Stress free configuration of the human eye

Numerical simulations of eye globes often rely on topographies that have been measured in vivo using devices such as the Pentacam or OCT. The topographies, which represent the form of the already stressed eye under the existing intraocular pressure, introduce approximations in the analysis. The accuracy of the simulations could be improved if either the stress state of the eye under the effect of intraocular pressure is determined, or the stress-free form of the eye estimated prior to conducting the analysis. This study reviews earlier attempts to address this problem and assesses the performance of an iterative technique proposed by Pandolfi and Holzapfel [1], which is both simple to implement and promises high accuracy in estimating the eye's stress-free form. A parametric study has been conducted and demonstrated reliance of the error level on the level of flexibility of the eye model, especially in the cornea region. However, in all cases considered 3-4 analysis iterations were sufficient to produce a stress-free form with average errors in node location <10(-6)mm and a maximal error <10(-4)mm. This error level, which is similar to what has been achieved with other methods and orders of magnitude lower than the accuracy of current clinical topography systems, justifies the use of the technique as a pre-processing step in ocular numerical simulations.

Stress hormones in patients with posttraumatic stress disorder caused by myocardial infarction and role of comorbid depression

Chronic posttraumatic stress disorder (PTSD) has been associated with perturbed hypothalamic-pituitary-adrenal (HPA) axis function and a hyperadrenergic state. We hypothesized that patients with PTSD attributable to myocardial infarction (MI) would show peripheral hypocortisolemia and increased norepinephrine levels, whereby taking into account that depressive symptoms would affect this relationship.

Psychosocial stress and cardiovascular risk : current opinion

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Epidemiologic research of the last half-century has clearly shown that psychosocial factors related to the social environment, personality characteristics, and negative affect increase the risk of incident CVD and also impact prognosis of cardiac patients. Several mechanisms may explain this link, including a genetic predisposition, poor lifestyle choices, low adherence to health recommendations, and direct pathophysiologic perturbations. The latter include alteration of the hypothalamic-pituitary adrenal axis and autonomic dysfunction resulting in endothelial dysfunction, inflammation, and a prothrombotic state further downstream. Screening for psychosocial factors seems appropriate as part of the standard history and based on the clinician's knowledge of the patient and the purpose of the visit. Psychological interventions generally alleviate distress in cardiac patients, but whether they reduce the risk of hard cardiovascular endpoints and all-cause mortality is less evident. Cardiac patients with more severe depression may particularly profit from antidepressant medications. Due to their pharmacologic properties, selective serotonin reuptake inhibitors were shown to improve cardiovascular outcome. The most effective psychosocial treatment is multicomponent therapy that combines elements of cognitive behaviour therapy ("stress management") and changes in health behaviours, including the adoption of a regular exercise regimen. Gender-specific issues should probably be considered. The field of behavioural cardiology has accumulated a wealth of epidemiological, mechanistic and clinical knowledge that undoubtedly has furthered our understanding about the important role of psychosocial risk factors in patients with a heart disease.

Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) may increase cardiovascular risk but the psychophysiological mechanisms involved are elusive. We hypothesized that proinflammatory activity is elevated in patients with PTSD as diagnosed by the Clinician Administered PTSD Scale (CAPS) interview. Plasma levels of proinflammatory C-reactive protein (CRP), interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, and of anti-inflammatory IL-4 and IL-10 were measured in 14 otherwise healthy PTSD patients and in 14 age- and gender-matched healthy non-PTSD controls. Levels of TNF-alpha (p=0.038; effect size Cohen's d=0.58) and of IL-1beta (p=0.075, d=0.68) were higher in patients than in controls. CRP (d=0.10), IL-6 (d=0.18), IL-4 (d=0.42), and IL-10 (d=0.37) were not significantly different between groups. Controlling for traditional cardiovascular risk factors, mood, and time since trauma revealed lower IL-4 in patients than in controls (p=0.029) and rendered group differences in TNF-alpha and IL-1beta insignificant. In all subjects, TNF-alpha correlated with total (frequency and intensity) PTSD symptom cluster of re-experiencing (r=0.49, p=0.008), avoidance (r=0.37, p=0.050), and hyperarousal (r=0.42, p=0.026), and with PTSD total symptom score (r=0.37, p=0.054). Controlling for time since trauma attenuated these associations. The correlation between IL-1beta and total avoidance symptoms (r=0.42, p=0.028) became insignificant when controlling for anxiety and depression. IL-4 correlated with total hyperarousal symptoms (r=-0.38, p=0.047), and after controlling for systolic blood pressure and smoking status, with PTSD total symptom score (r=-0.41, p=0.035). PTSD patients showed a low-grade systemic proinflammatory state, which, moreover, was related to PTSD symptom levels suggesting one mechanism by which PTSD could contribute to atherosclerotic disease.

