Attachment orientations and loss adjustment among bereaved spouses.

Stressful life events such as losing a spouse can enhance inflammation. Responses to loss may depend, in part, on individual differences in attachment anxiety and avoidance. An individual's attachment orientation (i.e., an individual's levels of attachment anxiety and avoidance) reflects how an individual relates to others-- specifically, whether they feel their trusted others will reliably be there for them, and whether they feel comfortable opening up to and depending on their relationship partners. This study investigated the association between attachment orientations and poor loss adjustment in recently bereaved individuals (N = 100). Poor loss adjustment was operationalized as greater levels of inflammation and grief symptoms, as well as poorer self-reported mental and physical health. Attachment anxiety was associated with increased stimulated monocyte IL-6 and CCL4 production, but not TNFα. Likewise, attachment anxiety was associated with greater grief symptoms as well as poorer mental and physical health. In contrast, attachment avoidance was not associated with inflammation; it was, however, associated with less grief symptoms as well as better self-reported mental and physical health. Our findings provide evidence that attachment orientations may be associated with loss adjustment and adverse health outcomes following the recent loss of a spouse.

Inflammation and fatigue in early, untreated Parkinson's Disease.

OBJECTIVES: Parkinson's disease (PD)-related fatigue is a significant clinical problem, and the pathological processes that cause fatigue remain unknown. The aim of the present study was to explore the possible association of peripheral inflammation markers and fatigue in PD. MATERIALS & METHODS: We included 47 drug naïve, newly diagnosed PD patients with low (≤3.0) or high (>5.5) fatigue levels as evaluated by the Fatigue Severity Scale (FSS). Strict diagnostic criteria were applied for inclusion. Patients with possible confounding causes for fatigue were excluded. Serum concentrations of a panel of inflammatory markers (IL-8, TNF-α, MCP1, MIP-1ß, IL-6, IL-6R, p-selectin, E-selectin-1, ICAM, VCAM-1, CCL5, IL1-Ra, and TNFR1) were measured using ELISA technology in PD patients with and without fatigue to assess the potential relationships of fatigue in newly diagnosed, treatment-naïve patients. RESULTS: Fatigued PD patients had significantly higher levels of the IL-1 receptor antagonist (IL1-Ra) (1790 pg/mL (SD1007) vs 1262 pg/mL (SD379)) and of the adhesion molecule VCAM 1 (1071 ng/mL (SD276) vs 895 ng/mL (SD229)) than non-fatigued patients. A binary logistic regression model, including high or low FSS score as the dependent variable and UPDRS motor score, MADRS, MMSE, ESS, and IL1-Ra/VCAM-1 as independent variables, showed a significant effect both for IL1-Ra and VCAM-1. CONCLUSIONS: Higher serum levels of the inflammatory molecules IL1-Ra and VCAM-1 were associated with higher fatigue levels in patients with newly diagnosed, drug-naïve PD. These findings highlight an altered immune response as a potential contributor to PD-related fatigue, from the earliest clinical stages of the disease.

Longitudinal changes in glucocorticoid receptor exon 1F methylation and psychopathology after military deployment.

Several cross-sectional studies have demonstrated the relevance of DNA methylation of the glucocorticoid receptor exon 1F region (GR-1F) for trauma-related psychopathology. We conducted a longitudinal study to examine GR-1F methylation changes over time in relation to trauma exposure and the development of post-deployment psychopathology. GR-1F methylation (52 loci) was quantified using pyrosequencing in whole blood of 92 military men 1 month before and 6 months after a 4-month deployment period to Afghanistan. GR-1F methylation overall (mean methylation and the number of methylated loci) and functional methylation (methylation at loci associated with GR exon 1F expression) measures were examined. We first investigated the effect of exposure to potentially traumatic events during deployment on these measures. Subsequently, changes in GR-1F methylation were related to changes in mental health problems (total Symptom Checklist-90 score) and posttraumatic stress disorder (PTSD) symptoms (Self-Report Inventory for PTSD). Trauma exposure during deployment was associated with an increase in all methylation measures, but development of mental health problems 6 months after deployment was only significantly associated with an increased functional methylation. Emergence of post-deployment PTSD symptoms was not related to increased functional methylation over time. Pre-deployment methylation levels did not predict post-deployment psychopathology. To our knowledge, this is the first study to prospectively demonstrate trauma-related increases in GR-1F methylation, and it shows that only increases at specific functionally relevant sites predispose for post-deployment psychopathology.

