The effect of stress on the expression of the amyloid precursor protein in rat brain

AbstractThe abnormal processing of the amyloid precursor protein (APP) is a pivotal event in the development of the unique pathology that defines Alzheimer's disease (AD). Stress, and the associated increase in corticosteroids, appear to accelerate brain ageing and may increase vulnerability to Alzheimer's disease via altered APP processing. In this study, rats were repeatedly exposed to an unavoidable stressor, an open elevated platform. Previous studies in this laboratory have shown that a single exposure produces a marked increase in plasma corticosterone levels but animals develop tolerance to this effect between 10 and 20 daily sessions. Twenty-four hours after stress, there was an increase in the ratio of the deglycosylated form of APP in the particulate fraction of the brain, which subsequently habituated after 20 days. The levels of soluble APP (APPs) tended to be lower in the stress groups compared to controls except for a significant increase in the hippocampus after 20 days of platform exposure. Since APPs is reported to have neurotrophic properties, this increased release may represent a neuroprotective response to repeated stress. It is possible that the ability to mount this response decreases with age thus increasing the vulnerability to stress-induced AD-related pathology

The effect of dietary intervention on the metabolic and behavioural impairments generated by short term high fat feeding in the rat

AbstractPrevious studies have shown that rats fed a high calorie diet rich in saturated fat for 12weeks exhibit peripheral insulin resistance and impairments of behavioural flexibility when switched from an operant delayed matching to place (DMTP) schedule to a delayed non-matching to place (DNMTP) schedule. However, the metabolic changes evoked by feeding a high fat (HF) diet can be observed within two weeks of commencing the diet. The current study has confirmed that 4weeks exposure to an HF diet resulted in increased body weight, peripheral insulin resistance and plasma leptin. Studies performed during weeks 3 and 4 on the HF diet revealed suppressed lever pressing rates and impaired behavioural flexibility in the operant DMTP/DNMTP task. When animals fed the HF diet were then returned to a standard chow (SC) diet for 5weeks their weight and blood biochemistry no longer differed from those measured in animals that had never been exposed to the HF diet. The animals restored to the SC diet exhibited a clear ability to acquire the DNMTP schedule of reinforcement although these animals continued to lever press at a lower rate when compared with animals that received the SC diet throughout. The data suggest that exposure to an HF diet diminishes the motivation to respond for a reward and, thus, the capacity to adapt behavioural performance. This deficit was ameliorated, but not totally reversed, by the dietary intervention. If also true for humans, the results suggest that deficits in behavioural flexibility develop after only a short period on a high calorie diet but may be largely reversible through simple dietary intervention, at least in the early stages of deficit development. However, the putative effects of short-term exposure to an HF diet on behavioural motivation may persist for some time after switching to a healthier low fat diet and remain a problem for those seeking to adopt a healthier diet

Pulmonary hypertension in infants with bronchopulmonary dysplasia

An increase in the number of preterm infants and a decrease in the gestational age at birth have resulted in an increase in the number of patients with significant bronchopulmonary dysplasia (BPD) and secondary pulmonary hypertension (PH). PH contributes significantly to the high morbidity and mortality in the BPD patients. Therefore, regular monitoring for PH by using echocardiography and B-type natriuretic peptide (BNP) or N-terminal-proBNP must be conducted in the BPD patients with greater than moderate degree to prevent PH and to ensure early treatment if PH is present. In the BPD patients with significant PH, multi-modality treatment, including treatment for correcting an underlying disease, oxygen supply, use of diverse selective pulmonary vasodilators (inhaled nitric oxide, inhaled prostacyclins, sildenafil, and endothelin-receptor antagonist) and other methods, is mandatory

Contamination of wild plants near neonicotinoid seed-treated crops, and implications for non-target insects

Neonicotinoid insecticides are commonly-used as seed treatments on flowering crops such as oilseed rape. Their persistence and solubility in water increase the chances of environmental contamination via surface-runoff or drainage into areas adjacent to the crops. However, their uptake and fate into non-target vegetation remains poorly understood. In this study, we analysed samples of foliage collected from neonicotinoid seed-treated oilseed rape plants and also compared the levels of neonicotinoid residues in foliage (range: 1.4 – 11 ng/g) with the levels found in pollen collected from the same plants (range: 1.4 – 22 ng/g). We then analysed residue levels in foliage from non-target plants growing in the crop field margins (range: ≤ 0.02 – 106 ng/g). Finally, in order to assess the possible risk posed by the peak levels of neonicotinoids that we detected in foliage for farmland phytophagous and predatory insects, we compared the maximum concentrations found against the LC50 values reported in the literature for a set of relevant insect species. Our results suggest that neonicotinoid seed-dressings lead to widespread contamination of the foliage of field margin plants with mixtures of neonicotinoid residues, where levels are very variable and discontinuous, but sometimes overlap with lethal concentrations reported for some insect species. Understanding the distribution of pesticides in the environment and their potential effects on biological communities is crucial to properly assess current agricultural management and schemes with biodiversity conservation aims in farmland

