Right-sided aortic arch with Kommerell's diverticulum: a case report of a rare cause of type B dissection.

Background: A right-sided aortic arch (RAArch) is present in approximately 0.1% of the population. A Kommerell's diverticulum (KD), a remnant of the dorsal aortic arch usually refers to an aneurysmal aortic enlargement at the origin of an aberrant left subclavian artery (ALSA) and is associated with an increased risk of aortic dissection. Case summary: A 59-year-old female smoker with a history of hypertension and hypercholesterolaemia presented with a 24-hour history of sudden-onset and severe stabbing chest pain radiating to the interscapular region. Physical examination was normal except for bilateral basal crepitations. Computed tomography angiography (CTA) showed a type B aortic dissection in a RAArch with an ALSA arising from KD with a peri-aortic haematoma and haemothorax without any active contrast extravasation. After medical stabilization, a semi-urgent hybrid repair was performed with a right carotid-subclavian bypass, thoracic endovascular aortic repair (TEVAR), a plug in the left subclavian artery, and left carotid-subclavian bypass due to severe ischaemia of the left arm. The postoperative CTA showed patent bypasses, aortic remodelling, and a minimal type IIa endoleak at the level of the ALSA. Discussion: In patients with a type B dissection and KD, hybrid repair including TEVAR is feasible after careful pre-operative assessment of the patient's unique anatomy and may reduce post-surgical morbidity and mortality compared to open surgery. Prophylactic repair may be considered in patients with an asymptomatic RAArch and KD.

Effective Connectivity of Beta Oscillations in Endometriosis-Related Chronic Pain During rest and Pain-Related Mental Imagery.

Using the EEG recordings of patients with endometriosis-related chronic pelvic pain, we have examined the effective connectivity within the cortical pain-related network during rest and during pain-related imagery. During rest, an altered connectivity was hypothesized between cortical somatosensory pain areas and regions involved in emotional and cognitive modulation of pain. During pain-related imagery, alterations in prefrontal-temporal connectivity were expected. The effective connectivity was estimated using the Directed Transfer Function method. Differences between endometriosis patients and controls were found in the beta band (14-25 Hz). During rest, endometriosis was associated with an increased connectivity from the left dorsolateral prefrontal cortex to the left somatosensory cortex and also from the left somatosensory cortex to the orbitofrontal cortex and the right temporal cortex. These results might be related to sustained activation of the somatosensory pain system caused by the ongoing pain. During pain-related imagery, endometriosis patients showed an increased connectivity from the left dorsolateral prefrontal cortex to the right temporal cortex. This finding might point to impaired emotional regulation when processing pain-related stimuli, or it might be related to altered memorization of pain experiences. Results of this study open up new directions in chronic pain research aimed at exploring the beta band connectivity alterations. PERSPECTIVE: This study examined the pain system's dynamics in endometriosis patients with chronic pelvic pain during resting-state and pain-related mental imagery. The results could contribute to the development of new therapies using guided mental imagery.

Management of abdominal aortic aneurysm and concomitant malignant disease.

INTRODUCTION: Concomitant malignant disease and abdominal aortic aneurysms (AAA) represent a challenging issue in terms of treatment priority, timing and perspectives. This systematic review provides an overview of the available literature about AAA and concomitant malignant disease. EVIDENCE ACQUISITION: We conducted a literature search of all the English-language medical literature in Medline (through PubMed), Embase, Clinical Trial databases and the Cochrane Library up to December 31st, 2018. EVIDENCE SYNTHESIS: The literature about AAA and concomitant malignant disease is mostly based on retrospective small case series. Two recently published meta-analyses focusing on the management of AAA and concomitant abdominal neoplasms came to the same conclusion "treat what is most threatening or symptomatic first." The threshold to treat asymptomatic AAA should not be altered in patients with AAA and concomitant cancer including cases under chemotherapy. An asymptomatic AAA of at least 55 mm anatomically suitable for EVAR, should only be treated first in patients with at least a life expectancy of two years followed by staged cancer surgery two weeks later. CONCLUSIONS: Decisions about management of AAA and concomitant malignant disease should be based on clinical judgment applied individually in a multidisciplinary setting ("treat first what kills first"). The indication for treatment is not different than in patients with AAA without cancer. A staged approach is preferable and ideally the AAA should be excluded by endovascular means if anatomically suitable. An international registry should be initiated to gather more evidence about the management and outcomes of patients with AAA and concomitant carcinoma.

