Neuroendocrine carcinomas (NECs) of the colorectum are rare but highly aggressive neoplasms. These tumors show some shared genetic alterations with colorectal adenocarcinomas, and most of them have adjacent glandular adenoma or adenocarcinoma components. However, genetic data on colorectal NECs still are sparse and insufficient for definite conclusions regarding their molecular origin. Based on morphological characterization, panel and whole-exome sequencing, we here present results from an in-depth analysis of a collection of 15 colorectal NECs with glandular components, 10 of which by definition were mixed adenoneuroendocrine carcinomas (MANECs). Among shared genetic alterations of both tumor components, we most frequently found TP53, KRAS and APC mutations that also had highest allele frequencies. Mutations exclusive to glandular or neuroendocrine components outnumbered shared mutations but occurred at lower allele frequencies. Our findings not only provide additional evidence for a common clonal origin of colorectal NECs and adjacent glandular tumor components, but strongly suggest their development through the classical adenoma-carcinoma sequence. Moreover, our data imply early separation of glandular and neuroendocrine components during malignant transformation with subsequent independent mutational evolution.

A growing body of evidence suggests glutamate excess in schizophrenia and that N-methyl-d-aspartate receptor (NMDAR) hypofunction on γ-aminobutyric acid (GABA) interneurons disinhibiting pyramidal cells may be relevant to this hyperglutamatergic state. To better understand how NMDAR hypofunction affects the brain, we used Magnetic Resonance Spectroscopy and resting state functional MRI to study the effects of ketamine on hippocampal neurometabolite levels and functional connectivity in 15 healthy human subjects. We observed a ketamine induced increase of hippocampal Glx (glutamate+glutamine; F= 3.76; p= 0.04), a decrease in fronto-temporal (t=4.92, pFDR< .05, kE= 2198, x= -30, y= 52, z= 14) and temporo-parietal functional connectivity (t=5.07, pFDR< .05, kE= 6094, x= -28, y= -36, z= -2), and a possible link between connectivity changes and elevated Glx. Our data empirically support that hippocampal glutamatergic elevation and resting state network alterations may arise from NMDAR hypofunction and establish a proof of principle whereby experimental modelling of a disorder can help mechanistically integrate distinct neuroimaging abnormalities in schizophrenia.

Baseline HR may be predictive of obstetric spinal hypotension. Higher baseline HR, possibly reflecting a higher sympathetic tone, may be a useful parameter to predict postspinal hypotension.

Study Objective To study the effect of intravenous (IV) sedation on blood pressure (BP), heart rate (HR), and respiratory rates (RR) to determine if IV sedatives differ with respect to their effect on BP, HR, and RR. Design Prospective, randomized, single-blinded, placebo-controlled study. Setting Monitored patient care room at a clinical research center. Subjects 60 healthy ASA physical status 1 volunteers. Interventions Subjects were randomized to receive, in increasing doses, one of three IV sedatives: propofol, midazolam, or dexmedetomidine; or saline control. Measurements Blood pressure (systolic, diastolic), HR, and RR were recorded. Main Results A significant dose-dependent BP reduction occurred with dexmedetomidine and, to a lesser degree, with propofol; and there was good agreement of predicted versus measured drug concentrations for all sedatives. Blood pressure and HR of participants who received midazolam did not change. Conclusions When administered in sedative doses, dexmedetomidine and, to a lesser extent, midazolam, reduces BP in a dose-dependent fashion. Dexmedetomidine also reduces HR. Midazolam does not affect BP or HR.