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J. Neurochem. (2010) 113, 563–575. The importance of stress in modifying human behavior and lifestyle is no longer a matter of debate. Although mild stress enhances the immune response and prevents infections, prolonged stress seems to play pathogenic roles in depression and neurodegenerative disorders. The body has developed an adaptive stress response consisting of cardiovascular, metabolic, and psychological changes, which act in concert to eliminate stressors. One of the major components of this response is the hypothalamic–pituitary–adrenal axis, also known as the stress axis. Over the last 30 years, many studies have documented the integrated stress-axis regulation by neurotransmitters. They have also demonstrated that gaseous neuromodulators, such as NO, CO, and H2S, regulate the hypothalamic release of neuropeptides. The specific effects (stimulatory vs. inhibitory) of these gases on the stress axis varies, depending on the type of stress (neurogenic or immuno-inflammatory), its intensity (low or high), and the species studied (rodents or humans). This review examines the complex roles of NO, CO, and H2S in modulation of stress-axis activity, with particular emphasis on the regulatory effects they exert at the hypothalamic level. [ABSTRACT FROM AUTHOR]

Iatrogenic pelvic pseudoaneurysm with concomitant arteriovenous fistula has been described as a rare and challenging complication, which may occur during transurethral resection of the prostate. We provide the first report of this complication after holmium laser enucleation of the prostate for the treatment of benign prostatic hyperplasia. The attempt to control the bleeding by conversion to open surgery and placement of haemostatic stitches into the prostatic fossa failed. Angiography with superselective arterial embolization proved to be a modern, quick, safe, and efficient treatment of this uncommon complication. [ABSTRACT FROM AUTHOR]

We determined the prevalence of incidental extracardiac findings (IEF) at Magnetic Resonance Imaging (MRI) potentially related to anemia and hypoxia in age- and sex-matched populations (N = 318) with thalassemia major (TM) and thalassemia intermedia (TI) enrolled in the Myocardial Iron Overload in Thalassemia network. Overall, IEFs were detected in 33.3% and 25.8% of patients with TI and TM, respectively (P = 0.114). TI and TM patients had elevated but comparable prevalence of renal, splenic and liver cysts, and vertebral hemangiomas while TI patients had a significant higher frequency of extramedullary hematopoiesis (EMH) (15.1% vs 4.4%; P = 0.002). The prevalence of total IEFs increased with advancing age. TI non-transfusion-dependent patients had a significantly lower frequency of renal cysts than TI transfusion-dependent patients (8.8% vs 26.4%; P = 0.005). The prevalence of renal cysts in the thalassemic population was significantly higher than that in the general population (19.2% vs 1.9%; P < 0.0001). Our data on renal cysts indicate a significant higher prevalence of these IEFs compared to the general population, suggesting the role of the inappropriate activation of the hypoxia-inducible factor system linked to the chronic hypoxia. The significant prevalence of IEF in thalassemia patients undergoing MRI for iron quantification should prompt the discussion of the inclusion of IEF in the MRI report. [ABSTRACT FROM AUTHOR]