CRF1 but not glucocorticoid receptor antagonists reduce separation-induced distress vocalizations in guinea pig pups and CRF overexpressing mouse pups. A combination study with paroxetine.

RATIONALE: Given the large number of patients that does not respond sufficiently to currently available treatment for anxiety disorders, there is a need for improved treatment. OBJECTIVES: We evaluated the anxiolytic effects of corticotropin releasing factor (CRF)1 receptor antagonists and glucocorticoid receptor (GR) antagonists in the separation-induced vocalization test in guinea pigs and transgenic mice with central CRF overexpression. Furthermore, we explored effects of these drugs when given in combination with a suboptimal dose of a selective serotonin re-uptake inhibitor (SSRI). METHODS: In guinea pig pups, the CRF1 receptor antagonists CP-154,526 and DMP695, and the GR antagonists mifepristone and Org34517 (all at 2.5, 10 and 40mg/kg intraperitoneally (IP)) were tested alone or in combination with 0.63mg/kg paroxetine IP. In CRF overexpressing mouse pups and wild type littermates, effects of CP-154,526 (10, 20 and 40mg/kg subcutaneously (SC)) and mifepristone (5, 15, 45mg/kg SC) were studied alone or in combination with 0.03mg/kg paroxetine SC. RESULTS: CRF1 but not GR antagonists reduced the number of calls relative to vehicle in guinea pigs and mice, independent of genotype. Treatment of CRF1 receptor or GR antagonists with paroxetine had no combined effect in guinea pigs, wild type or CRF overexpressing mice. CONCLUSIONS: Current results indicate robust anxiolytic properties of CRF1 receptor antagonists in guinea pigs and mice overexpressing CRF, and lack thereof of GR antagonists. Although no combined treatment effects were observed, it would be interesting to study combined treatment of CRF1 receptor antagonists with SSRIs following chronic drug administration.

Sex-dependent and differential responses to acute restraint stress of corticotropin-releasing factor-producing neurons in the rat paraventricular nucleus, central amygdala, and bed nucleus of the stria terminalis.

Male and female rodents respond differently to acute stress. We tested our hypothesis that this sex difference is based on differences in stress sensitivity of forebrain areas, by determining possible effects of a single acute psychogenic stressor (1-hr restraint stress) on neuronal gene expression (c-Fos and FosB immunoreactivities), storage of corticotropin-releasing factor (CRF) immunoreactivity, and CRF production (CRF mRNA in situ hybridization) as well as the expression of genes associated with epigenetic processes (quantitative RT-PCR) in the rat paraventricular nucleus (PVN), the oval and fusiform subdivisions of the bed nucleus of the stria terminalis (BSTov and BSTfu, respectively), and the central amygdala (CeA), in both males and females. Compared with females, male rats responded to the stressor with a stronger rise in corticosterone titer and a stronger increase in neuronal contents of c-Fos, CRF mRNA, and CREB-binding protein mRNA in the PVN. In the BSTov, females but not males showed an increase in c-Fos, whereas the CRF mRNA content was increased in males only. In the BSTfu, males and females showed similar stress-induced increases in c-Fos and FosB, whereas in the CeA, both sexes revealed similar increases in c-Fos and in CRF mRNA. We conclude that male and female rats differ in their reactivity to acute stress with respect to possibly epigenetically mediated (particularly in the PVN) neuronal gene expression and neuropeptide dynamics (PVN and BSTov) and that this difference may contribute to the sex dependence of the animal's physiological and behavioral responses to an acute stressor.

Chronic stress induces sex-specific alterations in methylation and expression of corticotropin-releasing factor gene in the rat.