Altered blood coagulation in patients with posttraumatic stress disorder

OBJECTIVE: Posttraumatic stress disorder (PTSD) has been associated with an increased cardiovascular risk, though the pathophysiologic mechanisms involved are elusive. A hypercoagulable state before occurrence of coronary thrombosis contributes to atherosclerosis development. We investigated whether PTSD would be associated with increased coagulation activity. METHODS: We measured resting plasma levels of clotting factor VII activity (FVII:C), FVIII:C, FXII:C, fibrinogen, and D-dimer in 14 otherwise healthy patients with PTSD and in 14 age- and gender-matched, trauma-exposed non-PTSD controls. Categorical and dimensional diagnoses of PTSD were made using the Clinician-Administered PTSD Scale (CAPS) interview. We also investigated to what extent the relationship between PTSD and coagulation measures would be confounded by demographics, cardiovascular risk factors, lifestyle variables, time since trauma, and mood. RESULTS: Coagulation factor levels did not significantly differ between patients with a categorical diagnosis of PTSD and controls while controlling for covariates. In all subjects, FVIII:C was predicted by hyperarousal severity (beta = 0.46, p = .014) independent of covariates and by overall PTSD symptom severity (beta = 0.38, p = .045); the latter association was of borderline significance when separately controlling for gender, smoking, exercise, and anxiety (p values <.07). In patients, fibrinogen was predicted by hyperarousal severity (beta = 0.70, p = .005) and by overall PTSD symptom severity (beta = 0.61, p = .020), with mood partially affecting these associations. FVII:C, fibrinogen, and D-dimer showed no independent association with PTSD symptoms. CONCLUSIONS: PTSD may elicit hypercoagulability, even at subthreshold levels, offering one psychobiological pathway by which posttraumatic stress might contribute to atherosclerosis progression and clinical cardiovascular disease.

Myocardial infarction and post-traumatic stress disorder: frequency, outcome, and atherosclerotic mechanisms

BACKGROUND: Post-traumatic stress disorder (PTSD) may develop in the aftermath of an acute myocardial infarction (MI). Whether PTSD is a risk factor for cardiovascular disease (CVD) is elusive. The biological mechanisms linking PTSD with atherosclerosis are unclear. DESIGN: A critical review of 31 studies in the English language pursuing three aims: (i) to estimate the prevalence of PTSD in post-MI patients; (ii) to investigate the association of PTSD with cardiovascular endpoints; and (iii) to search for low-grade systemic inflammatory changes in PTSD pertinent to atherosclerosis. METHODS: We located studies by PubMed electronic library search and through checking the bibliographies of these sources. RESULTS: The weighted prevalence of PTSD after MI was 14.7% (range 0-25%; a total of 13 studies and 827 post-MI patients). Two studies reported a prospective association between PTSD and an increased risk of cardiovascular readmission in post-MI patients and of cardiovascular mortality in combat veterans, respectively. In a total of 11 studies, patients with PTSD had increased rates of physician-rated and self-reported cardiovascular diseases. Various cytokines and C-reactive protein were investigated in a total of seven studies suggesting that PTSD confers a pro-inflammatory state. CONCLUSIONS: Increasing evidence suggests that PTSD specifically related to MI develops considerably frequently in post-MI patients. More research is needed in larger cohorts applying a population design to substantiate findings suggesting PTSD is an atherogenic risk factor and to understand better the suspected behavioural and biological mechanisms involved.

