DHA-Enriched Fish Oil Ameliorates Deficits in Cognition Associated with Menopause and the APOE4 Genotype in Rodents

Female APOE4 carriers have a greater predisposition to developing Alzheimer’s disease (AD) compared to their male counterparts, which may partly be attributed to menopause. We previously reported that a combination of menopause and APOE4 led to an exacerbation of cognitive and neurological deficits, which were associated with reduced brain DHA and DHA:AA ratio. Here, we explored whether DHA-enriched fish oil (FO) supplementation mitigated the detrimental impact of these risk factors. Whilst DHA-enriched fish oil improved recognition memory (NOR) in APOE4 VCD (4-vinylcyclohexene diepoxide)-treated mice (p < 0.05), no change in spatial working memory (Y-maze) was observed. FO supplementation increased brain DHA and nervonic acid and the DHA:AA ratio. The response of key bioenergetic and blood–brain barrier related genes and proteins provided mechanistic insights into these behavioural findings, with increased BDNF protein concentration as well as mitigation of aberrant Erβ, Cldn1 and Glut-5 expression in APOE4 mice receiving fish oil supplementation (p < 0.05). In conclusion, supplementation with a physiologically relevant dose of DHA-enriched fish oil appears to offer protection against the detrimental effects of menopause, particularly in “at-risk” APOE4 female carriers.     

Phase I and scintigraphy studies to evaluate safety,tolerability, pharmacokinetics,and lung deposition of inhaled GDC‐0214 in healthy volunteers

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (^99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. ^99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma C_max similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Many factors drive asthma pathogenesis, including several cytokines that signal through the Janus kinase 1 (JAK1) pathway. Inhibition of JAK1 is a possible target for asthma treatments, but previous studies show oral JAK1 inhibitors lead to increased risk of severe infections, malignancy and cardiovascular events.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study investigated the safety, pharmacokinetics, and lung deposition of GDC‐0214, an inhaled JAK1 inhibitor designed to target the lungs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Inhaled delivery of a JAK inhibitor for 14 days exhibited low systemic exposure, leading to few adverse events and limited systemic toxicity, while demonstrating high deposition in the lungs.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Local pulmonary application of JAK inhibitors may be an effective treatment for asthma with limited systemic risks.     

INVESTIGATION OF APPARENT HEARING LOSS BY OPERANT AUDIOLOGICAL TECHNIQUE

Traditional audiological techniques have relied upon the subject making a distinct response if he/she can hear a certain sound, usually a pure tone. However, such approaches require that the instructions to make this response at a specific time be imparted to the subject before his/her hearing can be assessed. This is clearly not possible if there is a basic communication problem as with many young deaf children or with severely retarded persons. To overcome this, techniques using the principles of operant conditioning have been used with notable success. Fulton and Lloyd (1969) reported having assessed successfully the hearing of over a dozen severely retarded children, although a few cases required a more complex procedure than the simple positive reinforcement discrimination method described here.     

Adverse events caused by MRI contrast agents: Implications for radiographers who inject

This article provides a comprehensive literature review regarding side effects both minor and major associated with contrast agent injection. This includes a discussion of nephrogenic systemic fibrosis (NSF), which remains highly topical. Radiographers now commonly are responsible for injection of contrast agent in patients, in keeping with their extended role. Therefore it is incumbent on them to understand the agents they inject, the contra-indications for injection and any potential associated risks, so that they can act and react accordingly in a timely manner. The need for this knowledge was made very evident after the recent death of a patient from anaphylactic shock when there was a delay in mounting the appropriate procedure. This paper represents a synthesis of relevant articles and reflects on the results, before drawing appropriate conclusions particularly those of special relevance to radiographers.     

Social network influences on smoking,drinking and drug use in secondary school: centrifugal and centripetal forces

We explore how school experiences and social networks structure young people’s substance use in different institutional contexts. The concepts of ‘selection’ and ‘influence’ are situated within the context of bounded agency, counter‐school cultures and Bourdieusian notions of capital. We employed individual and group interviews, network‐mapping, and observations at two contrasting English secondary schools. Both schools were characterised by extended social network structures that appeared to influence patterns of substance use, although the mechanisms via which this occurred varied according to school context. At Grange House school (suburban context) a minority of students from disadvantaged families were alienated by the attainment‐focused regime, marginalised by a strong peer‐led centrifugal force pushing them outwards, and substance use was an alternative source of bonding and identity for these students. In contrast, at North Street a centripetal force operated whereby the majority of students were pulled towards highly‐visible, normative markers of ‘safe’, ‘road culture’, such as cannabis use and gang‐involvement, as they attempted to fit in and survive in an inner‐city school environment. We conclude that health inequalities may be reproduced through these distinctive centrifugal and centripetal forces in different institutional contexts, and this should be the focus of quantitative examination in the UK and elsewhere.     

Measuring health outcomes of adolescents: report from a pilot study

There is a need to understand the practicality, validity and reliability of using utility measures with children and adolescents. We designed a pilot study in order to help guide the selection of an appropriate health-related quality-of-life (HRQoL) questionnaire for adolescents to be used in the context of a large randomised controlled trial (RCT) of family therapy versus standard treatment for adolescents aged 11–17 years. The pilot study was carried out on a school sample of adolescents in the same age range as the RCT. Adolescents were asked to fill in three HRQoL questionnaires: the standard EQ-5D, the licensed Health Utilities Index HUI, and the child-friendly version of the standard EQ-5D: the EQ-5D for youth (EQ-5D-Y). This report explores the problems with the language and concepts embodied within those HRQoL questionnaires and open discussion regarding how we can value the health of adolescents for cost-utility analysis in a larger study.