Evidence that N-acetylcysteine inhibits TNF-alpha-induced cerebrovascular endothelin-1 upregulation via inhibition of mitogen- and stress-activated protein kinase

N-acetylcysteine (NAC) is neuroprotective in animal models of acute brain injury such as caused by bacterial meningitis. However, the mechanism(s) by which NAC exerts neuroprotection is unclear. Gene expression of endothelin-1 (ET-1), which contributes to cerebral blood flow decline in acute brain injury, is partially regulated by reactive oxygen species, and thus a potential target of NAC. We therefore examined the effect of NAC on tumor necrosis factor (TNF)-alpha-induced ET-1 production in cerebrovascular endothelial cells. NAC dose dependently inhibited TNF-alpha-induced preproET-1 mRNA upregulation and ET-1 protein secretion, while upregulation of inducible nitric oxide synthase (iNOS) was unaffected. Intriguingly, NAC had no effect on the initial activation (i.e., IkappaB degradation, nuclear p65 translocation, and Ser536 phosphorylation) of NF-kappaB by TNF-alpha. However, transient inhibition of NF-kappaB DNA binding suggested that NAC may inhibit ET-1 upregulation by inhibiting (a) parallel pathway(s) necessary for full transcriptional activation of NF-kappaB-mediated ET-1 gene expression. Similar to NAC, the MEK1/2 inhibitor U0126, the p38 inhibitor SB203580, and the protein kinase inhibitor H-89 selectively inhibited ET-1 upregulation without affecting nuclear p65 translocation, suggesting that NAC inhibits ET-1 upregulation via inhibition of mitogen- and stress-activated protein kinase (MSK). Supporting this notion, cotreatment with NAC inhibited the TNF-alpha-induced rise in MSK1 and MSK2 kinase activity, while siRNA knock-down experiments showed that MSK2 is the predominant isoform involved in TNF-alpha-induced ET-1 upregulation.

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.

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.

[MRI-based diagnosis of an acute bilateral compartment syndrome]

The acute compartment syndrome describes a posttraumatic or inflammatory edema, which leads to a painful constraint of muscular movement and paresthesia. An increase in pressure in the anatomical compartment is postulated. The main symptoms include local swelling, sensory loss, local muscle weakness as well as late livid discoloration. Therapy of choice is an early fasciotomy with decompression to avoid serious complications like muscle necrosis. Here we report a 22 year old patient who postoperatively suffered from a bilateral paresis of the foot jack. Further examinations by electromyography and magnetic resonance imaging (MRI) led to the diagnosis of an acute bilateral compartment syndrome.

Alterations in nitric oxide synthase isoforms in acute lower limb ischemia and reperfusion

Alterations in nitric oxide synthase (NOS) are implicated in ischemia and ischemia-reperfusion injury. Changes in the 3 NOS isoforms in human skeletal muscle subjected to acute ischemia and reperfusion were studied. Muscle biopsies were taken from patients undergoing total knee replacement. Distribution of the specific NOS isoforms within muscle sections was studied using immunohistochemistry. NOS mRNA levels were measured using real-time reverse transcription-polymerase chain reaction and protein levels studied using Western blotting. NOS activity was also assessed using the citrulline assay. All 3 NOS isoforms were found in muscle sections associated with muscle fibers and microvessels. In muscle subjected to acute ischemia and reperfusion, NOS I/neuronal NOS mRNA and protein were elevated during reperfusion. NOS III/endothelial NOS was also upregulated at the protein level during reperfusion. No changes in NOS II/inducible NOS expression or NOS activity occurred. In conclusion, alterations in NOS I and III (neuronal NOS and endothelial NOS) at different levels occurred after acute ischemia and reperfusion in human skeletal muscle; however, this did not result in increased NOS activity. In the development of therapeutic agents based on manipulation of the NO pathway, targeting the appropriate NOS isoenzymes may be important.