The role of stress hormones in the relationship between resting blood pressure and coagulation activity

BACKGROUND: Systemic hypertension confers a hypercoagulable state. We hypothesized that resting mean blood pressure (MBP) interacts with stress hormones in predicting coagulation activity at rest and with acute mental stress. METHODS: We measured plasma clotting factor VII activity (FVII:C), FVIII:C, fibrinogen, D-dimer, epinephrine and norepinephrine, and saliva cortisol in 42 otherwise healthy normotensive and hypertensive medication-free men (mean age 43 +/- 14 years) at rest, immediately after stress, and twice during 60 min of recovery from stress. RESULTS: At rest, the MBP-by-epinephrine interaction predicted FVII:C (beta = -0.33, P < 0.04) and D-dimer (beta = 0.26, P < 0.05), and the MBP-by-cortisol interaction predicted D-dimer (beta = 0.43, P = 0.001), all independent of age and body mass index (BMI). Resting norepinephrine predicted fibrinogen (beta = 0.42, P < 0.01) and D-dimer (beta = 0.37, P < 0.03), both independent of MBP. MBP predicted FVIII:C change from rest to immediately post-stress independent of epinephrine (beta = -0.37, P < 0.03) and norepinephrine (beta = -0.38, P < 0.02). Cortisol change predicted FVIII:C change (beta = -0.30, P < 0.05) independent of age, BMI and MBP. Integrated norepinephrine change from rest to recovery (area under the curve, AUC) predicted D-dimer AUC (beta = 0.34, P = 0.04) independent of MBP. The MBP-by-epinephrine AUC interaction predicted FVII:C AUC (beta = 0.28) and fibrinogen AUC (beta = -0.30), and the MBP-by-norepinephrine AUC interaction predicted FVIII:C AUC (beta = -0.28), all with borderline significance (Ps < 0.09) and independent of age and BMI. CONCLUSIONS: MBP significantly altered the association between stress hormones and coagulation activity at rest and, with borderline significance, across the entire stress and recovery interval. Independent of MBP, catecholamines were associated with procoagulant effects and cortisol reactivity dampened the acute procoagulant stress response.

Low social support and poor emotional regulation are associated with increased stress hormone reactivity to mental stress in systemic hypertension

CONTEXT: There is strong evidence for a physiological hyperreactivity to stress in systemic hypertension, but data on associated or potentially moderating psychological factors are scarce. OBJECTIVE: The objective of the study was to identify psychological correlates of physiological stress reactivity in systemic hypertension. DESIGN: This was a cross-sectional, quasi-experimentally controlled study. Study participants underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. SETTING: The study was conducted in the population in the state of Zurich, Switzerland. SUBJECTS: Subjects included 22 hypertensive and 26 normotensive men (mean +/- sem 44 +/- 2 yr). MAIN OUTCOME MEASURES: We assessed the psychological measures social support, emotional regulation, and cognitive appraisal of the stressful situation. Moreover, we measured salivary cortisol and plasma epinephrine and norepinephrine before and after stress and several times up to 60 min thereafter as well as blood pressure and heart rate. RESULTS: We found poorer hedonistic emotional regulation (HER) and lower perceived social support in hypertensives, compared with normotensives (P < 0.01). Compared with normotensives, hypertensives showed higher cortisol, epinephrine, and norepinephrine secretions after stress (P < 0.038) as well as higher systolic and diastolic blood pressure (P < 0.001). Cortisol reactivity and norepinephrine secretion were highest in hypertensive men with low HER (P < 0.05). In contrast, hypertensives with high HER did not significantly differ from normotensives in both cortisol and norepinephrine secretion after stress. Epinephrine secretion was highest in hypertensives with low social support but was not different between hypertensives with high social support and normotensives. CONCLUSIONS: The findings suggest that both low social support and low HER are associated with elevated stress hormone reactivity in systemic hypertension.

