Neuroendocrine Activation Research Articles

Plasma chromogranin A after severe burn trauma

BackgroundChromogranin A (CgA) in plasma (P-CgA), a neuroendocrine marker of sympathetic stress, has been shown to predict mortality in medical intensive care. We hypothesized that the magnitude of CgA release would reflect stress load, and thereby injury severity in burn intensive care patients. MethodsFifty-one consecutive patients with a burn area exceeding 10% were included. P-CgA was measured twice daily for seven days after injury. The point value at 24h, the mean and maximum values and the AUC at days 1–7, were tested as possible predictors. Injury severity in the form of organ dysfunction was measured as SOFA score at day 7. ResultsP-CgA could be classified into two types with respect to variability over time. Patients with high variability had more deep injuries and were older than those with low variability. All measures of CgA correlated with SOFA score at day 7, but not with total burn size. Univariate regressions showed that age, burn size and three of four measures of P-CgA predicted organ dysfunction. Multiple regressions showed that age, burn size, and either P-CgA at 24h, the mean value up to day 7, or the maximum value up to day 7, were independent predictors for organ dysfunction. Significant organ dysfunction was best predicted by age, burn area and the CgA point value at 24h with an AUC value of 0.91 in a ROC-analysis. ConclusionsThe extent of neuroendocrine activation assessed as P-CgA after a major burn injury is independently related to organ dysfunction.

Meta-analyses Indicate Associations between Neuroendocrine Activation, Deactivation in Neurotrophic and Neuroimaging Markers in Depression after Stroke

The association between stroke and depression is well established and has been suggested to be bidirectional. Systemic immune activation, hypothalamic-pituitary-adrenal axis hyperactivity, physiologic changes in the perfusion of blood vessels, the downregulation of neurotrophic factors, and apoptosis and necrosis of neuronal, glial, and endothelial cells have been frequently implicated in this relationship. A better understanding of the biology of poststroke depression could be important for enhancing clinical management. We review the currently available biologic markers of stroke-associated depressive illness (i.e., neurophysiologic, neuroendocrine, immunologic, and neuroimaging markers as well as neurotrophic factors). Search strategies included the electronic databases PubMed, PsycINFO, EMBASE, CINAHL, the Cochrane Library, and Proquest Dissertations (all records through June 2012), the reference lists of retrieved articles, the reference list of relevant reviews, and direct contact with authors of retrieved articles for any additional unpublished data. Thirty-three papers fulfilled the criteria for inclusion. We detected moderate effects for high postdexamethasone cortisol levels (odds ratio [OR] 3.28; 95% confidence interval [CI] 1.28-8.39; P = .01), lower serum brain-derived neurotrophic factor levels (standardised mean difference [SMD] -0.52; 95% CI -0.84 to -0.21; P = .001), smaller amygdala volumes (SMD -0.45; 95% CI -0.89 to -0.02; P = .04), and a small effect for overall brain perfusion reduction (SMD -0.35; 95% CI -0.64 to -0.06; P = .02), respectively, to poststroke depression. Cortisol-lowering therapies and those that increase blood flow and neurotrophic factors represent promising novel therapeutics for depression subtypes and may reduce the risk of depression in stroke patients.

Plants as medicinal stressors, the case of depurative practices in Chazuta valley (Peruvian Amazonia)

Ethnopharmacological relevanceDepurative practices, based on taking emetic plants and the restriction of food intake, are very much used in the traditional medicine of Chazuta (Peruvian Amazon) not only to restore health but also to maintain it. Aim of the studyTo describe Chazuta’s depurative practices, within a theoretical framework that involves the stress system and which defines the role played by the medicinal plants used as medicinal stressors. This biomedical model is more inclusive in relation to the variety of medicinal uses found for these practices. Material and methodsThe information was obtained in the valley of Chazuta from October 2004 to August 2005 through semi-structured interviews to the 6.3% of its rural adult population (i.e., 140 individuals, 75% belonging to the San Martin Quechua’s ethnic group). Thereafter, results were analysed and confronted to the existing literature. ResultsOverall, 191 depurative practices were reported in Chazuta where 114 different plant species were recorded and identified. Depending on their level of severity and duration, depurative practices can be classified as mild or strict. The wide range of medicinal uses reported supports both the involvement of adaptive stress responses in depurative practices and the consideration of the plants employed in this practices as medicinal stressors. ConclusionsBy inducing moderate stress within safe levels, depurative practices in Chazuta could produce adaptive responses that would protect against the detrimental consequences of chronic stress and stress-related diseases. This hypothesis could help to understand the diversity of the medicinal uses recorded in the field. Thus, plant remedies used in these practices in Chazuta could be considered as “medicinal stressors” as through vomiting the necessary neuroendocrine stress activation would be produced. In addition, other bioactivities that plants may harbour could converge with the whole stress reactivity process.

