Chronic excitotoxin-induced axon degeneration in a compartmented neuronal culture model

Glutamate excitotoxicity is a major pathogenic process implicated in many neurodegenerative conditions, including AD (Alzheimer's disease) and following traumatic brain injury. Occurring predominantly from over-stimulation of ionotropic glutamate receptors located along dendrites, excitotoxic axonal degeneration may also occur in white matter tracts. Recent identification of axonal glutamate receptor subunits within axonal nanocomplexes raises the possibility of direct excitotoxic effects on axons. Individual neuronal responses to excitotoxicity are highly dependent on the complement of glutamate receptors expressed by the cell, and the localization of the functional receptors. To enable isolation of distal axons and targeted excitotoxicity, murine cortical neuron cultures were prepared in compartmented microfluidic devices, such that distal axons were isolated from neuronal cell bodies. Within the compartmented culture system, cortical neurons developed to relative maturity at 11 DIV (days in vitro) as demonstrated by the formation of dendritic spines and clustering of the presynaptic protein synaptophysin. The isolated distal axons retained growth cone structures in the absence of synaptic targets, and expressed glutamate receptor subunits. Glutamate treatment (100 μM) to the cell body chamber resulted in widespread degeneration within this chamber and degeneration of distal axons in the other chamber. Glutamate application to the distal axon chamber triggered a lesser degree of axonal degeneration without degenerative changes in the untreated somal chamber. These data indicate that in addition to current mechanisms of indirect axonal excitotoxicity, the distal axon may be a primary target for excitotoxicity in neurodegenerative conditions

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Target = nidgaʔ (nonword); prime = hitxanex (real word)

Currently, the treatment of choice of HIV/AIDS in South Africa is the multidrug combination regimen known as HAART (highly active antiretroviral treatment). HAART, which commonly consists of nucleoside or non-nucleoside reverse transcriptase inhibitors and protease inhibitors, has radically decreased mortality and morbidity rates among people living with HIV/AIDS. The emphasis of the original development of the antiretroviral drugs was on clinical effectiveness (reducing mortality). Presently, emphasis has shifted from the initial short- term considerations to the long-term undesirable or harmful effects induced by this treatment regimen. Whether antiretroviral compounds are oncogenic is widely speculated, which led to this investigation into the effects of protease inhibitors on the expression of key apoptotic regulatory genes, BAX and BCL-2, in two human breast cell lines, MCF-7 and MCF-10A by real-time qPCR gene expression and immunofluorescence. The anti-apoptotic effects of the protease inhibitors – LPV/r were also investigated by cell death detection ELISA and acridine orange staining. This study also evaluated the cytotoxicity of the antiretroviral drugs in normal and cancer cell lines of the breast (at clinically relevant concentrations of the drugs and at different time points, 24–96 h), employing the neutral red uptake assay. The drugs and combinations tested did not alter BAX and BCL-2 gene expression and protein expression and localisation in both cell lines. In addition, the protease inhibitors–LPV/r did not inhibit camptothecin-induced apoptosis in both cell lines. We have shown that the protease inhibitors demonstrated varying degrees of cytotoxicity in the breast cells. The resulting DNA damage associated with cytotoxicity is strongly implicated in the processes of tumour initiation

A Multicomponent Nonpharmacological Intervention to Prevent Delirium for Hospitalized People with Advanced Cancer:A Phase II Cluster Randomized Waitlist Controlled Trial (The PRESERVE Pilot Study)

Background: Delirium is a common debilitating complication of advanced cancer. Objective: To determine if a multicomponent nonpharmacological delirium prevention intervention was feasible for adult patients with advanced cancer, before a phase III (efficacy) trial. Design: Phase II (feasibility) cluster randomized controlled trial. All sites implemented delirium screening and diagnostic assessment. Strategies within sleep, vision and hearing, hydration, orientation, mobility, and family domains were delivered to enrolled patients at intervention site admission days 1-7. Control sites then implemented the intervention ("waitlist sites"). Setting: Four Australian palliative care units. Measurements: The primary outcome was adherence, with an a priori endpoint of at least 60% patients achieving full adherence. Secondary outcomes were interdisciplinary care delivery, delirium measures, and adverse events, analyzed descriptively and inferentially. Results: Sixty-five enrolled patients (25 control, 20 intervention, and 20 waitlist) had 98% delirium screens and 75% diagnostic assessments completed. Nurses (67%), physicians (16%), allied health (8.4%), family (7%), patients (1%), and volunteers (0.5%) delivered the intervention. There was full adherence for 5% patients at intervention sites, partial for 25%. Both full and partial adherence were higher at waitlist sites: 25% and 45%, respectively. One-third of control site patients (32%) became delirious within seven days of admission compared to one-fifth (20%) at both intervention and waitlist sites (p = 0.5). Mean (standard deviation) Delirium Rating Scale-Revised-1998 scores were 16.8 + 12.0 control sites versus 18.4 + 8.2 (p = 0.6) intervention and 18.7 + 7.8 (p = 0.5) waitlist sites. The intervention caused no adverse events. Conclusion: The intervention requires modification for optimal adherence in a phase III trial.</p

Identification of extracolonic pathologies by computed tomographic colonography in colorectal cancer symptomatic patients

BACKGROUND & AIMS: Symptoms suggestive of colorectal cancer may originate outside the colorectum. Computed tomographic colonography (CTC) is used to examine the colorectum and abdominopelvic organs simultaneously. We performed a prospective randomized controlled trial to quantify the frequency, nature, and consequences of extracolonic findings. METHODS: We studied 5384 patients from 21 UK National Health Service hospitals referred by their family doctor for the investigation of colorectal cancer symptoms from March 2004 through December 2007. The patients were assigned randomly to groups that received the requested test (barium enema or colonoscopy, n = 3574) or CTC (n = 1810). We determined the frequency and nature of extracolonic findings, subsequent investigations, ultimate diagnosis, and extracolonic cancer diagnoses 1 and 3 years after testing patients without colorectal cancer. RESULTS: Extracolonic pathologies were detected in 959 patients by CTC (58.7%), in 42 patients by barium enema analysis (1.9%), and in no patients by colonoscopy. Extracolonic findings were investigated in 142 patients (14.2%) and a diagnosis was made for 126 patients (88.1%). Symptoms were explained by extracolonic findings in 4 patients analyzed by barium enema (0.2%) and in 33 patients analyzed by CTC (2.8%). CTC identified 72 extracolonic neoplasms, however, barium enema analysis found only 3 (colonoscopy found none). Overall, CTC diagnosed extracolonic neoplasms in 72 of 1634 patients (4.4%); 26 of these were malignant (1.6%). There were significantly more extracolonic malignancies detected than expected 1 year after examination, but these did not differ between patients evaluated by CTC (22.2/1000 person-years), barium enema (26.5/1000 person-years; P = .43), or colonoscopy (32.0/1000 person-years; P = .88). CONCLUSIONS: More than half of the patients with symptoms of colorectal cancer are found to have extracolonic pathologies by CTC analysis. However, the proportion of patients found to have extracolonic malignancies after 1 year of CTC examination is not significantly greater than after barium enema or colonoscopy examinations. International Standard Randomised Controlled Trials no: 95152621.isrctn.com