Viral etiology of acute respiratory infections with cough in infancy: a community-based birth cohort study

BACKGROUND: Acute respiratory infections (ARI) are a major cause of morbidity in infancy worldwide, with cough and wheeze being alarming symptoms to parents. We aimed to analyze in detail the viral aetiology of ARI with such symptoms in otherwise healthy infants, including rhinoviruses and recently discovered viruses such as human metapneumovirus (HMPV), coronavirus NL63 and HKU1, and human bocavirus (HBoV). METHODS: We prospectively followed 197 unselected infants during their first year of life and assessed clinical symptoms by weekly standardized interviews. At the first ARI with cough or wheeze, we analyzed nasal swabs by sensitive individual real time polymerase chain reaction assays targeting 16 different respiratory viruses. RESULTS: All 112 infants who had an ARI had cough, and 39 (35%) had wheeze. One or more respiratory viruses were found in 88 of 112 (79%) cases. Fifteen (17%) dual and 3 (3%) triple infections were recorded. Rhino- (23% of all viruses) and coronaviruses (18%) were most common, followed by parainfluenza viruses (17%), respiratory syncytial virus (RSV) (16%), HMPV (13%), and HBoV (5%). Together rhinoviruses, coronaviruses, HMPV, and HBoV accounted for 60% (65 of 109) of viruses. Although symptom scores and need for general practitioner (GP) consultations were highest in infants infected with RSV, they were similar in infants infected with other viruses. Viral shedding at 3 weeks occurred in 20% of cases. CONCLUSIONS: Rhinoviruses, coronaviruses, HMPV, and HBoV are common pathogens associated with respiratory symptoms in otherwise healthy infants. They should be considered in the differential diagnosis of the aetiology of ARI in this age group.

Value of a novel Neisseria meningitidis--specific polymerase chain reaction assay in skin biopsy specimens as a diagnostic tool in chronic meningococcemia

BACKGROUND: Chronic meningococcemia (CM) is a diagnostic challenge. Skin lesions are frequent but in most cases nonspecific. Polymerase chain reaction (PCR)-based diagnosis has been validated in blood and cerebrospinal fluid for acute Neisseria meningitidis infection, in patients in whom routine microbiologic tests have failed to isolate the bacteria. In 2 patients with CM, we established the diagnosis by a newly developed PCR-based approach performed on skin biopsy specimens. OBSERVATIONS: Two patients presented with fever together with systemic and cutaneous manifestations suggestive of CM. Although findings from blood cultures remained negative, we were able to identify N meningitidis in the skin lesions by a newly developed PCR assay. In 1 patient, an N meningitidis strain of the same serogroup was also isolated from a throat swab specimen. Both patients rapidly improved after appropriate antibiotherapy. CONCLUSIONS: To our knowledge, we report the first cases of CM diagnosed by PCR testing on skin biopsy specimens. It is noteworthy that, although N meningitidis-specific PCR is highly sensitive in blood and cerebrospinal fluid in acute infections, our observations underscore the usefulness of PCR performed on skin lesions for the diagnosis of chronic N meningitidis infections. Whenever possible, this approach should be systematically employed in patients for whom N meningitidis infection cannot be confirmed by routine microbiologic investigations.

Overcommitment but not effort-reward imbalance relates to stress-induced coagulation changes in teachers

BACKGROUND: Stress-related hypercoagulability might link job stress with atherosclerosis. PURPOSE: This paper aims to study whether overcommitment, effort-reward imbalance, and the overcommitment by effort-reward imbalance interaction relate to an exaggerated procoagulant stress response. METHODS: We assessed job stress in 52 healthy teachers (49 +/- 8 years, 63% women) at study entry and, after a mean follow-up of 21 +/- 4 months, when they underwent an acute psychosocial stressor and had coagulation measures determined in plasma. In order to increase the reliability of job stress measures, entry and follow-up scores of overcommitment and of effort-reward imbalance were added up to total scores. RESULTS: During recovery from stress, elevated overcommitment correlated with D-dimer increase and with smaller fibrinogen decrease. In contrast, overcommitment was not associated with coagulation changes from pre-stress to immediately post-stress. Effort-reward imbalance and the interaction between overcommitment and effort-reward imbalance did not correlate with stress-induced changes in coagulation measures. CONCLUSIONS: Overcommitment predicted acute stress-induced hypercoagulability, particularly during the recovery period.