Objectives: To assess the transferability of the magnetic resonance imaging (MRI) multislice multiecho T2* technique for pancreatic iron overload assessment.Methods: Multiecho T2* sequences were installed on ten 1.5-T MRI scanners of the three main vendors. Five healthy subjects (n = 50) were scanned at each site. Five patients with thalassemia (n = 45) were scanned locally at each site and were rescanned at the reference site within 1 month. T2* images were analyzed using a previously validated software and the global pancreatic T2* value was calculated as the mean of T2* values over the head, body, and tail.Results: T2* values of healthy subjects were above 26 ms and showed inter-site homogeneity. The T2* values measured in the MRI sites were comparable to the correspondent values observed in the reference site (12.02 ± 10.20 ms vs 11.98 ± 10.47 ms; p = 0.808), and the correlation coefficient was 0.978 (p < 0.0001). Coefficients of variation (CoVs) ranged from 4.22 to 9.77%, and the CoV for all the T2* values independently from the sites was 8.55%. The intraclass correlation coefficient (ICC) for each MRI site was always excellent and the global ICC was 0.995, independently from the sites. The mean absolute difference in patients with pancreatic iron (n = 39) was -0.15 ± 1.38 ms.Conclusion: The gradient-echo T2* MRI technique is an accurate and reproducible means for the quantification of pancreatic iron and may be transferred among MRI scanners by different vendors in several centers.Key Points: • The gradient-echo T2* MRI technique is an accurate and reproducible means for the quantification of pancreatic iron. • The gradient-echo T2* MRI technique for the quantification of pancreatic iron may be transferred among MRI scanners by different vendors in several centers. • Pancreatic iron might serve as an early predictor of cardiac siderosis and is the strongest overall predictor of glucose dysregulation. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic cardiomyopathy (HCM), the most common genetic heart disease, is characterized by heterogeneous phenotypic expression. Body mass index has been associated with LV mass and heart failure symptoms in HCM. The aim of our study was to investigate whether regional (trunk, appendicular, epicardial) fat distribution and extent could be related to hypertrophy severity and pattern in HCM. Methods: Cardiovascular magnetic resonance was performed in 32 subjects with echocardiography-based diagnosis of HCM (22M/10F, 57.2±12.6 years) characterized by predominant hypertrophy at the interventricular septum (IVS). Regional fat distribution was assessed by dual-energy X-ray absorptiometry. Results: Gender differences were detected in maximum IVS thickness (M: 18.3±3.8 mm vs. F: 14.3±4 mm, p = 0.012), right ventricle (RV) systolic function (M: 61.3±6.7%; F: 67.5±6.3%, p = 0.048), indexed RV end-diastolic (M: 64.8±16.3 ml/m2; F: 50.7±15.5 ml/m2, p = 0.04) and end-systolic volumes (M: 24.3±8.3 ml/m2; F: 16.7±7.4 ml/m2, p = 0.04). After adjusting for age and gender, maximum IVS thickness was associated with truncal fat (Tr-FAT) (β = 0.43, p = 0.02), but not with either appendicular or epicardial fat. Epicardial fat resulted independently associated with NT-proBNP levels (β = 0.63, p = 0.04). Late Gadolinium Enhancement-positive subjects displayed greater maximum IVS thickness (p = 0.02), LV mass index (p = 0.015) and NT-proBNP levels (p = 0.04), but no associations with fat amount or distribution were observed. Conclusion: Truncal, but not appendicular or epicardial fat amount, seems to be related with maximum IVS thickness, the hallmark feature in our cohort of HCM patients. Further prospective researches are needed to assess a potential causative effect of central adiposity on HCM phenotype. [ABSTRACT FROM AUTHOR]

Accumulation of fat at ectopic sites has been gaining attention as pivotal contributor of insulin resistance, metabolic syndrome and related cardiovascular complications. Intermuscular adipose tissue (IMAT), located between skeletal muscle bundles and beneath muscle fascia, has been linked to physical inactivity, ageing and body mass index, but little is known about its relationship with the other AT compartments, in particular with increasing age. To address this issue, erector spinae IMAT, epicardial (EAT), intraabdominal (IAAT) and abdominal subcutaneous adipose tissue (SAT) were simultaneously measured by Magnetic Resonance Imaging (MRI) and related to waist circumference measurements and age in 32 sedentary subjects without cardiovascular disease (18 men; 14 women; mean age 48.5±14 years). Fasting glucose, triglycerides and HDL-cholesterol were also assessed. We observed that, after dividing individuals according to age (≤ or >50 years), IMAT and EAT depots were significantly more expanded in older subjects (63.2±8.3 years) than in the younger ones (38.4±5.2 years) (p<0.001). Overall, both IMAT and EAT showed stronger positive associations with increasing age (β = 0.63 and 0.67, respectively, p<0.001 for both) than with waist circumference (β = 0.55 and 0.49, respectively, p<0.01 for both) after adjusting for gender. In addition, the gender-adjusted associations of IMAT and EAT with waist circumference and IAAT were significant in individuals ≤50 years only (p<0.05 for all) and not in the older ones. In contrast, no age-related differences were seen in the relationships of IAAT and SAT with waist circumference. Finally, serum triglycerides levels turned out not to be independently related with ectopic IMAT and EAT. In conclusion, the expansion of IMAT and EAT in sedentary subjects is more strongly related to age than waist circumference, and a positive association of these ectopic depots with waist circumference and IAAT amount can be postulated in younger individuals only. [ABSTRACT FROM AUTHOR]