The Role of NMDA Receptor Antagonists in Nicotine Tolerance, Sensitization, and Physical Dependence: A Preclinical Review

Nicotine, the primary psychoactive component of tobacco products, produces diverse neurophysiological, motivational, and behavioral effects through several brain regions and neurochemical pathways. Various neurotransmitter systems have been explored to understand the mechanisms behind nicotine tolerance, dependence, and withdrawal. Recent evidence suggests that glutamate neurotransmission has an important role in this phenomenon. The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation

The Role of NMDA Receptor Antagonists in Nicotine Tolerance, Sensitization, and Physical Dependence: A Preclinical Review

Nicotine, the primary psychoactive component of tobacco products, produces diverse neurophysiological, motivational, and behavioral effects through several brain regions and neurochemical pathways. Various neurotransmitter systems have been explored to understand the mechanisms behind nicotine tolerance, dependence, and withdrawal. Recent evidence suggests that glutamate neurotransmission has an important role in this phenomenon. The aim of the present review is to discuss preclinical findings concerning the role of N-methyl-D-aspartate (NMDA) receptor neurotransmission in mediating the behavioral effects of nicotine, tolerance, sensitization, dependence, and withdrawal. Based on preclinical findings, it is hypothesized that NMDA receptors mediate the common adaptive processes that are involved in the development, maintenance, and expression of nicotine addiction. Modulation of glutamatergic neurotransmission with NMDA receptor antagonists may prove to be useful in alleviating the symptoms of nicotine abstinence and facilitate tobacco-smoking cessation

Establishing a large prospective clinical cohort in people with head and neck cancer as a biomedical resource: head and neck 5000

BACKGROUND: Head and neck cancer is an important cause of ill health. Survival appears to be improving but the reasons for this are unclear. They could include evolving aetiology, modifications in care, improvements in treatment or changes in lifestyle behaviour. Observational studies are required to explore survival trends and identify outcome predictors. METHODS: We are identifying people with a new diagnosis of head and neck cancer. We obtain consent that includes agreement to collect longitudinal data, store samples and record linkage. Prior to treatment we give participants three questionnaires on health and lifestyle, quality of life and sexual history. We collect blood and saliva samples, complete a clinical data capture form and request a formalin fixed tissue sample. At four and twelve months we complete further data capture forms and send participants further quality of life questionnaires. DISCUSSION: This large clinical cohort of people with head and neck cancer brings together clinical data, patient-reported outcomes and biological samples in a single co-ordinated resource for translational and prognostic research

Book illustration

Book synopsis: William Blake, poet and artist, is a figure often understood to have 'created his own system'. Combining close readings and detailed analysis of a range of Blake's work, from lyrical songs to later myth, from writing to visual art, this collection of thirty-eight lively and authoritative essays examines what Blake had in common with his contemporaries, the writers who influenced him, and those he influenced in turn. Chapters from an international team of leading scholars also attend to his wider contexts: material, formal, cultural, and historical, to enrich our understanding of, and engagement with, Blake's work. Accessibly written, incisive, and informed by original research, William Blake in Context enables readers to appreciate Blake anew, from both within and outside of his own idiom

Maria Cosway’s Hours: Cosmopolitan and Classical Visual Culture in Thomas Macklin’s Poets Gallery

Thomas Macklin’s Gallery of Poets opened at the Mitre Tavern in Fleet Street in 1788 with the aim to ‘display British Genius’ through ‘Prints Illustrative of the Most Celebrated British Poets’. Early newspaper coverage promised ‘a monument of the powers of the pencil in England, as the Vatican is at Rome’. The incongruous juxtaposition between Fleet Street and the Vatican spells out the cosmopolitan ambition of the literary gallery phenomenon through its real and imagined geographies of display. Through the format of the paper gallery of prints, Macklin’s Poets offered the inventions of British Poets as a repository of painting. This chapter examines how the cosmopolitan idiom of the paper gallery is negotiated in the first number of Macklin’s Poets. This essay examines the extent to which this ambition was achieved in the first Number of Macklin’s Poets which carried an engraving of Maria Cosway’s The Hours, originally a painting with an impressively European iconographic heritage. The painting was first exhibited at the Royal Academy in 1783, and was retroactively associated by Macklin with Thomas Gray’s ‘Ode on the Spring’. The trope of the Hours brought with it a weighty provenance derived from classical marble bas-relief, through the antiquarian pages of Pietro Santi Bartoli and Bernard de Montfaucon to Flaxman’s designs for Wedgwood plaques and vases. Cosway’s name also imported into Gray’s poem her reputation as a cosmopolitan, cultured woman who had completed the Grand Tour and who moved in elite circles including those of the Prince of Wales in London and the Duke of Orleans, Pierre d’Hancarville and Thomas Jefferson in Paris. The iconographies of the painting, the print, and the poem articulate a European cosmopolitan tradition for British Art

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome