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The purpose of this study was to evaluate the role of the non-canonical DLK2 NOTCH ligand in the regulation of emotional behavior. To this aim, anxiety and depressive-like behaviors were examined in Dlk2 knock-out (Dlk2 -/- ) and its corresponding wild-type (WT) mice. Furthermore, relative gene expression analyses of corticotropin releasing hormone (Crh) in the paraventricular nucleus (PVN), glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5) in the hippocampus (HIPP), and the transcription factors Hes1, Hes5 and Hey1 in the PVN, HIPP and amygdala (AMY) were carried out in Dlk2 -/- and WT mice under basal conditions and after exposure to restraint stress. The anxiolytic action of alprazolam and the relative gene expression levels of the GABA-A alpha 2 and gamma 2 receptor subunits (Gabra2 and Gabrg2) were also evaluated in the HIPP and AMY of WT and Dlk2 -/- mice. The results reveal that deletion of Dlk2 increased anxiety and depressive-like behaviors and altered the vulnerability to restraint stress on Crh gene expression in the PVN, Nr3c1 and Fkbp5 gene expression in the HIPP, and Hes1, Hes5 and Hey1 gene expression in the PVN, HIPP and AMY. Interestingly, the administration of alprazolam failed to produce an anxiolytic action in Dlk2 -/- mice. Indeed, Gabra2 and Gabrg2 gene expression levels were significantly affected under basal conditions and after stress exposure in Dlk2 -/- mice compared with WT mice. In conclusion, the results suggest that DLK2 plays an important role in the regulation of emotional behaviors and relevant targets of the stress axis, NOTCH pathway and GABAergic neurotransmission. In addition, the deletion of Dlk2 blocked the anxiolytic response to alprazolam. Future studies are needed to determine the relevance of DLK2 as a potential therapeutic target for the treatment of neuropsychiatric disorders with anxiety or depressive-like behaviors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Ethanol (EtOH) research has focused on stages of dependence. It is of paramount importance to more deeply understand the neurobehavioral factors promoting increased risk for EtOH binge drinking during the early stages of the addiction cycle. The first objective of this study was to evaluate whether C57BL/6J mice showing high drinking in the dark (DID) exhibit neurobehavioral traits known to contribute to EtOH binge-drinking disorders. Comparing high vs. low drinkers (HD/LD), we evaluated different types of basal anxiety-like responses, EtOH preference and sensitivity to the reinforcing properties of EtOH, and basal mRNA expression of the OX1/OX2 receptors (OX1r/OX2r) within the prefrontal cortex (PFC) and the nucleus accumbens (NAcc). Additionally, we tested binge drinking by LD/HD in response to a selective OX1r antagonist following intermittent episodes of DID (iDID). We report that DID consistently segregates two neurobehavioral endophenotypes, HD vs. LD, showing differences in neophobia and/or impulsivity/compulsivity traits. Additionally, HD mice show decreased basal OX1r and OX2r mRNA expression within the NAcc and elevated OX1r within the PFC. Exposure to several intermittent episodes of EtOH DID triggered a rapid increase in EtOH intake over time in LD mice matching that observed in HD mice. Despite HD/LD endophenotypes did not show differences in EtOH intake, they still predicted the response to a pharmacological challenge with a selective OX1r antagonist. The present data underscore the relevance of HD/LD endophenotypes stemming from DID procedures for exploring neurobehavioral processes underlying the early stages of the addiction cycle and EtOH binge-drinking disorders.

The structural elements of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway have been described in the vestibular peripheral system. However, the functions of NO in the vestibular endorgans are still not clear. We evaluated the action of NO on the Ca(2+) currents in hair cells isolated from the semicircular canal crista ampullaris of the rat (P14-P18) by using the whole cell and perforated-cell patch-clamp technique. The NO donors 3-morpholinosydnonimine (SIN-1), sodium nitroprusside (SNP), and (+/-)-(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexen-1-yl-nicotinamide (NOR-4) inhibited the Ca(2+) current in hair cells in a voltage-independent manner. The NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (CPTIO) prevented the inhibitory effect of SNP on the Ca(2+) current. The selective inhibitor of the soluble form of the enzyme guanylate cyclase (sGC), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), also decreased the SNP-induced inhibition of the Ca(2+) current. The membrane-permeant cGMP analogue 8-Br-cGMP mimicked the SNP effect. KT-5823, a specific inhibitor of cGMP-dependent protein kinase (PGK), prevented the inhibition of the Ca(2+) current by SNP and 8-Br-cGMP. In the presence of N-ethylmaleimide (NEM), a sulfhydryl alkylating agent that prevents the S-nitrosylation reaction, the SNP effect on the Ca(2+) current was significantly diminished. These results demonstrated that NO inhibits in a voltage-independent manner the voltage-activated Ca(2+) current in rat vestibular hair cells by the activation of a cGMP-signaling pathway and through a direct action on the channel protein by a S-nitrosylation reaction. The inhibition of the Ca(2+) current by NO may contribute to the regulation of the intracellular Ca(2+) concentration and hair-cell synaptic transmission.

Background/aims: To improve esophagectomy outcome, preoperative identification of high-risk patients should allow the surgical approach to be modified or alternative treatment methods to be employed., Methodology: Preoperative risk assessment of 114 patients with resected esophageal cancer. One half of the cases affected the middle third of the esophagus. The tumor stage was III (33.3%) or IV (29.8%). The combined thoracoabdominal approach was the preferred route for resection (88.6%). We analyzed the influence of different variables (epidemiological, clinicopathological and surgical) affecting postoperative mortality., Results: Sixty-six (57.9%) patients developed postoperative complications, mainly pulmonary. The mortality rate was 12.3% (14 patients). Multivariate analysis of preoperative variables found significant association between postoperative death and previous neoplasm (p=0.01), liver cirrhosis (p=0.001), abnormal functional respiratory test (p=0.01) and low serum cholesterol (p=0.005) and albumin (p=0.01). Using those variables, we created a composite scoring system that provides a separation of patients into three postoperative death risk groups. If this knowledge was used, we could avoid 50% of postoperative mortality via improved patient selection., Conclusions: The development of risk scales based on preoperative mortality risk factors may be useful in the selection and preparation of patients suitable for esophageal resection in order to diminish postoperative mortality.

Background/aims: The term "micrometastases" has been confused in many aspects. While the influence of lymph node metastases in esophageal and colorectal cancer is well known, the presence and importance of micrometastases is under debate. We investigated micro lymph node invasion in two different kinds of digestive tumors with very high mortality, and identified its possible repercussion on patient survival., Methodology: Lymph nodes of two groups of patients N0 on routine histopathology after radical resection (R0): 21 with esophageal carcinoma (Group I), and 21 with colorectal carcinoma (Group II), were studied by immunohistochemistry using monoclonal antibodies directed against cytokeratins of wide spectrum. The results were classified as positive or negative and compared with patient survival., Results: Five of twenty-one (5/21) patients in group I and eight of twenty-one (8/21) in group II were positive for micrometastases. Median survival time in the positive esophageal group was 9.5 months vs. 68 in the negative one (p=0.16). Median survival time in the positive subset colorectal group was 54.5 months vs. 76.8 in the negative subgroup (p=0.5). Our results did not show statistical differences in survival time between patients positive or negative for micrometastases; however it is evident, especially in the esophageal cancer group, that there is a negative tendency of positive micrometastases on survival time., Conclusions: The presence of micrometastases in lymph nodes of patients N0 after conventional histopathology is frequent. Our preliminary results did not allow definitive conclusions but we may suppose its negative influence on patient survival.