Stress effects on working memory, explicit memory, and implicit memory for neutral and emotional stimuli in healthy men

Stress is a strong modulator of memory function. However, memory is not a unitary process and stress seems to exert different effects depending on the memory type under study. Here, we explored the impact of social stress on different aspects of human memory, including tests for explicit memory and working memory (for neutral materials), as well as implicit memory (perceptual priming, contextual priming and classical conditioning for emotional stimuli). A total of 35 young adult male students were randomly assigned to either the stress or the control group, with stress being induced by the Trier Social Stress Test (TSST). Salivary cortisol levels were assessed repeatedly throughout the experiment to validate stress effects. The results support previous evidence indicating complex effects of stress on different types of memory: A pronounced working memory deficit was associated with exposure to stress. No performance differences between groups of stressed and unstressed subjects were observed in verbal explicit memory (but note that learning and recall took place within 1 h and immediately following stress) or in implicit memory for neutral stimuli. Stress enhanced classical conditioning for negative but not positive stimuli. In addition, stress improved spatial explicit memory. These results reinforce the view that acute stress can be highly disruptive for working memory processing. They provide new evidence for the facilitating effects of stress on implicit memory for negative emotional materials. Our findings are discussed with respect to their potential relevance for psychiatric disorders, such as post traumatic stress disorder.

Postpartum osteoporosis associated with proximal tibial stress fracture

A 33-year-old woman presented with acute nonspecific knee pain, 6 months postpartum. MR imaging, computed tomography and radiography were performed and a proximal tibia plateau insufficiency fracture was detected. Bone densitometry demonstrated mild postpartum osteoporosis. To our knowledge these findings have not been described in this location and in this clinical setting. The etiology of the atraumatic fracture of the tibia is presumed to be due to a low bone mineral density. The bone loss was probably due to pregnancy, lactation and postpartum hormonal changes. There were no other inciting causes and the patient was normocalcemic. We discuss the presence of a postpartum stress fracture in a hitherto undescribed site in a patient who had lactated following an uncomplicated pregnancy and had no other identifiable cause for a stress fracture.

Small intestinal intussusception in five dogs with acute renal failure and suspected leptospirosis (L. australis)

OBJECTIVES This case series describes 5 dogs with small intestinal intussusception and acute kidney injury due to infection with Leptospira interrogans serovar Australis. CASE SERIES SUMMARY Small intestinal intussusception was observed in 4 dogs diagnosed with acute kidney injury due to leptospirosis presented between 1997 and 2005. Intussusception was diagnosed at initial presentation or later during hospitalization. An additional dog fulfilling our inclusion criteria was presented to a small animal specialty clinic nearby and was included. Upon admission, all dogs were severely azotemic and thrombocytopenic. All 5 dogs showed the strongest microscopic agglutination test serology reaction to L. interrogans serovar Australis. Two dogs survived with no apparent residual renal damage, 1 survived with subsequent mild chronic kidney disease, and 2 dogs were euthanized at the owners' request due to a guarded prognosis. NEW OR UNIQUE INFORMATION PROVIDED Intussusception can occur or may be seen in dogs with leptospirosis due to L. interrogans serovar Australis and patients should be monitored closely for this potential complication. As all 5 dogs described in this case series showed the highest titer for L. interrogans serovar Australis, these precautions may be especially applied in geographic areas where this particular serovar is seen.

Autonomic stress responses elicited by watching a live broadcast soccer game: a pilot study

Aim: Increased rates of hospitalization due to cardiovascular events have been reported during phases of World Soccer Championships (WSC). The purpose of this pilot study was to explore acute psychological and physiological effects of watching a live broadcast soccer game during the WSC 2006. Methods: Seven male supporters (age: M=24; SD=2.7) of the Swiss National Soccer Team watched a game of their team in a controlled laboratory setting. Heart rate (HR), heart rate variability (HRV), salivary cortisol, alpha-amylase (sAA), and testosterone concentrations, as well as several mood ratings were captured repeatedly before, during, and after the game. Results: Subjects reported feeling stressed, and HR and sAA activity showed an increase during the game. In contrast, HRV, cortisol and testosterone were unaffected. Conclusion: Watching a sports competition seems to specifically affect the sympathetic nervous system, which can be measured by sensitive electrocardiographic and salivary markers.

Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia

BACKGROUND Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A •- ], via electron paramagnetic resonance spectroscopy, and nitrite [NO 2 2 ], via ozone-based chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n 5 13, CMS 1 ) and without CMS (n 5 12, CMS 2 ). Twelve age- and activity-matched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured fl ow-mediated dilatation (FMD), arterial stiffness defined by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT). RESULTS Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS 2 group ( P , .05), as indicated by elevated A •- (3,191 457 arbitrary units [AU] vs 2,640 445 AU) and lower NO 2 2 (206 55 nM vs 420 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS 1 group (A •- , 3,765 429 AU; NO 2 2 , 148 50 nM) compared with both the CMS 2 group and lowlanders ( P , .05). This was associated with systemic vascular dysfunction as indicated by lower ( P , .05 vs CMS 2 ) FMD (4.2% 0.7% vs 7.6% 1.7%) and increased AIx-75 (23% 8% vs 12% 7%) and carotid IMT (714 127 m M vs 588 94 m M). CONCLUSIONS Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.

Plasma homocysteine levels increase following stress in older but not younger men

BACKGROUND: The incidence and prevalence of cardiovascular disease (CVD) increases with age. Some evidence suggests that mental stress may increase plasma homocysteine (Hcy), an amino acid relating to CVD. However, none of these studies assessed age effects on Hcy stress reactivity, nor did they control for age. The objective of this study was (a) to investigate whether Hcy reactivity to psychosocial stress differs between younger and middle-aged to older men and (b) to study whether psychosocial stress induces Hcy increases independent of age. METHODS: Twenty eight younger (20-30 years) and 22 middle-aged to older (47-65 years) apparently healthy men underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. Blood samples for Hcy measurements were obtained immediately before and after, as well as 10 and 20min after stress. Moreover, salivary cortisol was repeatedly measured to test the effectiveness of the stress task in triggering a neuroendocrine stress response. RESULTS: Hcy reactivity to stress differed between age groups (F(1.4, 60.7)=5.41, p=.014). While the older group displayed an increase in the Hcy response to stress (F(2.5, 39.8)=3.86, p=.022), Hcy levels in the younger group did not change (p=.27). Psychosocial stress per se did not change Hcy levels independent of age (p=.53). CONCLUSIONS: Our findings suggest that psychosocial stress does not evoke an Hcy response per se, but only in interaction with age pointing to a mechanism by which mental stress may increase CVD risk in older individuals.

Psychoendocrine validation of a short measure for assessment of perceived stress management skills in different non-clinical populations

BACKGROUND: We investigated the psychometric properties of a short questionnaire for combined assessment of different perceived stress management skills in the general population and tested whether scores relate to physiological stress reactivity. METHODS: For psychometric evaluation, we determined the factor structure of the questionnaire and investigated its measurement invariance in the participant groups and over time in three different independent samples representing the general population (total N=332). Reliability was tested by estimating test-retest reliability, internal consistency, and item reliabilities. We examined convergent and criterion validity using selected criterion variables. For endocrine validation, 35 healthy non-smoking and medication-free men in a laboratory study and 35 male and female employees in a workplace study underwent an acute standardized psychosocial stress task. We assessed stress management skills and measured salivary cortisol before and several times up to 60 min (workplace study) and 120 min (laboratory study) after stress. Potential confounders were controlled. RESULTS: The factor structure of the questionnaire consists of five scales reflecting acceptably distinct stress management skills such as cognitive strategies, use of social support, relaxation strategies, anger regulation, and perception of bodily tension. This factor structure was stable across participant groups and over time. Internal consistencies, item reliabilities, and test-retest reliabilities met established statistical requirements. Convergent and criterion validity were also established. In both endocrine validation studies, higher stress management skills were independently associated with lower cortisol stress reactivity (p's<.029). CONCLUSIONS: Our findings suggest that the questionnaire has good psychometric properties and that it relates to subjective psychological and objective physiological stress indicators. Therefore, the instrument seems a suitable measure for differential assessment of stress management skills in the general population.