BACKGROUND: Although the higher prevalence of depression in women than in men is well known, the neuronal basis of this sex difference is largely elusive. METHODS: Male and female rats were exposed to chronic variable mild stress (CVMS) after which immediate early gene products, corticotropin-releasing factor (CRF) mRNA and peptide, various epigenetic-associated enzymes and DNA methylation of the Crf gene were determined in the hypothalamic paraventricular nucleus (PVN), oval (BSTov) and fusiform (BSTfu) parts of the bed nucleus of the stria terminalis, and central amygdala (CeA). RESULTS: CVMS induced site-specific changes in Crf gene methylation in all brain centers studied in female rats and in the male BST and CeA, whereas the histone acetyltransferase, CREB-binding protein was increased in the female BST and the histone-deacetylase-5 decreased in the male CeA. These changes were accompanied by an increased amount of c-Fos in the PVN, BSTfu and CeA in males, and of FosB in the PVN of both sexes and in the male BSTov and BSTfu. In the PVN, CVMS increased CRF mRNA in males and CRF peptide decreased in females. CONCLUSIONS: The data confirm our hypothesis that chronic stress affects gene expression and CRF transcriptional, translational and secretory activities in the PVN, BSTov, BSTfu and CeA, in a brain center-specific and sex-specific manner. Brain region-specific and sex-specific changes in epigenetic activity and neuronal activation may play, too, an important role in the sex specificity of the stress response and the susceptibility to depression.

Acute ether stress differentially affects corticotropin-releasing factor and urocortin 1 in the Brattleboro rat.

Arginine-vasopressin (AVP), corticotropin-releasing factor (CRF) and urocortin 1 (Ucn1) play a role in the stress response. The CRF-producing paraventricular nucleus of the hypothalamus (PVN), oval bed nucleus of the stria terminalis (BSTov) and central amygdala (CeA), and the Ucn1-expressing non-preganglionic Edinger-Westphal nucleus (npEW) all possess AVP receptors. We hypothesized that AVP is involved in the response of these four brain centers to acute physiological (ether) stress. To test this hypothesis, we studied AVP-deficient Brattleboro (BB) rats using quantitative immunocytochemistry. First, we showed that non-stressed wild-type (WT) and BB rats did not differ from each other in Fos contents, indicating similar (immediate early) gene expression activity, but that in BB rats CRF contents were lower in the PVN and higher in the CeA. Second, we found that stress induced Fos response in the PVN, CeA and npEW with strengths different for each center, but similar for BB and WT rats. Finally, no effects of stress on CRF and Ucn1 contents were seen in the WT rat brain, but in BB rats stress increased CRF contents in the PVN, and the CeA revealed more CRF in stressed BB than in WT rats. On the basis of these results we propose that during acute stress AVP interacts with, especially, the PVN and the CeA, to change their rates of biosynthesis and/or release of CRF.

Differential effect of glucocorticoid receptor antagonists on glucocorticoid receptor nuclear translocation and DNA binding.

The effects of RU486 and S-P, a more selective glucocorticoid receptor antagonist from Schering-Plough, were investigated on glucocorticoid receptor nuclear translocation and DNA binding. In the in vitro study, AtT20 cells were treated with vehicle or with RU486, S-P or corticosterone (3-300 nM) or co-treated with vehicle or glucocorticoid receptor antagonists (3-300 nM) and 30 nM corticosterone. Both glucocorticoid receptor antagonists induced glucocorticoid receptor nuclear translocation but only RU486 induced DNA binding. RU486 potentiated the effect of corticosterone on glucocorticoid receptor nuclear translocation and DNA binding, S-P inhibited corticosterone-induced glucocorticoid receptor nuclear translocation, but not glucocorticoid receptor-DNA binding. In the in vivo study, adrenalectomized rats were treated with vehicle, RU486 (20 mg/kg) and S-P (50 mg/kg) alone or in combination with corticosterone (3 mg/kg). RU486 induced glucocorticoid receptor nuclear translocation in the pituitary, hippocampus and prefrontal cortex and glucocorticoid receptor-DNA binding in the hippocampus, whereas no effect of S-P on glucocorticoid receptor nuclear translocation or DNA binding was observed in any of the areas analysed. These findings reveal differential effects of RU486 and S-P on areas involved in regulation of hypothalamic-pituitary-adrenal axis activity in vivo and they are important in light of the potential use of this class of compounds in the treatment of disorders associated with hyperactivity of the hypothalamic-pituitary-adrenal axis.