Exhaustion is associated with reduced habituation of free cortisol responses to repeated acute psychosocial stress

We investigated the association between exhaustion and the habituation of free cortisol responses to repeated stress exposure. The study comprised 25 healthy male subjects (38-59 years) who were confronted three times with the Trier Social Stress Test. Mean cortisol responses showed the well-known general habituation effect. A two-way interaction day by exhaustion (p<0.05) indicated that mean cortisol responses vary across stress sessions depending on the extent of exhaustion. Linear regression revealed a negative dose-response relationship between exhaustion and the degree of habituation (p<0.02). We identified 19 individuals showing a response habituation (negative slope) and 6 individuals showing a response sensitization over the three sessions (positive slope) with the latter reporting higher exhaustion scores. It might be hypothesized that impaired habituation to repeated exposure to the same stressor could reflect a state of increased vulnerability for allostatic load. Absence of normal habituation might be one potential mechanism how exhaustion relates to increased disease vulnerability.

Oxidative stress in lungs of mice infected with influenza A virus

As oxidative stress has been implicated in the pathogenesis of certain viral diseases we determined antioxidant and prooxidant parameters in lungs and bronchoalveolar lavage fluid (BALF) of mice infected with a lethal dose of influenza A/PR8/34 virus. Viral infection was characterized by massive infiltration of leukocytes, mainly polymorphonuclear leukocytes, into the alveolar space. The total number of BALF cells increased up to 8-fold (day 3 post-infection) and these cells appeared activated as judged by their increased rates of superoxide anion radical (O2-.) generation upon stimulation. Maximal rates of radical generation by BALF cells during the early stages of infection were 15- or 70-fold higher than those of cells from control animals when expressed per cell or total BALF cells, respectively. At the terminal stages of infection the total capacity of BALF cells to release O2-. declined to approximately 35-fold the control values. Infection also resulted in increased in vivo formation of hydrogen peroxide (H2O2) within the lungs at a time that coincided with the maximal capacity of BALF cells to release O2-.. Whereas pulmonary activities of glutathione peroxidase and reductase remained unaltered, levels of ascorbate in the cell-free BALF decreased significantly during the early stages of the infection and then returned to normal levels and above, late in infection. The oxidation state of the dehydroascorbic acid/ascorbate couple increased concomitantly with the decrease in ascorbate concentrations early in infection and remained elevated throughout the infection. As assessed by the prevention of peroxyl radical-induced loss of phycoerythrin fluorescence, the total antioxidant capacity present in lung tissue homogenate from terminally ill animals was not diminished when compared to that prepared from lungs of control mice. We conclude that although early stages of influenza infection are associated with the presence of oxidative stress in the lung tissue and alveolar fluid lining the epithelial cells, this stress does not appear to overwhelm local antioxidant defenses. The results therefore do not support a direct causative role of oxidative tissue damage in the pathogenesis of influenza virus infection.

Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function

In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded alpha1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

Steady-state function of the ubiquitous mammalian Na/H exchanger (NHE1) in relation to dimer coupling models with 2Na/2H stoichiometry