Neuroinflammation and comorbidity of pain and depression.

Comorbid depression and chronic pain are highly prevalent in individuals suffering from physical illness. Here, we critically examine the possibility that inflammation is the common mediator of this comorbidity, and we explore the implications of this hypothesis. Inflammation signals the brain to induce sickness responses that include increased pain and negative affect. This is a typical and adaptive response to acute inflammation. However, chronic inflammation induces a transition from these typical sickness behaviors into depression and chronic pain. Several mechanisms can account for the high comorbidity of pain and depression that stem from the precipitating inflammation in physically ill patients. These mechanisms include direct effects of cytokines on the neuronal environment or indirect effects via downregulation of G protein-coupled receptor kinase 2, activation of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase that generates neurotropic kynurenine metabolites, increased brain extracellular glutamate, and the switch of GABAergic neurotransmission from inhibition to excitation. Despite the existence of many neuroimmune candidate mechanisms for the co-occurrence of depression and chronic pain, little work has been devoted so far to critically assess their mediating role in these comorbid symptoms. Understanding neuroimmune mechanisms that underlie depression and pain comorbidity may yield effective pharmaceutical targets that can treat both conditions simultaneously beyond traditional antidepressants and analgesics.

Cerebral and hepatic inflammatory response after neonatal hypoxia-ischemia in newborn rats.

BACKGROUND: Neonatal encephalopathy induced by perinatal asphyxia is a serious condition associated with high mortality and morbidity. Inflammation after the insult is thought to contribute to brain injury. This inflammatory response to hypoxia-ischemia (HI) may not only occur in the brain but also in peripheral organs. The aim of the present study was to investigate the effect of neonatal HI on the inflammatory response in the liver in comparison to inflammation in the brain. METHODS: HI was induced in P7 Wistar rats by unilateral carotid artery occlusion and hypoxia. Cytokine and chemokine mRNA levels were determined in the brain and liver by quantitative PCR. Polarization of brain macrophages to the M1/M2-like phenotype and infiltration of neutrophils were characterized by immunohistochemistry. RESULTS: 3 h after HI, an upregulation of the proinflammatory cytokines TNF-α and IL-1ß and anti-inflammatory IL-10 was observed in the ipsilateral hemisphere of the brain compared to mRNA levels in sham-operated animals. Additionally, cerebral CINC-1 and MCP-1 mRNA expressions were increased. We also observed increased numbers of macrophages/microglia of the M1-like phenotype as well as a small increase in granulocyte influx in the ipsilateral hemisphere. Conversely, in the liver 3 h after HI, a downregulation of TNF-α, IL-1ß, and MCP-1 and a trend towards an upregulation of IL-10 were observed compared to mRNA levels of sham-operated animals. However, hepatic CINC-1 expression was increased compared to levels in sham-operated animals. Following systemic hypoxia only, no significant changes in the expression of TNF-α, CINC-1 or MCP-1 were observed in the liver compared to sham-operated littermates, except for an upregulation in hepatic IL-1ß expression 3 h after hypoxia. Twenty-four hours after insult, cerebral ipsilateral TNF-α, MCP-1 and CINC-1 mRNA expression was still increased, together with an increase in TGF-ß expression. Moreover, an increase in macrophages/microglia of the M1-like phenotype was observed together with the appearance of macrophages/microglia of the M2-like phenotype around the cerebral lesion as well as an increase in granulocyte influx in comparison to 3 h after HI. In the liver, 24 h after HI, cytokine and chemokine responses were similar to mRNA levels in sham-operated animals except for a decrease in IL-10 and MCP-1. CONCLUSION: We describe for the first time that brain damage following neonatal HI induces an early downregulation of the proinflammatory response in the liver. HI induces an early proinflammatory response in the brain with a concomitant increase in influx of neutrophils and polarization of macrophages/microglia to the M1-like phenotype starting at 3 h and increasing up to 24 h after HI. The inflammatory state of the brain changes after 24 h, with an increase in the anti-inflammatory cytokine TGF-ß together with the appearance of macrophages/microglia of the M2-like phenotype. The downregulation of proinflammatory cytokines in the liver is not due to systemic hypoxia only, but is induced by the cerebral damage.

