Restraint-induced Corticosterone Secretion and Hypothalamic CRH mRNA Expression are Augmented During Acute Withdrawal from Chronic Cocaine Administration

Stress responses during cocaine withdrawal likely contribute to drug relapse and may be intensified as a consequence of prior cocaine use. The present study examined changes in stressor-induced activation of the hypothalamic–pituitary–adrenal (HPA) axis during acute withdrawal from chronic cocaine administration. Adult male Sprague–Dawley rats received daily administration of cocaine (30 mg/kg, i.p.) or saline for 14 days. Twenty-four hours after the last injection, rats in each group were sacrificed under stress-free conditions or following 30 min of immobilization. Plasma corticosterone (CORT) was measured in trunk-blood using radioimmunoassay, corticotropin-releasing hormone (CRH) mRNA levels in the paraventricularnucleus (PVN) of the hypothalamus were measured using in situ hybridization and glucocorticoid receptor (GR) protein expression in the pituitary gland and dissected brain regions was measured using Western blot analysis. Basal CRH mRNA in the PVN was unaltered as a result of prior cocaine administration. However, a significant increase in CRH mRNA was observed 90 min following the termination of restraint in cocaine withdrawn, but not saline-treated, rats. Basal CORT was also unaffected by prior cocaine administration, but the CORT response measured immediately after restraint was significantly augmented in cocaine-withdrawn rats. Differences in GR protein expression in number of regions implicated in negative feedback regulation of HPA function, including the hypothalamus, were not observed. These findings indicate that the HPA response to stressors is intensified during early withdrawal from cocaine administration and may be independent of changes in GR-mediated negative feedback

Development and Demonstration of a Wireless Ultraviolet Sensing Network for Dose Monitoring and Operator Safety in Room Disinfection Applications

The use of mobile ultraviolet-C (UV-C) disinfection devices for the decontamination of surfaces in hospitals and other settings has increased dramatically in recent years. The efficacy of these devices relies on the UV-C dose they deliver to surfaces. This dose is dependent on the room layout, the shadowing, the position of the UV-C source, lamp degradation, humidity and other factors, making it challenging to estimate. Furthermore, since UV-C exposure is regulated, personnel in the room must not be exposed to UV-C doses beyond occupational limits. We proposed a systematic method to monitor the UV-C dose administered to surfaces during a robotic disinfection procedure. This was achieved using a distributed network of wireless UV-C sensors that provide real-time measurements to a robotic platform and operator. These sensors were validated for their linearity and cosine response. To ensure operators could safely remain in the area, a wearable sensor was incorporated to monitor the UV-C exposure of an operator, and it provided an audible warning upon exposure and, if necessary, ceased the UV-C emission from the robot. Enhanced disinfection procedures could then be conducted as items in the room could be rearranged during the procedure to maximise the UV-C fluence delivered to otherwise inaccessible surfaces while allowing UVC disinfection to occur in parallel with traditional cleaning. The system was tested for the terminal disinfection of a hospital ward. During the procedure, the robot was manually positioned in the room by the operator repeatedly, who then used feedback from the sensors to ensure the desired UV-C dose was achieved while also conducting other cleaning tasks. An analysis verified the practicality of this disinfection methodology while highlighting factors which could affect its adoption.</jats:p

What role for asbestos in idiopathic pulmonary fibrosis? Findings from the IPF job exposures case–control study

Background Asbestos has been hypothesised as the cause of the recent global increase in the incidence of ‘idiopathic’ pulmonary fibrosis (IPF). Establishing this has important diagnostic and therapeutic implications. The association between occupational asbestos exposure and IPF, and interaction with a common (minor allele frequency of 9% in European populations) genetic variant associated with IPF, MUC5B rs35705950, is unknown. Methods Multicentre, incident case–control study. Cases (n=494) were men diagnosed with IPF at 21 UK hospitals. Controls (n=466) were age-matched men who attended a hospital clinic in the same period. Asbestos exposure was assessed at interview using a validated job exposure matrix and a source-receptor model. The primary outcome was the association between asbestos exposure and IPF, estimated using logistic regression adjusted for age, smoking and centre. Interaction with MUC5B rs35705950 was investigated using a genetic dominant model. Results 327 (66%) cases and 293 (63%) controls ever had a high or medium asbestos exposure risk job; 8% of both cases and controls had cumulative exposure estimates ≥25 fibre ml⁻¹ years. Occupational asbestos exposure was not associated with IPF, adjusted OR 1.1 (95% CI 0.8 to 1.4; p=0.6) and there was no gene–environment interaction (p=0.3). Ever smoking was associated with IPF, OR 1.4 (95% CI 1 to 1.9; p=0.04) and interacted with occupational asbestos exposure, OR 1.9 (95% CI 1 to 3.6; p=0.04). In a further non-specified analysis, when stratifying for genotype there was significant interaction between smoking and work in an exposed job (p<0.01) for carriers of the minor allele of MUC5B rs35705950. Conclusion Occupational asbestos exposure alone, or through interaction with MUC5B rs35705950 genotype, was not associated with IPF. Exposure to asbestos and smoking interact to increase IPF risk in carriers of a common genetic variant, the minor allele of MUC5B rs35705950

Developing reading-writing connections; the impact of explicit instruction of literary devices on the quality of children's narrative writing

