceding a pressure spike was significantly higher in the midurethra compared with the bladder and it seemed to be initiated in the midurethra. These findings seem to reflect a defective active closure mechanism in GSI which may be a contributing factor in its pathogenesis.

Adult↗

Recent rise in supposedly stress dependent causes of death in psychiatric hospitals in Norway indicating increased "stress" in hospitals?

The present study comprises all deaths in Norwegian psychiatric hospitals in 1950-74 with the diagnosis of non-organic (functional) psychosis: 5106 deaths. Mortality declined in both sexes as did excess mortality which is now 1.7 times the general population in the male, and 2.3 times in the female sex. However, a significant rise in unnatural deaths (suicides and accidents) took place in both sexes during 1963-74, as mortality increased 2-3 times in comparison with 1950-62. This rise in unnatural deaths is probably directly related to the introduction of drug therapy, which created an increased need for protection of the hospital population. A challenge which the accompanying changes in the hospital environment have failed to meet. Cardio-vascular mortality increased considerably during 1963-74 in both sexes. The rise is most likely the combined result of an adverse effect of drug therapy in individual patients (obesity, physical inactivity, increased smoking habits), the reduced stress-relieving effect of hospitalisation through shorter stays in hospital and the liberalization policy. We may not yet have experienced the total adverse effect on mortality of the increase in behavioural risk factors in psychiatric patients. It is suggested that future mortality studies include psychiatric out-patients.

Adult↗

Contribution of dps to acid stress tolerance and oxidative stress tolerance in Escherichia coli O157:H7.

An Escherichia coli O157:H7 dps::nptI mutant (FRIK 47991) was generated, and its survival was compared to that of the parent in HCl (synthetic gastric fluid, pH 1.8) and hydrogen peroxide (15 mM) challenges. The survival of the mutant in log phase (5-h culture) was significantly impaired (4-log(10)-CFU/ml reduction) compared to that of the parent strain (ca. 1.0-log(10)-CFU/ml reduction) after a standard 3-h acid challenge. Early-stationary-phase cells (12-h culture) of the mutant decreased by ca. 4 log(10) CFU/ml while the parent strain decreased by approximately 2 log(10) CFU/ml. No significant differences in the survival of late-stationary-phase cells (24-h culture) between the parent strain and the mutant were observed, although numbers of the parent strain declined less in the initial 1 h of acid challenge. FRIK 47991 was more sensitive to hydrogen peroxide challenge than was the parent strain, although survival improved in stationary phase. Complementation of the mutant with a functional dps gene restored acid and hydrogen peroxide tolerance to levels equal to or greater than those exhibited by the parent strain. These results demonstrate that decreases in survival were from the absence of Dps or a protein regulated by Dps. The results from this study establish that Dps contributes to acid tolerance in E. coli O157:H7 and confirm the importance of Dps in oxidative stress protection.

Animals↗

Nitric oxide releasing aspirin protects the gastric mucosa against stress and promotes healing of stress-induced gastric mucosal damage: role of heat shock protein 70.

BACKGROUND/AIM: Nitric oxide (NO) releasing nonsteroidal anti-inflammatory drugs do not cause gastric mucosal damage, despite inhibition of the cyclooxygenase activity to a similar extent as conventional nonsteroidal anti-inflammatory drugs that induce such damage. We compared the effects of native aspirin (ASA) with those of NO-releasing ASA (NO-ASA) on the development and healing of acute gastric lesions induced by water immersion and restraint stress (WRS) and the mucosal expression of heat shock protein 70 (HSP70). METHODS: Wistar rats received: (1). vehicle; (2). ASA (40 mg/kg i.g), and (3). NO-ASA (2.5-40 mg/kg i.g.), followed 0.5 h later by 3.5 h of WRS with or without glyceryl trinitrate, the donor of NO, and carboxy-PTIO, a NO scavenger. Healing of WRS lesions was assessed 0-24 h after termination of WRS. Number of gastric lesions, gastric mucosal blood flow (GBF), malondialdehyde (MDA) content, and RT-PCR expression of HSP70 mRNA were determined. RESULTS: WRS caused typical bleeding erosions that were aggravated by aspirin and this was accompanied by a fall in the GBF and a significant rise in the mucosal MDA concentrations. In contrast, NO-ASA, which raised significantly the luminal content of NO(x), reduced number of WRS lesions and mucosal MDA levels while increasing significantly the GBF. These protective and hyperemic effects of NO-ASA against WRS lesions were mimicked by addition of glyceryl trinitrate to native ASA and significantly attenuated by carboxy-PTIO added to NO-ASA. HSP70 mRNA was significantly upregulated by WRS, and this was significantly attenuated by ASA, but not by NO-ASA. NO-ASA decreased significantly the MDA content and induced overexpression of HSP70 mRNA during healing of WRS lesions. CONCLUSION: NO-ASA exhibits mucosal protective and healing effects against WRS-induced gastric lesions due to the release of NO, which induces gastric hyperemia, and the attenuation of lipid peroxidation and counteracts the inhibition of HSP70 expression induced by native ASA.

Animals↗

Stress and vulnerability to posttraumatic stress disorder in children and adolescents.