Liposome-encapsulated dexamethasone attenuates ventilator-induced lung inflammation.

BACKGROUND AND PURPOSE: Systemic glucocorticoid therapy may effectively attenuate lung inflammation but also induce severe side-effects. Delivery of glucocorticoids by liposomes could therefore be beneficial. We investigated if liposome-encapsulated dexamethasone inhibited ventilator-induced lung inflammation. Furthermore, we evaluated whether targeting of cellular Fcγ-receptors (FcγRs) by conjugating immunoglobulin G (IgG) to liposomes, would improve the efficacy of dexamethasone-liposomes in attenuating granulocyte infiltration, one of the hallmarks of lung inflammation. EXPERIMENTAL APPROACH: Mice were anaesthetized, tracheotomized and mechanically ventilated for 5 h with either 'low' tidal volumes ∼7.5 mL·kg(-1) (LV(T) ) or 'high' tidal volumes ∼15 mL·kg(-1) (HV(T) ). At initiation of ventilation, we intravenously administered dexamethasone encapsulated in liposomes (Dex-liposomes), dexamethasone encapsulated in IgG-modified liposomes (IgG-Dex-liposomes) or free dexamethasone. Non-ventilated mice served as controls. KEY RESULTS: Dex-liposomes attenuated granulocyte infiltration and IL-6 mRNA expression after LV(T) -ventilation, but not after HV(T) -ventilation. Dex-liposomes also down-regulated mRNA expression of IL-1ß and KC, but not of CCL2 (MCP-1) in lungs of LV(T) and HV(T) -ventilated mice. Importantly, IgG-Dex-liposomes inhibited granulocyte influx caused by either LV(T) or HV(T) -ventilation. IgG-Dex-liposomes diminished IL-1ß and KC mRNA expression in both ventilation groups, and IL-6 and CCL2 mRNA expression in the LV(T) -ventilated group. Free dexamethasone prevented granulocyte influx and inflammatory mediator expression induced by LV(T) or HV(T) -ventilation. CONCLUSIONS AND IMPLICATIONS: FcγR-targeted IgG-Dex-liposomes are pharmacologically more effective than Dex-liposomes particularly in inhibiting pulmonary granulocyte infiltration. IgG-Dex-liposomes inhibited most parameters of ventilator-induced lung inflammation as effectively as free dexamethasone, with the advantage that liposome-encapsulated dexamethasone will be released locally in the lung thereby preventing systemic side-effects.

[Chronic fatigue syndrome: a psychoneuroimmunological perspective]. / Chronischevermoeidheidssyndroom: een psychoneuro-immunologisch perspectief.

This article casts light on the contribution that psychoneuroimmunology can make in the search for the cause of chronic fatigue syndrome (cfs). Several studies suggest that psychosocial and physical stress may play an important predisposing, precipitating and perpetuating role in cfs. Moving on from these studies we now discuss recent research into the stress-related pathophysiological mechanisms of the illness. Although there is evidence for a hypofunctional stress response, a hyperactive immune response and disturbances in the interaction between both, the findings are not consistent. Longitudinal studies are needed to unravel the pathophysiology of cfs still further. In such studies the concept of 'sickness response' and 'sickness behaviour' may perform an important heuristic function.

Endometrial secretion analysis identifies a cytokine profile predictive of pregnancy in IVF.

BACKGROUND: The study of human endometrial-embryonic interactions is complicated by the disruptive impact of endometrial sample collection on the process of implantation itself. Endometrial secretion analysis is a novel technique, non-disruptive to implantation. The primary aim of this prospective cohort study was to explore whether a cytokine profile predictive of implantation and clinical pregnancy can be identified in endometrial secretions aspirated immediately prior to embryo transfer following IVF. METHODS: Endometrial secretions, aspirated immediately prior to embryo transfer from 210 women undergoing IVF, were analyzed using a multiplex immunoassay for 17 soluble regulators of implantation, namely interleukin (IL)-1beta, IL-5, IL-6, IL-10, IL-12, IL-15, IL-17, IL-18, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, macrophage migration inhibitory factor, eotaxin, IFN-gamma-inducible 10 kDa protein (IP-10), monocyte chemo-attractant protein-1 (MCP-1), Dickkopf homolog 1, heparin-binding epidermal growth factor and vascular endothelial growth factor (VEGF). In order to detect implantation, daily urine samples were collected after embryo transfer, and human Chorionic Gonadotropin (hCG) concentrations were analyzed by an immunoassay. RESULTS: Multivariable logistic regression analysis revealed significant associations (negative and positive association, respectively) between MCP-1 (P = 0.005) and IP-10 (P = 0.037) levels and implantation, and between IL-1beta (P = 0.047) and TNF-alpha (P = 0.023) levels and clinical pregnancy. The predictive value for pregnancy of IL-1beta and TNF-alpha was observed to be equivalent and additive to that of embryo quality. CONCLUSIONS: Endometrial secretion cytokine profiling offers a novel, non-disruptive approach to study the role of the endometrium in human embryo implantation and identifies a profile which appears to be conducive to clinical pregnancy. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (nCT00264992).

Cytokine profiling in endometrial secretions: a non-invasive window on endometrial receptivity.

Investigation of human embryo implantation requires a non-disruptive means of studying the endometrium during the window of implantation. This study describes a novel approach of cytokine profiling in endometrial secretions. Endometrial secretions aspirated prior to embryo transfer from 210 women undergoing IVF or intracytoplasmic sperm injection were analysed by a multiplex immunoassay. Ten mediators [interleukin (IL)-1beta, IL-6, IL-12, IL-18, tumour necrosis factor-alpha, macrophage migration inhibitory factor, eotaxin, monocyte chemotactic protein-1, interferon-gamma inducible protein-10, vascular endothelial growth factor] were detectable in 90-100% of the samples. Heparin-binding epidermal growth factor, IL-5, IL-17, IL-10, Dickkopf homologue-1 and IL-15 were detected in 23-76%, whereas interferon-gamma was not detectable in any of the samples. To assess possible contamination of samples, cervical mucus was also aspirated for comparative analysis in 22 women. The endometrial cytokine profile differed significantly from cervical mucus. Pregnancy rates of the study participants who underwent endometrial secretion aspiration were compared with 210 controls matched for important prognostic variables; no significant differences were found. In conclusion, cytokine profiling in endometrial secretion offers an objective, non-disruptive means of analysing the in-vivo milieu encountered by the embryo and offers a new and potentially valuable approach to studying the endometrial factor in human embryo implantation.

Elevated plasma corticotrophin-releasing hormone levels in veterans with posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is associated with alterations in corticotrophin-releasing hormone (CRH) secretion. Plasma CRH levels, which are easily acquired, might serve as a predictor of hypothalamic CRH levels. Assessment of plasma CRH, adrenocorticotrophin hormone (ACTH), and cortisol levels in 31 veterans with PTSD, 30 traumatized veterans without PTSD matched on age, year, and region of deployment (traumacontrols), and 28 age-matched healthy controls (HCs) was carried out. Plasma CRH levels were higher in PTSD patients compared to both HCs (p=0.005) and traumacontrols (p=0.007). This led to our conclusion, that elevated plasma CRH levels are specifically related to PTSD and not to exposure to traumatic stress during deployment.

Neuroendocrine and blood pressure responses to rectal distensions in individuals with high and low visceral pain sensitivity.