The purpose of this collaborative schools-university study was to investigate how the explicit instruction of literary devices during designated literacy sessions could improve the quality of children's narrative writing. A guiding question for the study was: Can children's writing can be enhanced by teachers drawing attention to the literary devices used by professional writers or “mentor authors”? The study was conducted with 18 teachers, working as research partners in nine elementary schools over one school year. The research group explored ways of developing children as reflective authors, able to draft and redraft writing in response to peer and teacher feedback. Daily literacy sessions were complemented by weekly writing workshops where students engaged in authorial activity and experienced writers' perspectives and readers' demands (Harwayne, 1992; May, 2004). Methods for data collection included video recording of peer-peer and teacher-led group discussions and audio recording of teacher-child conferences. Samples of children's narrative writing were collected and a comparison was made between the quality of their independent writing at the beginning and end of the research period. The research group documented the importance of peer-peer and teacher-student discourse in the development of children's metalanguage and awareness of audience. The study suggests that reading, discussing, and evaluating mentor texts can have a positive impact on the quality of children's independent writing

Sleep-wake sensitive mechanisms of adenosine release in the basal forebrain of rodents : an in vitro study

Adenosine acting in the basal forebrain is a key mediator of sleep homeostasis. Extracellular adenosine concentrations increase during wakefulness, especially during prolonged wakefulness and lead to increased sleep pressure and subsequent rebound sleep. The release of endogenous adenosine during the sleep-wake cycle has mainly been studied in vivo with microdialysis techniques. The biochemical changes that accompany sleep-wake status may be preserved in vitro. We have therefore used adenosine-sensitive biosensors in slices of the basal forebrain (BFB) to study both depolarization-evoked adenosine release and the steady state adenosine tone in rats, mice and hamsters. Adenosine release was evoked by high K+, AMPA, NMDA and mGlu receptor agonists, but not by other transmitters associated with wakefulness such as orexin, histamine or neurotensin. Evoked and basal adenosine release in the BFB in vitro exhibited three key features: the magnitude of each varied systematically with the diurnal time at which the animal was sacrificed; sleep deprivation prior to sacrifice greatly increased both evoked adenosine release and the basal tone; and the enhancement of evoked adenosine release and basal tone resulting from sleep deprivation was reversed by the inducible nitric oxide synthase (iNOS) inhibitor, 1400 W. These data indicate that characteristics of adenosine release recorded in the BFB in vitro reflect those that have been linked in vivo to the homeostatic control of sleep. Our results provide methodologically independent support for a key role for induction of iNOS as a trigger for enhanced adenosine release following sleep deprivation and suggest that this induction may constitute a biochemical memory of this state

Induction of cancer neoantigens facilitates development of clinically relevant models for the study of pancreatic cancer immunobiology

Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC. KP2 was treated with oxaliplatin and olaparib (OXPARPi), and a resistant cell line was subsequently cloned to generate multiple genetically distinct cell lines (KP2-OXPARPi clones). Clones A and E are sensitive to immune checkpoint inhibition (ICI), exhibit relatively high T cell infiltration, and have significant upregulation of genes involved in antigen presentation, T cell differentiation, and chemokine signaling pathways. Clone B is resistant to ICI and is similar to the parental KP2 cell line in terms of relatively low T cell infiltration and no upregulation of genes involved in the pathways noted above. Tumor/normal exome sequencing and in silico neoantigen prediction confirms successful generation of cancer neoantigens in the KP2-OXPARPi clones and the relative lack of cancer neoantigens in the parental KP2 cell line. Neoantigen vaccine experiments demonstrate that a subset of candidate neoantigens are immunogenic and neoantigen synthetic long peptide vaccines can restrain Clone E tumor growth. Compared to existing models, the KP2-OXPARPi clones better capture the diverse immunobiology of human PDAC and may serve as models for future investigations in cancer immunotherapies and strategies targeting cancer neoantigens in PDAC

Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer: results of secondary end points analyses

In advanced pancreatic cancer, level one evidence has established a significant survival advantage with chemotherapy, compared to best supportive care. The treatment-associated toxicity needs to be evaluated. This study examines the secondary outcome measures for chemotherapy in advanced pancreatic cancer using meta-analyses. A systematic review was undertaken employing Cochrane methodology, with search of databases, conference proceedings and trial registers. The secondary end points were progression-free survival (PFS)/time to progression (TTP) (summarised using the hazard ratio (HR)), response rate and toxicity (summarised using relative risk). There was no significant advantage of 5FU combinations vs 5FU alone for TTP (HR=1.02; 95% CI=0.85–1.23) and toxicity. Progression-free survival (HR 0.78; CI 0.70–0.88), TTP (HR=0.85; 95% CI=0.72–0.99) and overall response rate (RR=0.56; 95% CI=0.46–0.68) were significantly better for gemcitabine combination chemotherapy, but offset by the greater grade 3/4 toxicity thrombocytopenia (RR=1.94; 95% CI=1.32–2.84), leucopenia (RR=1.46; 95% CI=1.15–1.86), neutropenia (RR=1.48; 95% CI=1.07–2.05), nausea (RR=1.77; 95% CI=1.37–2.29), vomiting (RR=1.64; 95% CI=1.24–2.16) and diarrhoea (RR=2.73; 95% CI=1.87–3.98). There is no significant advantage on secondary end point analyses for administering 5FU in combination over 5FU alone. There is improved PFS/TTP and response rate, with gemcitabine-based combinations, although this comes with greater toxicity

What, When and Who:Manager Involvement in Predicting Employee Resistance to Acquisition Integration

Applying sensemaking research to acquisition integration, we outline factors that influence employee resistance to acquisitions. While integration is widely viewed as important to acquisition outcomes, there is limited systematic study of how employees react to the integration process. Using survey data from Chinese acquirers and applying partial least squares structural equation modeling, we examine what changes with human and task integration with the speed of when changes are made to explore relationships with employee resistance. Consistent with a temporal perspective of acquisition processes and sensemaking we find slower task integration may mitigate employee resistance to acquisition integration. However, employee resistance to the speed that changes are made likely varies for who is involved, suggesting different roles for top and middle managers. Specifically, middle management involvement with slow human integration and top management involvement with fast task integration reduces employee resistance following an acquisition