Hypertensive left ventricular hypertrophy

Neuroendocrine activation may be an important adjunctive mechanism for left ventricular hypertrophy (LVH) development. Controversy exists to as to whether LVH regression occurs due to blood pressure (BP) reduction alone or if adjunctive mechanisms play a role. We planned to test the hypothesis that for a similar BP reduction, LVH regression would be greater using a drug combination selected specifically to reduce neuroendocrine activity compared with one that did not. Forty-two patients with hypertension and cardiovascular magnetic resonance (CMR) proven LVH were allocated to one of two equipotent antihypertensive regimens for 6 months. Treatments were chosen on the basis of opposing mechanistic actions on the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS); one arm inhibitory (valsartan and moxonidine), the other neutral (bendroflumethiazide and amlodipine). The primary end point was absolute reduction in CMR-determined left ventricular mass (LVM). All BP indices were highly comparable at the start and end of the trial (P > 0.6 between groups). BP was reduced (always P < 0.0001) by 37/17 mmHg in the valsartan and moxonidine group and 38/19 mmHg in the bendroflumethiazide and amlodipine group. CMR quantified LVM was comparable between the two groups at baseline and decreased significantly in both treatment groups (P < 0.0001). Reduction in LVM was significantly greater in valsartan and moxonidine [-25.9 g; 95% confidence interval (CI) -31.6 to -20.2] compared with bendroflumethiazide and amlodipine (-18.3 g; -23.3 to -13.4) (P < 0.05). The magnitude of LVH regression achieved by inhibiting the RAAS and SNS neuroendocrine pathways is greater than that produced by comparable BP reduction alone. This supports the hypothesis that neuroendocrine mechanisms are important in the regression of LVH.

Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats

Catecholaminergic neurons within the central nervous system are an integral part of stress-related neurocircuitry, and the nucleus of the solitary tract (NTS) plays a critical role in cardiovascular regulation. We tested the hypothesis that NTS catecholaminergic neurons attenuate psychological stress-induced increases in blood pressure and promote neuroendocrine activation in response to psychological stress.Anti-dopamine-β-hydroxylase antibody conjugated to the neurotoxin saporin (DSAP) or saline vehicle was microinjected into the NTS to lesion catecholaminergic neurons in male Sprague-Dawley rats, and 17 days later the rats were subjected to 60 min of restraint stress for five consecutive days. DSAP treatment significantly enhanced the integrated increase in mean arterial pressure during restraint on the first (800 ± 128 and 1115 ± 116 mmHg (min) for saline- and DSAP-treated rats) and fifth days (655 ± 116 and 1035 ± 113 mmHg (min) for saline- and DSAP-treated rats; P<0.01 for overall effect of DSAP treatment) of restraint. In contrast, after 60 min of restraint plasma corticosterone concentration was significantly lower in DSAP-treated compared with saline-treated rats (25.9 ± 7 compared with 46.8 ± 7 μg dl(-1) for DSAP- and saline-treated rats; P <0.05). DSAP treatment also significantly reduced baseline plasma adrenaline concentration (403 ± 69 compared with 73 ± 29 pg ml(-1) for saline- and DSAP-treated rats), but did not alter the magnitude of the adrenaline response to restraint. The data suggest that NTS catecholaminergic neurons normally inhibit the arterial pressure response, but help maintain the corticosterone response to restraint stress.

Physiological correlates of bereavement and the impact of bereavement interventions

The death of a loved one is recognized as one of life's greatest stresses, with reports of increased mortality and morbidity for the surviving spouse or parent, especially in the early months of bereavement. The aim of this paper is to review the evidence to date to identify physiological changes in the early bereaved period, and evaluate the impact of bereavement interventions on such physiological responses, where they exist. Research to date suggests that bereavement is associated with neuroendocrine activation (cortisol response), altered sleep (electroencephalography changes), immune imbalance (reduced T-lymphocyte proliferation), inflammatory cell mobilization (neutrophils), and prothrombotic response (platelet activation and increased vWF-ag) as well as hemodynamic changes (heart rate and blood pressure), especially in the early months following loss. Additional evidence suggests that bereavement interventions have the potential to be of value in instances where sleep disturbance becomes a prolonged feature of complicated grief, but have limited efficacy in maintaining immune function in the normal course of bereavement.

Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder

In 2000, Gorman et al. published a widely acknowledged revised version of their 1989 neuroanatomical hypothesis of panic disorder (PD). Herein, a 'fear network' was suggested to mediate fear- and anxiety-related responses: panic attacks result from a dysfunctional coordination of 'upstream' (cortical) and 'downstream' (brainstem) sensory information leading to heightened amygdala activity with subsequent behavioral, autonomic and neuroendocrine activation. Given the emergence of novel imaging methods such as fMRI and the publication of numerous neuroimaging studies regarding PD since 2000, a comprehensive literature search was performed regarding structural (CT, MRI), metabolic (PET, SPECT, MRS) and functional (fMRI, NIRS, EEG) studies on PD, which will be reviewed and critically discussed in relation to the neuroanatomical hypothesis of PD. Recent findings support structural and functional alterations in limbic and cortical structures in PD. Novel insights regarding structural volume increase or reduction, hyper- or hypoactivity, laterality and task-specificity of neural activation patterns emerged. The assumption of a generally hyperactive amygdala in PD seems to apply more to state than trait characteristics of PD, and involvement of further areas in the fear circuit, such as anterior cingulate and insula, is suggested. Furthermore, genetic risk variants have been proposed to partly drive fear network activity. Thus, the present state of knowledge generally supports limbic and cortical prefrontal involvement as originally proposed in the neuroanatomical hypothesis. Some modifications might be suggested regarding a potential extension of the fear circuit, genetic factors shaping neural network activity and neuroanatomically informed clinical subtypes of PD potentially guiding future treatment decisions.

Renal dysfunction in acute and chronic heart failure: prevalence, incidence and prognosis

Most patients with heart failure have mild or moderate renal dysfunction. This reflects the combined impact of chronic renal parenchymal disease, renal artery disease, renal congestion and hypoperfusion, neuroendocrine and cytokine activation and the effects of treatments for heart failure. Remarkably, with good treatment, the average annual rate of decline in renal function is similar in patients with chronic heart failure and healthy people of a similar age. Urea appears to be a stronger marker of an adverse prognosis than creatinine-based measures of renal function. Recent evidence suggests that minor, transient increases in creatinine in the setting of acute heart failure are not prognostically important but persistent deterioration does indicate a higher mortality. The poor prognosis of patients with worsening renal function ensures that few require renal dialysis but this may change as methods to prevent sudden death improve and new ways are found to control fluid congestion. Reversing renal dysfunction and stopping its progression remain important targets for treatment of heart failure.

Secondary Hyperparathyroidism

Elevation in serum parathyroid hormone (PTH) often accompanies vitamin D deficiency and renal impairment. PTH elevation in renal failure is viewed as an unfavorable development. Evidence is increasing that PTH elevation may be associated with increased morbidity and mortality. In many instances these PTH effects appear to be independent of vitamin D status. PTH mediates its effects through the ubiquitous type 1 PTH/PTH-related peptide receptor, which is notably present in the cardiovascular system. Increased PTH may promote cardiovascular disease through diminished cardiac contractility, enhanced coronary risk, and cardiac valvular and vascular calcification. High PTH levels appear to be linked to the metabolic syndrome and are aligned with hyperlipidemia, decreased insulin sensitivity, and, perhaps, decreased insulin secretion. Increased PTH also is associated with neuroendocrine activation, increased sympathetic activity, and endothelial stress. The relation between PTH and vitamin D is complex and may show significant threshold variations, especially when calcium intake, age, and race are considered. Moreover, evidence is increasing that fragments of PTH may not only be hormonally active but also may have opposing effects to PTH. Despite these caveats, PTH values provide useful clinical diagnostic and prognostic information in monitoring many chronic ailments such as heart and renal failure and multiple sclerosis.

Prognostic Significance of Long-Period Heart Rate Rhythms in Chronic Heart Failure

Abnormalities in autonomic control are a feature of neuroendocrine activation in HF and are responsible for dysregulation of biological rhythms. The purpose was to investigate the presence and the prognostic significance of long-period heart rate (HR) rhythms in heart failure (HF) patients. In the study, 92 HF patients were enrolled (age 53 ± 14 years and left ventricular ejection fraction [LVEF] 37 ± 10%). A rhythmometric analysis was used to assess the HR rhythms in 7-days (7D) Holter recordings. Rhythms properties were quantified by mesor and amplitude, in beats/min and by acrophase, in hours. Cardiac death or HF decompensation were registered. All patients had 24-h rhythm, 61 patients (77%) had 8-h rhythm, and 66 patients (83%) had 7D rhythm. Twelve patients (15%) experienced events. Among rhythm parameters only 7D median amplitude was different between patients with or without events: 1.1 beats/min [0.5-1.5] vs. 2.0 beats/min [0.0-3.9], P=0.049 respectively. After multivariate adjustment, LVEF (per 1%, hazard ratio 0.92, 95% confidence interval (CI) 0.87 to 0.98, P=0.01), N-terminal portion of pro-natriuretic hormone type B (per 100 pg/ml, hazard ratio 1.036, 95% CI 1.005-1.069, P=0.022), and 7D amplitude of the HR ≤1.71 beats/min (hazard ratio 5.4, 95% CI 1.2-34.4, P=0.047) were independent predictors of events. A 7D HR rhythm is present in most patients with HF, and has prognostic significance.

Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

BackgroundNeuroendocrine activation and local mediators such as transforming growth factor-β1 (TGF-β1) contribute to the pathobiology of cardiac hypertrophy and failure, but the underlying mechanisms are incompletely understood. We aimed to characterize the functional network involving TGF-β1, the renin-angiotensin system, and the β-adrenergic system in the heart.MethodsTransgenic mice overexpressing TGF-β1 (TGF-β1-Tg) were treated with a β-blocker, an AT1-receptor antagonist, or a TGF-β-antagonist (sTGFβR-Fc), were morphologically characterized. Contractile function was assessed by dobutamine stress echocardiography in vivo and isolated myocytes in vitro. Functional alterations were related to regulators of cardiac energy metabolism.ResultsCompared to wild-type controls, TGF-β1-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-β1 overexpression increased the hypertrophic responsiveness to β-adrenergic stimulation. In contrast, the inotropic response to β-adrenergic stimulation was diminished in TGF-β1-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-βR-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic β-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to β-adrenergic stimulation without affecting TGF-β1 levels, whereas AT1-receptor blockade had no effect. The impaired contractile reserve in TGF-β1-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by β-adrenoceptor blockade. UCP-inhibition restored the contractile response to β-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-β1 and UCP expression were elevated in heart failure in humans, and UCP – but not TGF-β1 – was downregulated by β-blocker treatment.ConclusionsOur data support the concept that TGF-β1 acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the β-adrenergic system in TGF-β1-induced cardiac phenotype. Our data indicate for the first time, that TGF-β1 directly influences mitochondrial energy metabolism by regulating UCP3 expression. β-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism.

Social deprivation stress is a triggering factor for the emergence of anxiety- and depression-like behaviours and leads to reduced brain BDNF levels in C57BL/6J mice

Stress is a main risk factor that can trigger psychiatric disorders, including anxiety and major depression. Neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF), have been identified as neuroendocrine effectors involved in the response to stress and in the neurobehavioural changes associated with depression. Aim of this paper was to study the relationship between neuroendocrine activation (circulating corticosterone and brain BDNF levels) and a wide array of depression- and anxiety-like behaviours (anhedonia, behavioural despair, generalised and social anxiety) resulting from exposure to chronic stress. To this end, 3-month-old C57BL/6J male mice were exposed to either chronic disruption of the social structure (SS), to a stable social structure (SG) or to social deprivation (SD), a condition lacking social stimuli. Results show that, despite not developing anhedonia (decreased preference for a sucrose solution), SD mice were characterised by increased emotionality and hypothalamic-pituitary-adrenal axis reactivity in addition to reduced BDNF levels. By contrast, SG and SS mice showed increased anhedonia accompanied by no alterations in the behavioural and neuroendocrine profile. The results here reported indicate that mice exposed to different social housing conditions use different behavioural strategies to cope with external challenges. In addition they suggest that social deprivation might represent a stressful condition triggering the emergence of both anxiety- and depression-like behaviours and clearly indicate BDNF as a main neurobiological variable mediating these responses.

Neuroendocrine Changes and Natriuresis in Response to Social Stress in Rats

Sympathetic activation is detected by the tachycardic, hypertensive and hyperthermic responses during social conflicts in rodents and primates. Sympathetic nervous system activation promoting sodium retention has long been recognized to play a significant role in the development and maintenance of salt-sensitive hypertension. The objective was to investigate neuroendocrine activation and renal sodium excretion in response to chronic social stress. Male Wistar rats were subjected to social stress in accordance with the resident-intruder paradigm. Intruder rats were subjected to social confrontation once daily for 6 days. After the last confrontation, plasma corticosterone and urinary catecholamines were determined to assess the neuroendocrine activation. Plasma aldosterone, plasma and urinary creatinine, Na(+) , K(+) and urinary volume were also measured. Chronic social stress increased the urinary norepinephrine, dopamine and plasma corticosterone levels, with no changes in epinephrine levels. On the other hand, high plasma aldosterone levels and low urinary sodium excretion without differences in creatinine clearance were observed. In conclusion, social stress had a strong antinatriuretic effect, which is coincident with noradrenergic and corticoadrenal activation and an increase in plasma aldosterone levels. Activation of these factors may promote sodium retention, which has long been recognized to play a significant role in the development and maintenance of hypertension.

168 -Blocker therapy improves clinical outcomes in patients with moderate to severe mitral regurgitation

<h3>Background</h3> Volume overload seen in mitral regurgitation (MR) leads to neuro-endocrine activation including heightened sympathetic activity. Experimental data have reported protective effects of beta-blockers (BBs) on myocardial function in MR suggesting that BB therapy may be beneficial in MR. However, the effect of BB therapy on clinical outcomes in MR has not been defined. Hence, in this large observational study we investigated the impact of BB therapy on clinical outcome in patients with moderate to severe MR. <h3>Methods</h3> The Health Informatics dispensed prescribing, morbidity and mortality database for the population of Tayside, Scotland was linked through a unique patient identifier to the Tayside echocardiography database (&gt;110 000 scans). Patients with a diagnosis of moderate or severe MR from 1993 to 2008 were identified. Cox regression model (adjusted for age, gender, left ventricular dimensions and function, left atrial diameter, cardiovascular (CV) history and concurrent CV medications) was used to assess the impact of BB therapy on all-cause mortality and cardiovascular events (CV death or hospitalisations). <h3>Results</h3> A total of 4437 patients with moderate to severe MR (mean age 74 ±11 years, 46% males) were identified. MR was categorised as functional in 2523 (57%) and organic in 1894 (43%) while 1324 (30%) were on BBs. Over a mean follow-up of 3.9 years there were 2287 (51%) all-cause deaths and 2333 (52%) CV events. Those treated with BBs had a significantly lower all-cause mortality with an adjusted HR of 0.65 (95% CI 0.56 to 0.75, p&lt;0.0001) and fewer CV events with an adjusted HR of 0.79 (95% CI 0.69 to 0.90, p&lt;0.0001). <h3>Conclusions</h3> This large observational study suggests that BB therapy is associated with an improved survival and a lower risk of CV events in patients with moderate to severe MR. These observations needs to be confirmed in prospective studies and support the rationale for undertaking a future randomised clinical trial.