BACKGROUND: The mechanisms of interindividual variations in visceral pain sensitivity remain poorly understood. We characterized the neuroendocrine responses to rectal distensions in healthy individuals with high vs. low rectal pain sensitivity. METHODS: Rectal sensory and pain thresholds were determined, and a series of random painful distensions was carried out. Eighteen subjects were stratified into groups with a low rectal pain threshold ("High Sensitivity" group) vs. a high rectal pain threshold ("Low Sensitivity" group) by median split, and were compared with regard to adrenocorticotropic hormone (ACTH) and cortisol, cardiovascular, and emotional responses. RESULTS: Distensions led to an anticipatory stress response, reflected by elevated baseline anxiety, and increased baseline ACTH and cortisol in both groups. In response to distensions, the "Low Sensitivity" group showed significantly greater ACTH and cortisol concentrations analysis of variance (ANOVA time x group for ACTH: p<.05; for cortisol: p<.01), and elevated diastolic blood pressures (BP) (ANOVA group: p<.01) when compared to the "High Sensitivity" group. CONCLUSIONS: Painful rectal distensions are associated with a pronounced anticipatory stress response, reflected by elevated anxiety and elevated stress hormones. Individuals with high rectal pain sensitivity differ from those with low pain sensitivity in distension-induced hormonal and blood pressure responses, suggesting that neuroendocrine responses may be relevant to the pathophysiology of visceral hyperalgesia.

Enhanced cortisol suppression in response to dexamethasone administration in traumatized veterans with and without posttraumatic stress disorder.

BACKGROUND: While enhanced cortisol suppression in response to dexamethasone is one of the most consistent biological findings in posttraumatic stress disorder (PTSD), the relative contribution of trauma exposure to this finding remains unclear. METHODS: Assessment of diurnal salivary cortisol levels and 1600 h salivary cortisol before and after oral administration of 0.5mg dexamethasone in veterans with PTSD, veterans without PTSD (trauma controls) and healthy controls. Assessment of 1600 h plasma cortisol, ACTH and corticotrophin binding globulin (CBG) in response to dexamethasone in PTSD patients and trauma controls. RESULTS: Both PTSD patients and trauma controls demonstrated significantly more salivary cortisol suppression compared to healthy controls. Salivary cortisol, plasma cortisol and ACTH suppression as well as CBG levels did not differ between PTSD patients and trauma controls. PTSD patients showed a reduced awakening cortisol response (ACR) compared to healthy controls that correlated significantly with PTSD symptoms. No significant differences were observed in ACR between PTSD patients and trauma controls. CONCLUSIONS: These data suggest that enhanced cortisol suppression to dexamethasone is related to trauma exposure and not specifically to PTSD. The correlation between the ACR and PTSD severity suggests that a flattened ACR may be a result of clinical symptoms.

Leukocyte glucocorticoid receptor expression and immunoregulation in veterans with and without post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is associated with a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA axis). In addition, there is evidence for altered glucocorticoid receptor (GR) expression and function in peripheral blood mononuclear cells. The aim of the present study was to differentiate between the effect of trauma exposure and PTSD on leukocyte GR expression and glucocorticoid immune regulation. Leukocyte GR binding characteristics and glucocorticoid sensitivity of immune activity, determined as the effect of dexamethasone (DEX) on in vitro cytokine release and T-cell proliferation, were compared between veterans with PTSD, traumatized veterans without PTSD and healthy controls. Leukocyte GR density was significantly lower in veterans with and without PTSD compared to healthy controls. DEX-induced inhibition of T-cell proliferation was significantly lower in PTSD compared to trauma and healthy controls. DEX-induced increase in lipopolysaccharide-stimulated interleukin-10 was less pronounced in traumatized veterans with and without PTSD compared to healthy controls. No group differences were observed in the effect of DEX on other cytokines or in baseline immune activity, except for lower tumor necrosis factor-alpha production in PTSD patients compared to healthy controls. The results suggest that trauma exposure is sufficient to induce changes in GR binding characteristics, whereas resistance of T-cell proliferation to DEX only occurs in PTSD. DEX resistance of in vitro immune activity was not a general phenomenon, but was restricted to specific immune functions.

Hydrogen peroxide impairs GRK2 translation via a calpain-dependent and cdk1-mediated pathway.

