Cortical interneurons play a crucial role in the functioning of cortical microcircuitry as they provide inhibitory input to projection (pyramidal) neurons. Despite their involvement in various neurological and psychiatric disorders, our knowledge about their development in human cerebral cortex is still incomplete. Here we demonstrate that at the beginning of corticogenesis, at embryonic 5 gestation weeks (gw, Carnegie stage 16) in human, early neurons could be labeled with calretinin, calbindin and GABA antibodies. These immunolabeled cells show a gradient from the ganglionic eminences (GE) towards the neocortex, suggesting that GE is a well conserved source of early born cortical interneurons from rodents to human. At mid-term (20 gw), however, a subset of calretinin+ cells proliferates in the cortical subventricular zone (SVZ), suggesting a second set of interneuron progenitors that have neocortical origin. Neuropeptide Y, somatostatin or parvalbumin cells are sparse in mid-term cerebral cortex. In addition to the early source of cortical interneurons in the GE and later in the neocortical SVZ, other regions, such as the subpial granular layer, may also contribute to the population of human cortical interneurons. In conclusion, our findings from cryosections and previous in vitro results suggest that cortical interneuron progenitor population is more complex in humans relative to rodents. The increased complexity of progenitors is probably evolutionary adaptation necessary for development of the higher brain functions characteristic to humans.

BACKGROUND Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. METHODS Using dopamine β-hydroxylase (Dbh−/−) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. RESULTS We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators copackaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh−/− mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh−/− mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh−/− mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. CONCLUSIONS Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend upon inhibition of adrenergic neurotransmission.

Background.-Colorectal neuroendocrine tumors are a rare malignancy, yet their incidence appears to be increasing. The optimal treatment for the high-grade subset of these tumors remains unclear. We aimed to examine the relationship between different treatment modalities and outcomes for patients with high-grade neuroendocrine carcinomas (HGNECs) of the colon and rectum. Methods.-The National Cancer Database (2004-2015) was used to identify patients diagnosed with colorectal HGNECs. The primary outcome was overall survival. A Cox Proportional hazard model was used to identify risk factors for survival. Results.-Overall, 1208 patients had HGNECs; 452 (37.4%) patients had primary tumors of the rectum, and 756 (62.5%) patients had primary tumors of the colon. A total of 564 (46.7%) patients presented with stage IV disease. The median survival was 9.0 months [95% confidence interval (CI) 8.2-9.8]. In multivariable analysis, surgical resection [hazard ratio (HR) 0.54, 95% CI0.44-0.66; p < 0.001], chemotherapy (HR 0.74, 95% CI0.69-0.79; p < 0.001), and rectum as the primary site of tumor (HR 0.62, 95% CI 0.51-0.76; p < 0.001) were associated with better overall survival, while older age (HR1.01, 95% CI 1.00-1.01; p = 0.02) and the presence of metastatic disease (HR 3.34, 95% CI 2.69-4.15; p < 0.001) were associated with worse survival. Conclusions.-Patients with colorectal HGNECs selected for chemotherapy and surgical resection of the primary tumor demonstrated better overall survival than those managed without resection. Patients who were able to undergo systemic chemotherapy may benefit from potentially curative resection of the primary tumor. AUTHOR CONTRIBUTIONS All authors made substantial contributions to the design of the work, drafted the work, approved the final version submitted for publication, and agreed to be accountable for all aspects of the work. Adam C. Fields and Pamela Lu MD were co-first authors on this work. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background and Aims It is well known that Crohn's disease is a risk factor for the development of small bowel adenocarcinoma. However, the association between Crohn's disease-associated small bowel adenocarcinoma and survival is less understood. The goal of this study was to determine the impact of Crohn's disease on survival in small bowel adenocarcinoma. Methods Patients with small bowel adenocarcinoma, either associated with Crohn's disease or diagnosed sporadic, were identified in the National Cancer Database from 2004–2016. The primary outcome was overall survival. Results Of 2668 patients, 493 had Crohn's disease-associated small bowel adenocarcinoma and 2175 had sporadic small bowel adenocarcinoma. Crohn's disease patients were more likely to present at a younger age [62 vs 65, p &lt; 0.001], have tumours located in the ileum [62.7% vs 25.0%, p &lt; 0.001], and have poorly differentiated tumours [47.0% vs 31.7%, p &lt; 0.001] compared with sporadic small bowel adenocarcinoma. Factors associated with significantly decreased survival included older age (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.02–1.03, p &lt; 0.00)], higher Charlson score [HR: 1.39, 95% CI: 1.13–1.72, p = 0.002], higher tumour grade [HR: 1.09, 95% CI: 1.04–1.14, p &lt; 0.001], positive surgical margins [HR: 1.60, 95% CI: 1.39–1.84, p &lt; 0.001], and higher stage of disease [HR: 1.90, 3.75, 8.13, 95% CI: 1.37–2.64, 2.68–5.24, 5.77–11.47, for II, III, IV, respectively, compared with I, all p &lt; 0.001]. Receipt of chemotherapy was associated with significantly improved survival [HR: 0.61, 95% CI: 0.53–0.70, p &lt; 0.001]. Crohn's disease [HR: 1.01, 95% CI: 0.99–1.02, p = 0.39], was not significantly associated with survival. Conclusion Compared with sporadic patients, Crohn's disease patients have similar overall survival, and Crohn's disease is not an independent risk factor for mortality.