Introduction: Left ventricular thrombosis (LVT) is a possible complication of acute myocardial infarction. Aim of our study was to evaluate incidence and clinical characteristics of patients with LVT after ST elevation myocardial infarction (STEMI) using contrast- enhanced magnetic resonance (CMR). Methods and Results: In a prospective cohort of 36 consecutive patients with STEMI acutely reperfused with primary percutaneous coronary intervention, CMR was performed within one week. LVT was found in 7 patients (19%), and was located in left ventricle apex or adherent to antero-septum. Compared to the rest of population patients with LVT have lower ejection fraction (38 ± 7% versus 51 ± 6%, P = 0.009), larger left ventricle end systolic volume (95.8 ± 19 ml versus 68.9 ± 19 ml, P = 0.02), higher time to reperfusion (9.3 ± 7.2 versus 5 ± 3.6, P = 0.03) and left anterior descending artery was constantly involved (100% versus 41 %, P = 0.06). In 5 cases the LVT was also detected by echocardiography, however, in 2 cases it was missed. Conclusions: The incidence of LVT after STEMI is not negligible and was accurately detected by CMR. Localization of myocardial infarction, time to reperfusion, ejection fraction and left ventricle end systolic volume are the most important predictors of left ventricle thrombus formation. [ABSTRACT FROM AUTHOR]

Abstract: Reactive oxygen and reactive nitrogen species oxidize and nitrate DNA, lipid and proteins thus leading to neuronal death. Both endogenous and dietary antioxidants were shown to afford neuroprotection either by scavenging free radicals or inducing antioxidant enzymes. That said, the differential contribution of endogenous versus nutritional antioxidants to prevent neurodegeneration is still debated. In this study the free radical scavenging activity of two endogenous antioxidants, such as bilirubin and its precursor biliverdin, was compared with that of the dietary antioxidant alpha-tocopherol in rat brain microsomes exposed to peroxyl radical or peroxynitrite in vitro. Bilirubin and biliverdin (1–200μM) inhibited both peroxyl radical- and peroxynitrite-dependent lipid peroxidation with a greater potency and efficacy than alpha-tocopherol. However, both BV and BR displayed greater potency and efficacy in preventing peroxynitrite- than peroxyl radical-induced lipid peroxidation. The greater antioxidant effect of both bilirubin and biliverdin than alpha-tocopherol was also confirmed against peroxyl radical- and peroxynitrite-induced protein oxidation. In conclusion, both bilirubin and biliverdin exhibited a greater antioxidant activity than alpha-tocopherol in preventing oxidative stress damage in rat brain. [Copyright &y& Elsevier]

Abstract: Over the last 10years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer''s disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer''s disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer''s disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. [Copyright &y& Elsevier]

Abstract: Biliverdin reductase-A is a pleiotropic enzyme involved not only in the reduction of biliverdin-IX-alpha into bilirubin-IX-alpha, but also in the regulation of glucose metabolism and cell growth secondary to its serine/threonine/tyrosine kinase activity. Together with heme oxygenase, whose metabolic role is to degrade heme into biliverdin-IX-alpha, it forms a powerful system involved in the cell stress response during neurodegenerative disorders. In this paper, an up-regulation of the biliverdin reductase-A protein levels was found in the hippocampus of the subjects with Alzheimer disease and arguably its earliest form, mild cognitive impairment. Moreover a significant reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A was found, and this was paralleled by a marked reduction in its reductase activity. Interestingly, the levels of both total and phosphorylated biliverdin reductase-A were unchanged as well as its enzymatic activity in the cerebella. These results demonstrated a dichotomy between biliverdin reductase-A protein levels and activity in the hippocampus of subjects affected by Alzheimer disease and mild cognitive impairment, and this effect likely is attributable to a reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A. Consequently, not just the increased levels of biliverdin reductase-A, but also its changed activity and phosphorylation state, should be taken into account when considering potential biomarkers for Alzheimer disease and mild cognitive impairment. [Copyright &y& Elsevier]