Oxidative mechanisms of injury are involved in many neurodegenerative diseases such as stroke, ischemia-reperfusion injury and multiple sclerosis. G protein-coupled receptor kinase 2 (GRK2) plays a key role in G protein-coupled receptor (GPCR) signaling modulation, and its expression levels are decreased after brain hypoxia/ischemia and reperfusion as well as in several inflammatory conditions. We report here that hydrogen peroxide downregulates GRK2 expression in C6 rat glioma cells. The hydrogen peroxide-induced decrease in GRK2 is prevented by a calpain protease inhibitor, but does not involve increased GRK2 degradation or changes in GRK2 mRNA level. Instead we show that hydrogen peroxide treatment impairs GRK2 translation in a process that requires Cdk1 activation and involves the mTOR pathway. This novel mechanism for the control of GRK2 expression in glial cells upon oxidative stress challenge may contribute to the modulation of GPCR signaling in different pathological conditions.

Disturbed in vitro adrenergic modulation of cytokine production in inflammatory bowel diseases in remission.

OBJECTIVE: Psychological stress has been implicated in the pathophysiology of both inflammatory and functional gastrointestinal (GI) diseases. The goal of this study was to address neuroendocrine modulation of cytokine production by peripheral blood cells in GI diseases. METHODS: We analyzed the in vitro effects of the beta-adrenergic agonist terbutaline and the glucocorticoid agonist dexamethasone on TNF-alpha and IL-10 production by LPS-stimulated monocytes in whole cell blood cultures in patients with inflammatory bowel diseases in remission (N=10), diarrhoea-predominant irritable bowel syndrome (IBS, N=12), patients with a recent gastroenteritis (post-infectious group, N=10), and healthy controls (N=15). RESULTS: In response to terbutaline, there was a significant increase in IL-10 production (concentration effect: p<0.05), which was diminished in IBD (group effect: p<0.01), comparable in IBS and controls, but enhanced in the post-infectious group (group x concentration effect: p<0.05). In contrast, terbutaline resulted in a concentration-dependent suppression of TNF-alpha production, which was comparable in all groups. Dexamethasone suppressed TNF-alpha production in a dose-dependent manner in all groups, but this effect was significantly more pronounced in post-infectious subjects (group effect: p<0.05). CONCLUSIONS: In IBD, disturbed adrenergic regulation of IL-10 could be part of the mechanism(s) underlying the modulation of disease activity by psychological stress. Diarrhoea-predominant IBS was not associated with altered adrenergic or glucocorticoid regulation of cytokine production by peripheral blood cells, whereas a recent history of gastroenteritis was associated with disturbed neuroendocrine modulation of cytokine production, which may play role in the pathophysiology of post-infectious IBS.

Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review.

Posttraumatic stress disorder (PTSD) is typically accompanied by acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but several studies have also used a challenge model to further assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. This paper reviews common methodology and research findings on HPA function in PTSD, and discusses the pathophysiological mechanisms underlying these findings. We reviewed the literature and selected all English-language, human subject, data driven, pharmacological and non-pharmacological challenge studies pertaining to the HPA axis, and in vitro leukocyte glucocorticoid receptor studies in adult PTSD subjects. Studies using a non-pharmacological stress paradigm (cognitive stress, trauma reminders) to stimulate the HPA axis showed an exaggerated cortisol response in PTSD. The most widely used pharmacological challenge with consistent results was the low dose dexamethasone-suppression test (DST). These DST studies showed enhanced cortisol suppression in subjects with PTSD. Different hypotheses have been purported to explain the alterations in HPA axis functioning in PTSD. The results of the reviewed challenge tests, however, did not exclusively support one of the hypothesized mechanisms. Further research assessing hormones at all levels of the HPA axis at both baseline and at challenge conditions with a proper stratification of study population, will be necessary for a better understanding of stress-responsivity on the level of the HPA axis in PTSD.

Visceral pain and public speaking stress: neuroendocrine and immune cell responses in healthy subjects.