OBJECTIVE: This study examined the experiential factors and interacting vulnerabilities that contribute to the development of posttraumatic stress disorder (PTSD) in children and adolescents. METHOD: Of 100 consecutive referrals to an inner-city child and adolescent psychiatry clinic, 59 had experienced a trauma that qualified as a precipitant of PTSD. For those with trauma, ages ranged from 3 to 18 years (mean=9.9, SD=4.10); 39 (66%) were males. The authors used a series of multiple regression analyses to examine the contribution of demographic characteristics, the nature of the stressor(s), and the role of preexisting clinical signs in the development of PTSD. RESULTS: Twenty-two percent of the 59 children who had been traumatized met full criteria for PTSD, 32% had some symptoms of PTSD but did not meet full criteria, and 46% had no symptoms of PTSD. Witnessing domestic violence or being physically abused predicted severity of PTSD. Children with preexisting aggressive behavior were more likely to be victims of physical abuse. CONCLUSIONS: Traumatic experience interacts with factors in the child and family to contribute to the development of PTSD. Trauma that threatens family integrity appears to make a strong contribution to the development of PTSD. Increased understanding of the factors contributing to PTSD may provide additional opportunities for developing effective interventions.

Adolescent↗

Longitudinal course of posttraumatic stress disorder and posttraumatic stress disorder symptoms in a community sample of adolescents and young adults.

OBJECTIVE: Few studies have focused on the natural course of posttraumatic stress disorder (PTSD) and its determinants in samples of the general population. The authors examined determinants of remission and chronicity of PTSD and associations with other disorders in a prospective community sample. METHOD: The data were drawn from a prospective, longitudinal epidemiological study of adolescents and young adults (age 14-24 years) in Munich, Germany (N=2,548). The course of PTSD from baseline to follow-up 34-50 months later was studied in 125 respondents with DSM-IV PTSD or subthreshold PTSD at baseline. RESULTS: Although 52% of the PTSD cases remitted during the follow-up period, 48% showed no significant remission of PTSD symptoms. Respondents with a chronic course were more likely to experience new traumatic event(s) during follow-up (odds ratio=5.21, 95% confidence interval [CI]=1.95-13.92), to have higher rates of avoidant symptoms at baseline (odds ratio=10.16, 95% CI=1.73-59.51), and to report more help seeking (odds ratio=5.50, 95% CI=1.04-29.05), compared to respondents with remission. Rates of incident somatoform disorder (odds ratio=4.24, 95% CI=1.60-11.19) and other anxiety disorders (odds ratio=4.07, 95% CI=1.15-14.37) were also significantly associated with a chronic course. CONCLUSIONS: PTSD is often a persistent and chronic disorder. Specific symptom clusters--especially avoidant symptoms--might be associated with the course of PTSD. In addition, the occurrence of new traumatic events differentiates PTSD cases with a chronic course from those with remission.

Adolescent↗

Stress and vascular responses: oxidative stress and endothelial dysfunction in the insulin-resistant state.

Although insulin-resistant states have been associated with endothelial dysfunction due to increased vascular oxidative stress, the underlying mechanisms are pooly understood. Recent experimental evidence suggests that tetrahydrobiopterin (BH(4)), the natural and essential cofactor of NO synthases (NOS), plays a crucial role not only in increasing the rate of NO generation by NOS but also in controlling the formation of superoxide anion (O(2)(-)) in endothelial cells. Because insulin resistance has been suggested to be a significant contributing factor in the development of abnormal pteridine metabolism and endothelial dysfunction, we investigated pteridine content and NO/O(2)(-) production with the use of isolated thoracic aortas obtained from fructose-induced insulin-resistant rats. Under insulin-resistant conditions where BH(4) levels are suboptimal, the production of O(2)(-) by NOS leads to endothelial dysfunction. Furthermore, oral supplementation of BH(4) restores endothelial function and relieved oxidative tissue damage, at least in part, through activation of endothelial NOS (eNOS) in the aorta of insulin-resistant rats. These results indicate that insulin resistance may be a pathogenic factor for endothelial dysfunction through impaired eNOS activity and increased oxidative breakdown of NO due to enhanced formation of O(2)(-), which are caused by relative deficiency of BH(4) in vascular endothelial cells.

Administration, Oral↗

Arabidopsis and the heat stress transcription factor world: how many heat stress transcription factors do we need?

Sequencing of the Arabidopsis genome revealed a unique complexity of the plant heat stress transcription factor (Hsf) family. By structural characteristics and phylogenetic comparison, the 21 representatives are assigned to 3 classes and 14 groups. Particularly striking is the finding of a new class of Hsfs (AtHsfC1) closely related to Hsf1 from rice and to Hsfs identified from frequently found expressed sequence tags of tomato, potato, barley, and soybean. Evidently, this new type of Hsf is well expressed in different plant tissues. Besides the DNA binding and oligomerization domains (HR-A/B region), we identified other functional modules of Arabidopsis Hsfs by sequence comparison with the well-characterized tomato Hsfs. These are putative motifs for nuclear import and export and transcriptional activation (AHA motifs). There is intriguing flexibility of size and sequence in certain parts of the otherwise strongly conserved N-terminal half of these Hsfs. We have speculated about possible exon-intron borders in this region in the ancient precursor gene of plant Hsfs, similar to the exon-intron structure of the present mammalian Hsf-encoding genes.

Amino Acid Sequence↗