We describe the steady-state function of the ubiquitous mammalian Na/H exchanger (NHE)1 isoform in voltage-clamped Chinese hamster ovary cells, as well as other cells, using oscillating pH-sensitive microelectrodes to quantify proton fluxes via extracellular pH gradients. Giant excised patches could not be used as gigaseal formation disrupts NHE activity within the patch. We first analyzed forward transport at an extracellular pH of 8.2 with no cytoplasmic Na (i.e., nearly zero-trans). The extracellular Na concentration dependence is sigmoidal at a cytoplasmic pH of 6.8 with a Hill coefficient of 1.8. In contrast, at a cytoplasmic pH of 6.0, the Hill coefficient is <1, and Na dependence often appears biphasic. Results are similar for mouse skin fibroblasts and for an opossum kidney cell line that expresses the NHE3 isoform, whereas NHE1(-/-) skin fibroblasts generate no proton fluxes in equivalent experiments. As proton flux is decreased by increasing cytoplasmic pH, the half-maximal concentration (K(1/2)) of extracellular Na decreases less than expected for simple consecutive ion exchange models. The K(1/2) for cytoplasmic protons decreases with increasing extracellular Na, opposite to predictions of consecutive exchange models. For reverse transport, which is robust at a cytoplasmic pH of 7.6, the K(1/2) for extracellular protons decreases only a factor of 0.4 when maximal activity is decreased fivefold by reducing cytoplasmic Na. With 140 mM of extracellular Na and no cytoplasmic Na, the K(1/2) for cytoplasmic protons is 50 nM (pH 7.3; Hill coefficient, 1.5), and activity decreases only 25% with extracellular acidification from 8.5 to 7.2. Most data can be reconstructed with two very different coupled dimer models. In one model, monomers operate independently at low cytoplasmic pH but couple to translocate two ions in "parallel" at alkaline pH. In the second "serial" model, each monomer transports two ions, and translocation by one monomer allosterically promotes translocation by the paired monomer in opposite direction. We conclude that a large fraction of mammalian Na/H activity may occur with a 2Na/2H stoichiometry.

Coagulation activity before and after acute psychosocial stress increases with age

OBJECTIVE: To assess whether stress further increases hypercoagulation in older individuals. We investigated whether acute stress-induced changes in coagulation parameters differ with age. It is known that hypercoagulation occurs in response to acute stress and that a shift in hemostasis toward a hypercoagulability state occurs with age. However, it is not yet known whether acute stress further increases hypercoagulation in older individuals, and thus may increase their risk for cardiovascular disease (CVD). METHODS: A total of 63 medication-free nonsmoking men, aged between 20 and 65 years (mean +/- standard error of the mean = 36.7 +/- 1.7 years), underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We measured plasma clotting factor VII activity (FVII:C), fibrinogen, and D-dimer at rest, immediately, and 20 minutes after stress. RESULTS: Increased age predicted greater increases in fibrinogen (beta = 0.26, p = 0.041; DeltaR(2) = 0.05), FVII:C (beta = 0.40, p = .006; DeltaR(2) = 0.11), and D-dimer (beta = 0.51, p < .001; DeltaR(2) = 0.18) from rest to 20 minutes after stress independent of body mass index and mean arterial blood pressure. General linear models revealed significant effects of age and stress on fibrinogen, FVII:C, and D-dimer (main effects: p < .04), and greater D-dimer stress reactivity with older age (interaction age-by-stress: F(1.5/90.4) = 4.36, p = .024; f = 0.33). CONCLUSIONS: Our results suggest that acute stress might increase vulnerability in the elderly for hypercoagulability and subsequent hemostasis-associated diseases like CVD.

Three members of the connective tissue growth factor family CCN are differentially regulated by mechanical stress

Expression of connective tissue growth factor (CTGF), a member of the CCN gene family, is known to be significantly induced by mechanical stress. We have therefore investigated whether other members of the CCN gene family, including Cyr61 and Nov, might reveal a similar stress-dependent regulation. Fibroblasts growing under stressed conditions within a three-dimensional collagen gel showed at least a 15 times higher level of Cyr61 mRNA than cells growing under relaxed conditions. Upon relaxation, the decline of the Cyr61 mRNA to a lower level occurred within 2 h, and was thus quicker than the response of CTGF. The regulation was fully reversible when stress was reapplied. Thus, Cyr61 represents another typical example of a stress-responsive gene. The level of the Nov mRNA was low in the stressed state, but increased in the relaxed state. This CCN gene therefore shows an inverted regulation relative to that of Cyr61 and CTGF. Inhibition of protein kinases by means of staurosporine suppressed the stress-induced expression of Cyr61 and CTGF. Elevated levels of cAMP induced by forskolin mimicked the effects of relaxation on the regulation of Cyr61, CTGF and Nov. Thus, adenylate cyclase as well as one or several protein kinases might be involved in the mechanoregulation of these CCN genes.