Whereas responses to psychological stressors are well-characterized, little is known regarding responses to painful visceral stimuli. We analyzed the emotional, cardiovascular, neuroendocrine, and cellular immune responses to painful rectal stimulation and psychological stress in healthy individuals. Eleven healthy subjects were studied in three conditions on separate days: painful rectal distension, public speaking stress, and rest. Blood was drawn for endocrinological and immunological analyses; heart rate and blood pressure were measured continuously; state anxiety was assessed with a questionnaire (STAI-S). Anxiety scores were highest in the rectal distension condition. This was evident following rectal distension (mean STAI-S scores: 44.2+/-3.5 post-distension vs. 36.6+/-3.8 post-speech, p<.05), but anxiety was also elevated at baseline (41.6+/-3.9 vs. 32+/-3.2 recovery, p<.01). This anticipatory effect was reflected by elevated baseline cortisol (p<.05) and baseline ACTH (p<.01) levels, as well as circulating lymphocytes and lymphocyte subsets, including decreased basal CD3+CD4+ cells (p<.05) and increased CD16+CD56+ cells (p=.06) compared to rest. Both public speech and rectal distension induced cardiovascular activation, but the effect was more pronounced following rectal distension (+63.8+/-9.4 mmHg in response to distension vs. +36.4+/-6.2 mmHg in response to speech for systolic BP, p<.05). Different response patterns were also observed in the distribution of circulating leukocytes and lymphocyte subsets, including CD16+CD56+ cells (p<.05). An acute visceral pain stimulus causes profound emotional, neuroendocrine, and immune cell responses, which are markedly affected by anticipatory anxiety. These findings may have implications for conditions associated with visceral hyperalgesia.

Flavonoid galangin prevents smooth muscle fatigue of pig urinary bladder.

There is increasing evidence that the generation of free radicals plays a role in the development of bladder dysfunction. Flavonoids are a group of polyphenolic compounds with broad pharmacological activity. In the present study, the protective effects of the flavonoid galangin on the progressive decrease of bladder smooth muscle contractile responses during repetitive field stimulation (RFS; a model for muscular fatigue) were demonstrated. Pig detrusor strips were mounted for tension recording in organ baths aand were subjected to RFS for 90 min at 32 Hz for 15 s every 5 min. The strips were then washed four times with fresh buffer and allowed a period of recovery for 90 min. The 90 min of RFS caused a progressive decrease in maximal contractile response to electrical field stimulation and to muscarinic agonist-induced contractions (34% and 46% decrease, respectively). Galangin (10(-7) M) prevented the decrease in contractile smooth muscle response of strips to electrical field stimulation during RFS compared with untreated tissues. The antioxidant activity of galangin was assessed by measuring its ability to inhibit the lipid peroxidation induced by iron and ascorbate in rat liver microsomes (IC50 1.7+0.12x10(-6) M). If the data are confirmed in-vivo, exogenously administered galangin may be a new approach in the prevention and/or treatment of bladder dysfunction.

Mechanical ventilation of healthy rats suppresses peripheral immune function.

This study was designed to investigate the possible effect of injurious mechanical ventilation on peripheral immune function of healthy rats. Three ventilation strategies were compared: 1) low peak inspiratory pressure (PIP)/positive end-expiratory pressure (PEEP); 2) high PIP/PEEP; and 3) high PIP/zero PEEP (ZEEP). As a reference group, healthy, nonventilated, sham-operated, anaesthetised rats were used. After 4 h, rats were sacrificed and macrophage inflammatory protein (MIP)-2 levels in lung and plasma were determined. Peripheral immune function was determined by measurement of splenic natural killer (NK) activity, mitogen-induced splenocyte proliferation and in vitro cytokine production. All immune measurements in the low PIP/PEEP group did not differ from the immune measurements in the reference group. High PIP strategies, irrespective of applied PEEP, enhanced MIP-2 levels in lung and plasma. NK cell activity, mitogen-induced splenocyte proliferation and MIP-2 and interleukin (IL)-10 production significantly decreased after high PIP/PEEP ventilation. In the high PIP/ZEEP-ventilated group, the decrease in splenocyte proliferation, MIP-2 and IL-10 production and NK cell activity was more pronounced and interferon-gamma production was also significantly lower than in the low PIP/PEEP group. These data show that high positive inspiratory pressure ventilation induces an inflammatory response in the lung, whereas at the same time the peripheral immune response is downregulated. Ventilator-induced peripheral immune suppression may contribute to poor outcome in acute respiratory distress syndrome patients.