Abstract: An altered regulation of the corticotropin-releasing hormone (CRH) system in the CNS is consistently associated with anxiety and depression; several drugs used to treat CNS disorders modulate – usually in a negative manner – CRH turnover in the brain, and it can be postulated that their effectiveness may be at least in part related to their effects on CRH. This study was aimed to investigate the effects of two atypical antipsychotics also employed in the treatment of bipolar disorders, i.e. quetiapine (QTP) and olanzapine (OLZ), on CRH release from isolated rat brain regions. Acute rat hypothalamic and hippocampal explants were exposed for 1 h to plain medium or medium containing the test drugs, either under baseline conditions or after stimulation of CRH release by veratridine or 56 mM KCl. CRH immunoreactivity present in the incubation medium and in the tissues was assessed by radioimmunoassay. QTP 10 µM but not OLZ inhibited baseline CRH secretion from the hypothalamus; neither drug affected basal CRH release from the hippocampus. Both QTP and OLZ, 1 and 10 µM, inhibited veratridine- or K+-stimulated CRH release from the hypothalamus, whereas OLZ only, when given at 10 µM, was able to inhibit stimulated CRH release from the hippocampus. In conclusion, two widely used atypical antipsychotics, QTP and OLZ are able to acutely reduce the release of CRH from isolated rat hypothalami and hippocampi. [Copyright &y& Elsevier]

Abstract: We previously showed that the cytostatic drug hydroxyurea (HU) activates the hypothalamo–pituitary–adrenal (HPA) axis in intact rats, whereas it is lethal in rats with impaired HPA function. In these animals, HU toxicity is mediated by increased circulating levels of proinflammatory cytokines, whose secretion cannot be counteracted by glucocorticoids, suggesting that HPA activation blunts HU toxicity. Here we investigated the mechanisms through which HU activates the HPA axis, looking at the direct effects of the drug on the isolated hypothalamus. We found that HU significantly increases the release of arginine vasopressin but not that of corticotrophin-releasing hormone in short-term incubation experiments. The levels of arginine vasopressin are also increased in the hypothalamus and systemic circulation 2h after the in vivo administration of the drug. Furthermore, HU increased significantly the expression of interleukin-6 and, to a lesser extent, interleukin-1β in the hypothalamus. Interestingly, experiments with HU on primary cultures of rat microglia and astrocytes suggested that the increase in cytokine gene expression observed in hypothalamic explants is not accounted for by glial cells. Since both vasopressin and cytokines can activate the HPA axis, our present findings provide a reasonable explanation of the HPA activation elicited by HU in vivo in the rat. [Copyright &y& Elsevier]

Abstract: The effects of interleukin-18 (IL-18), a putative member of the IL-1 family, were investigated on basal and stimulated release of corticotropin-releasing hormone (CRH) and prostanoids from rat hypothalamic explants and glial cells in vitro. We found that IL-18 decreases basal and KCl-stimulated CRH release from the hypothalamus. IL-18 also reduced CRH gene expression after 1- and 3-h incubation. The cytokine did not modify basal PGE2 production by hypothalamic explants but abolished production stimulated by IL-1β. Similar effects were also observed on cultured glial cells. The present findings show that IL-18 possesses a profile of in vitro neuroendocrine activities opposing to, and even antagonizing, those of IL-1β. [Copyright &y& Elsevier]