Rapid glucocorticoid receptor-mediated inhibition of hypothalamic-pituitary-adrenal ultradian activity in healthy males.

A complex dynamic ultradian rhythm underlies the hypothalamic-pituitary-adrenal (HPA) circadian rhythm. We have investigated in normal human male subjects the importance, site of action, and receptor-mediated processes involved in rapid basal corticosteroid feedback and its interaction with corticotrophin releasing hormone (CRH) drive. Pro-opiomelanocortin (POMC), ACTH, and cortisol were measured every 10 min from healthy males during the awakening period or late afternoon using an automated blood sampling system. Mathematical modeling into discrete pulses of activity revealed that intravenous infusion of the synthetic mixed glucocorticoid/mineralocorticoid agonist prednisolone produced rapid inhibition of ACTH and cortisol pulsatility within 30 min in the morning and afternoon. Any pulse that had commenced at the time of injection was unaffected, and subsequent pulsatility was inhibited. Prednisolone also inhibited ACTH and cortisol secretion in response to exogenous CRH stimulation, inferring rapid feedback inhibition at the anterior pituitary. Circulating POMC peptide concentrations were unaffected, suggesting that the rapid corticosteroid inhibitory effect specifically targeted ACTH secretion from pituitary corticotrophs. Prednisolone fast feedback was only reduced by glucocorticoid receptor antagonist pretreatment and not by mineralocorticoid receptor antagonism, suggesting a glucocorticoid receptor-mediated pathway. The intravenous prednisolone suppression test provides a powerful new tool to investigate HPA abnormalities underlying metabolic and psychiatric disease states.

Antiglucocorticoids, neurogenesis and depression.

Recent evidence suggests that antiglucocorticoids, like conventional antidepressants, may recover depressive symptoms by boosting hippocampal neurogenesis. Here, we explore several possible antiglucocorticoid-based antidepressive therapeutic strategies. Firstly, we review specific glucocorticoid receptor/antagonist interactions. Secondly, we discuss a potential new therapeutic target, doublecortin-like kinase, which regulates glucocorticoid signaling in neuronal progenitor cells.

CRF1 not glucocorticoid receptors mediate prepulse inhibition deficits in mice overexpressing CRF.

BACKGROUND: Both corticotropin-releasing factor (CRF) and glucocorticoid receptors (GR) are implicated in the psychotic symptoms of psychiatric disorders. Correspondingly, it is of interest to determine their respective involvement in the sensorimotor gating deficits displayed by transgenic mice overexpressing CRF. These mice reveal lifelong elevations of CRF and corticosterone levels. METHODS: Effects of the GR antagonists ORG34517 (5-45 mg/kg by mouth [PO]) and mifepristone (5-45 mg/kg PO) and the CRF(1) receptor antagonists CP154,526 (20-80 mg/kg intraperitoneally [IP]) and DMP695 (2.5-40.0 mg/kg IP) on prepulse inhibition (PPI) of the acoustic startle response were studied in mice overexpressing CRF and in their wild-type littermates. In addition, PPI was measured in both genotypes 2 weeks after adrenalectomy with or without exogenous corticosterone administration via subcutaneous pellet implant (20 mg corticosterone). RESULTS: ORG34517 and mifepristone did not influence perturbation of PPI in mice overexpressing CRF; reducing corticosterone levels by adrenalectomy likewise did not improve PPI. Further, elevation in corticosterone levels by pellet implantation did not disrupt PPI in wild-type mice. Conversely, both CRF(1) receptor antagonists, CP154,526 (40-80 mg/kg IP) and DMP695 (40 mg/kg IP), significantly restored PPI in CRF-overexpressing mice. CONCLUSIONS: Sustained overactivation of CRF(1) receptors rather than excessive GR receptor stimulation underlies impaired sensorimotor gating in CRF-overexpressing mice. CRF(1) receptors thus may play a role in the expression of psychotic features in stress-related psychiatric disorders.