Dramatic changes in catestatin are associated with hemodynamics in acute myocardial infarction

Acute myocardial infarction (AMI) is characterized by complex neuroendocrine activation. To investigate catestatin profiles, serial catestatin levels were determined by enzyme-linked immunosorbent assay in the first week after AMI in 50 patients. Catestatin levels reduced at admission and negatively correlated with heart rates; it increased significantly on the third day but remained decreased at 1 week and positively with blood pressure. In a subgroup of 20 patients admitted within 4 h after onset, circulating catestatin correlated inversely with norepinephrine. Catestatin might be involved in the course of AMI and act as a tool in monitoring the progression of AMI.

A Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD) — Rationale and design of a multicenter, randomized trial in depressed patients with CAD

Objective Depressive symptoms are highly relevant for the quality of life, health behavior, and prognosis in patients with coronary artery disease (CAD). However, previous psychotherapy trials in depressed CAD patients produced small to moderate effects on depression, and null effects on cardiac events. In this multicentre psychotherapy trial, symptoms of depression are treated together with the Type D pattern (negative affectivity and social inhibition) in a stepwise approach. Methods Men and women (N=569, age 18–75 years) with any manifestation of CAD and depression scores ≥ 8 on the Hospital Anxiety and Depression Scale (HADS), will be randomized (allocation ratio 1:1) into the intervention or control group. Patients with severe heart failure, acutely life-threatening conditions, chronic inflammatory disease, severe depressive episodes or other severe mental illness are excluded. Both groups receive usual medical care. Patients in the intervention group receive three initial sessions of supportive individual psychotherapy. After re-evaluation of depression (weeks 4–8), patients with persisting symptoms receive an additional 25 sessions of combined psychodynamic and cognitive–behavioral group therapy. The control group receives one psychosocial counseling session. Primary efficacy variable is the change of depressive symptoms (HADS) from baseline to 18 months. Secondary endpoints include cardiac events, remission of depressive disorder (SCID) and Type D pattern, health-related quality of life, cardiovascular risk profile, neuroendocrine and immunological activation, heart rate variability, and health care utilization, up to 24 months of follow-up (ISRCTN: 76240576; NCT00705965). Funded by the German Research Foundation.

Neuroendocrine Target Therapies for Prostate Cancer

It is important to determine whether an increase in Chromogranin A levels and neuroendocrine (NE) cell activation are associated with progression towards on hormone-independent prostate-cancer. We proposed a combination of estrogens and somatostatin analogues as therapy of NE activation in hormone-independent prostate cancer. The combined therapy with ethinyl estradiol and lanreotide offered objective and symptomatic responses in patients with limited treatment options and refractoriness to conventional hormonal therapy strategies; in particular, it offered a median overall survival that was superior to the 10-month median survival in patients with hormone refractory disease. This combined therapy also sustains the new concept in cancer treatment in which therapies may target not only cancer cells but also its microenvironment, which can yield protection against apoptosis.

1971 COMPARATIVE EFFECT OF FINASTERIDE AND DUTASTERIDE ON CROMOGRANIN A LEVELS AS MARKER OF NEUROENDOCRINE DIFFERENTIATION IN PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA

INTRODUCTION AND OBJECTIVES: To verify and to compare in benign prostatic hyperplasia (BPH) patients the effect of finasteride versus dutasteride therapy on chromogranin A (CgA) serum levels, as possible marker of neuroendocrine (NE) differentiation and activity into the prostate gland. METHODS: This is a prospective randomized study in which 60 consecutive men with clinical diagnosis of benign prostatic hyperplasia (BPH) were randomized to a 6-month period of finasteride 5 mg/day versus dutasteride 4 mg/day versus control (no therapy) strategy. Total prostate specific antigen (PSA), testosterone and CgA were analysed in all cases at randomization and therefore at 1, 3 and 6 month interval. RESULTS: In both Group A (finasteride) and Group B (dutasteride), but not in Group C (no therapy) a statistically significant increase (p 0.05) in serum CgA levels was found at 3-months and 6-month interval of therapy when compared with visit 0 .Comparing the three groups,either at 3-month or at 6-month interval, serum CgA was significantly (p 0.05) higher in Group A and Group B than in Group C. At each interval, no significant (p 0.05) difference between Group A and Group B was found. CONCLUSIONS: In our BPH population, 5 alpha reductase inhibitors, with no difference between finasteride and dutasteride, produce a significant increase in serum CgA levels probably related to NE activation into the prostate gland.

FC25-05 - Revise the revised? the neuroanatomical hypothesis of panic disorder

Introduction/objectivesIn 2000 Gorman and colleagues published a widely cited revised version of their original neuroanatomical hypothesis of panic disorder from 1989. A “fear network” centered in the amygdala is supposed to be crucial in mediating fear-related responses. It is assumed that panic attacks result from a dysfunctional coordination of “upstream” (cortical) and “downstream” (brainstem) sensory information, resulting in heightened amygdalar activity with subsequent behavioral, autonomic, and neuroendocrine activation. The authors argue that many aspects of their revised neuroanatomical hypothesis are likely to prove incorrect, but hope it will stimulate research on anxiety disorders.MethodsWe reviewed neuroimaging studies on panic disorder to investigate in how far their results are in line with the neuroanatomical hypothesis and what inconsistencies emerge. Structural (CT, MRT), functional (PET, SPECT, fMRI, NIRS, EEG) and spectroscopic data (MRS) were considered.ResultsTo some extent studies investigating panic disorder found structurally and functionally altered brain areas that have been implicated in fear processing as supposed by the neuroanatomical hypothesis. However, inconsistencies regarding increased vs. decreased volume and increased vs. decreased activity in specific areas indicate aspects that cannot easily be explained by the hypothesis.ConclusionsThe neuroanatomical hypothesis is partially supported by empirical data that may have therapeutic consequences. However, inconsistencies should be a starting point to expand the hypothesis and modify some aspects. This may include the consideration of genetics, task-specificity and the definition of subgroups.

Serum soluble E-selectin and NT-proBNP levels additively predict mortality in diabetic patients with chronic heart failure

Neuroendocrine activation with endothelial dysfunction is a key pathophysiological process in chronic heart failure (CHF). Although increased soluble E-selectin (sE-selectin) levels predict adverse events in several forms of cardiovascular disease, there are only scarce data on its predictive value in CHF. The aim of our study was to investigate whether sE-selectin is a useful predictor of mortality in CHF patients and whether its predictive power is additive to that of NT-proBNP. Plasma levels of sE-selectin were measured by ELISA in 192 CHF patients with clinical systolic heart failure. The study population was followed up for 14.9months on average; 46 patients died during this period. Levels of sE-selectin were significantly higher in non-surviving patients than in survivors (p=0.005) and significantly correlated with the following inflammatory markers: CRP (r=0.242, p=0.001), TNF-α (r=0.201, p=0.005), TNF-RII (r=0.207, p=0.004), and IL-6 (r=0.339, p<0.0001). According to Cox regression analysis of the prediction power of sE-selectin for all-cause mortality, high sE-selectin levels independently and significantly predicted short-term mortality in CHF (HR 1.47, 95% CI 1.103-1.956). Furthermore, sE-selectin predicted mortality in CHF patients with concomitant diabetes mellitus, as well as simultaneously elevated sE-selectin and NT-proBNP levels additively predicted mortality. This study demonstrated a weak correlation of sE-selectin level with inflammatory markers and prediction of short-term mortality in diabetic CHF patients. Elevated serum sE-selectin levels and concomitantly increased NT-proBNP concentrations have additive predictive power in CHF. This suggests that parallel activation of various pathophysiological pathways confers increased risk of adverse outcome in CHF.