Objective: Corticotropin-releasing factor (CRF), the major adrenocorticotropic hormone (ACTH) secretagogue, acts within the brain to integrate the stress responses of the central nervous, endocrine and immune systems. The involvement of this peptide in the origin and pathophysiology of various endocrine, neurologic, inflammatory and psychiatric diseases, particularly affective disorders, has also been suggested. The antiepileptic drug valproic acid is frequently used as a mood-stabilizing agent in patients with bipolar disorders; however, its mechanism of action for the latter indication is still poorly characterized. We investigated whether valproic acid can directly modulate CRF production by using the incubation of rat hypothalamic explants as an in-vitro model. We then studied the involvement of the γ-aminobutyric acid (GABA) system as a putative mediator of the effects of valproic acid on CRF production. Methods: Rat hypothalamic explants were incubated in a 24-well plate (2 hypothalami per well) at 37°C in a humidified atmosphere (5% CO2 and 95% O2) in incubation medium, 700 μL, then were treated with medium alone (control) or test substances, namely, valproic acid, KCI, bicuculline methiodide and muscimol. Released CRF was measured by radioimmunoassay. CRF mRNA was measured by RNase protection analysis. Results: Incubation of the hypothalamic fragments with valproic acid, 100 μmol/L, resulted in a reduction of basal CRF secretion after 3 hours' treatment. The drug was also able to inhibit KCI-stimulated CRF release. Moreover, valproic acid, 100 μmol/L significantly decreased CRF mRNA levels after 3 hours. A specific GABAA receptor antagonist, bicuculline methiodide, completely reversed the inhibition of CRF gene expression and peptide release induced by valproic acid; in this paradigm, the GABAA-specific agonist muscimol inhibited both CRF gene expression and peptide release in a concentration-dependent manner. Conclusions: These results suggest that valproic acid may exert part of its therapeutic effect as a mood- stabilizing drug via the modulation of CRF secretion from the hypothalamus. This action may be mediated in part by the activation of GABAergic neurotransmission. [ABSTRACT FROM AUTHOR]

Prenatal exposure to diazepam (DZ), a positive allosteric modulator of the γ-aminobutyric acidA (GABAA) receptor complex, exerts profound effects that become more evident during puberty and in many cases are sex-specific, suggesting that such exposure interferes with the activity of steroid hormones. Apart from their well known effects on the genome, the reduced metabolites of many steroid hormones also interact directly with membrane receptors, including those for N-methyl-d-aspartate (NMDA). In this study, we compared the effects of several neurosteroids on NMDA receptors from normal rats and those exposed in utero to DZ (1.25 mg/kg per day) from the 14th through the 20th day of gestation.In superfused rat hippocampal synaptosomes, activation of the NMDA receptor stimulates the basal release of [3H]noradrenaline ([3H]NA), which was used in our study as an index of receptor function. [3H]NA release was evoked in a concentration-dependent manner by NMDA (100 μM) plus glycine (GLY). The maximal increase (68.23±3.86%) with respect to basal release was achieved with a GLY concentration of 10 μM, and the EC50 for GLY was 0.1 μM. Release stimulated by 100 μM NMDA+0.1μM GLY was not modified by any of the neurosteroids tested, with the exception of pregnenolone sulfate (PREG-S), which produced a 78.57±3.94% reduction in release at the maximal concentration used (0.3 μM). In synaptosomes from animals exposed in utero to DZ, the inhibitory effect of PREG-S was reduced by 46.55±2.33%.Given the important roles played by NMDA receptors in physiological and pathological processes within the central nervous system (CNS), characterization of NMDA receptor modulation is an important objective. The fact that this modulation can be altered by exposure in utero to DZ indicates that the behavioral abnormalities observed in exposed animals might be partially attributed to an altered sensitivity of NMDA receptors to the modulatory effects of neurosteroids. [Copyright &y& Elsevier]

Abstract Erythropoietin (EPO), a renal cytokine regulating haematopoiesis, is also produced by different cell types within the central nervous system, where it acts via the activation of specific receptors. Current evidence shows that EPO exerts neurotrophic and neuroprotective activities in different in vivo and in vitro models of brain damage. In the present study we investigated the effects of EPO on primary cultures of rat cortical microglia and astrocytes. We found that: (i) EPO exerted a marked stimulatory effect on microglial cell viability, assessed through the MTS assay, whereas astrocytes were almost unaffected; (ii) the cytokine increased microglial cell population size in a concentration-dependent manner; however, as microglia cultures undergo spontaneous apoptosis after separation from astrocytes, the apparent effect on cell proliferation could be attributed to EPO antagonism of normal apoptosis; (iii) subsequent flow cytometry analysis on microglial cells demonstrated both the trophic role of factor(s) released by astrocytes in mixed cultures, and the putative anti-apoptotic action of EPO; (iv) the latter was further confirmed through the assessment of gene expression of anti- and pro-apoptotic factors, which showed that EPO is able to shift the Bcl : Bax ratio towards a net anti-apoptotic effect; (v) EPO did not affect the pro-inflammatory function of microglial cells. [ABSTRACT FROM AUTHOR]