Neuronal Ca2+ sensor VILIP-1 leads to the upregulation of functional α4β2 nicotinic acetylcholine receptors in hippocampal neurons

The neuronal Ca²⁺-sensor protein VILIP-1, known to affect clathrin-dependent receptor trafficking, has been shown to interact with the cytoplasmic loop of the α4-subunit of the α4β2 nicotinic acetylcholine receptor (nAChR), which is the most abundant nAChR subtype with high-affinity for nicotine in the brain. The α4β2 nAChR is crucial for nicotine addiction and the beneficial effects of nicotine on cognition. Its dysfunction has been implicated in frontal lobe epilepsy, Alzheimer's disease and schizophrenia. Here we report that overexpression of VILIP-1 enhances ACh responsiveness, whereas siRNA against VILIP-1 reduces α4β2 nAChR currents of hippocampal neurons. The underlying molecular mechanism likely involves enhanced constitutive exocytosis of α4β2 nAChRs mediated by VILIP-1. The two interaction partners co-localize in a Ca²⁺-dependent manner with syntaxin-6, a Golgi-SNARE protein involved in trans-Golgi membrane trafficking. Thus, we speculate that regulation of VILIP-1-expression might modulate surface expression of ligand-gated ion channels, such as the α4β2 nAChRs, possibly comprising a novel form of physiological up-regulation of ligand-gated ion channels.     

Acute kidney injury is a frequent complication in critically ill neonates receiving extracorporeal membrane oxygenation: a 14-year cohort study

Introduction

Newborns in need of extracorporeal membrane oxygenation (ECMO) support are at high risk of developing acute kidney injury (AKI). AKI may occur as part of multiple organ failure and can be aggravated by exposure to components of the extracorporeal circuit. AKI necessitates adjustment of dosage of renally eliminated drugs and avoidance of nephrotoxic drugs. We aimed to define systematically the incidence and clinical course of AKI in critically ill neonates receiving ECMO support.

Methods

This study reviewed prospectively collected clinical data (including age, diagnosis, ECMO course, and serum creatinine (SCr)) of all ECMO-treated neonates within our institution spanning a 14-year period. AKI was defined by using the Risk, Injury, Failure, Loss of renal function, and End-stage renal disease (RIFLE) classification. SCr data were reviewed per ECMO day and compared with age-specific SCr reference values. Accordingly, patients were assigned to RIFLE categories (Risk, Injury, or Failure as 150%, 200%, or 300% of median SCr reference values). Data are presented as median and interquartile range (IQR) or number and percentage.

Results

Of 242 patients included, 179 (74%) survived. Median age at the start of ECMO was 39 hours (IQR, 26 to 63); median ECMO duration was 5.8 days (IQR, 3.9 to 9.4). In total, 153 (64%) patients had evidence of AKI, with 72 (30%) qualifying as Risk, 55 (23%) as Injury, and 26 (11%) as Failure. At the end of the study period, only 71 (46%) patients of all 153 AKI patients improved by at least one RIFLE category. With regression analysis, it was found that nitric oxide ventilation (P = 0.04) and younger age at the start of ECMO (P = 0.004) were significant predictors of AKI. Survival until intensive care unit discharge was significantly lower for patients in the Failure category (35%) as compared with the Non-AKI (78%), Risk (82%), and Injury category (76%), with all P < 0.001, whereas no significant differences were found between the three latter RIFLE categories.

Conclusions

Two thirds of neonates receiving ECMO had AKI, with a significantly increased mortality risk for patients in the Failure category. As AKI during childhood may predispose to chronic kidney disease in adulthood, long-term monitoring of kidney function after ECMO is warranted.     

Investigation of acute lower gastrointestinal bleeding with 16‐ and 64‐slice multidetector CT†

We evaluated the usefulness of 16‐ and 64‐slice multidetector CT (MDCT) in the detection of a bleeding site in acute lower gastrointestinal tract (GIT) haemorrhage by conducting a retrospective study of cases of presumed acute lower GIT haemorrhage imaged with CT in two teaching hospitals in an 11‐month period. The patients underwent contrast enhanced CT using either a 16 or 64 MDCT. No oral contrast was used. One hundred milliliters of non‐ionic intravenous contrast agent was injected at 4.5 mL/s, followed by a 60 mL saline flush at 4 mL/s through a dual head injector. Images were acquired in arterial phase with or without non‐contrast and portal phase imaging with 16 × 1.5 mm or 64 × 0.625 mm collimation. Active bleeding was diagnosed by the presence of iodinated contrast extravasation into the bowel lumen on arterial phase images with attenuation greater than and distinct from the normal mucosal enhancement or focal pooling of increased attenuation contrast material within a bowel segment on portal‐venous images. Further management and final diagnosis was recorded. Fourteen patients and 15 studies were reviewed. CT detected and localized a presumed bleeding site or potential causative pathology in 12 (80%) of the patients. Seven of these were supported by other investigations or surgery, while five were not demonstrated by other modalities. Eight patients had mesenteric angiography, of which only four corroborated the site of bleeding. CT did not detect the bleeding site in three patients, of which two required further investigation and definitive treatment. We propose that MDCT serves a useful role as the initial rapid investigation to triage patients presenting with lower GIT bleeding for further investigation and management.     

Pathogenesis of B cell lymphoma in a patient with AIDS

Lymphoma occurs at increased frequency in patients with the acquired immunodeficiency syndrome (AIDS). We studied, using serologic and molecular techniques, one such lymphoma for (a) evidence of infection with human T lymphotropic virus, type III (HTLV-III), and Epstein-Barr virus (EBV), (b) monoclonal rearrangement of immunoglobulin and T cell receptor genes, and (c) rearrangement of the c-myc oncogene. Immunoglobulin and T cell receptor gene studies demonstrated that the tumor was of monoclonal B cell origin. Similar to cases of Burkitt's lymphoma unrelated to AIDS, there were DNA sequences in the lymphoma that hybridized to EBV-specific probes and demonstrated evidence of c- myc rearrangement. HTLV-III sequences were not detected in the malignant B cells. The pathogenesis of some B cell neoplasms in patients with the syndrome may involve transformation by EBV and deregulation of oncogene expression without direct infection of the malignant B cells by HTLV-III.     

IS A MAN'S FACIAL APPEARANCE PREDICTIVE OF HOW HE WILL DIE?

The ability of a range of health professionals including an oncologist, a haematologist, a cardiologist, a general practitioner and a counsellor to predict the cause of death from facial appearance has been evaluated. Each participant was asked to predict the cause of death from facial photographs of 200 Caucasian male doctors whose cause of death was known to be due to either arterial disease or neoplasia. Statistically significant concordance was found between the oncologist and both the GP and the counsellor in their predictions of cause of death, although the individual accuracy was no greater than would be expected by chance. This suggests that common judgements based on facial appearances may be shared among certain health professionals.     

Active Immunotherapy Combined With Blockade of a Coinhibitory Pathway Achieves Regression of Large Tumor Masses in Cancer-prone Mice

Vaccines that aim to expand tumor-specific CD8⁺ T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8⁺ T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8⁺ T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.