Acetylcholinesterase activity measurement and clinical features of delirium

Aims: Cholinergic deficiency is commonly implicated in the pathophysiology of delirium. We aimed to investigate the relationship between directly measured serum AChE activity and (1) clinical features of delirium and (2) outcomes, among older hospital patients with delirium. Methods: Hospitalized patients with delirium were recruited and delirium motor subtype, severity and duration of delirium were measured. Serum AChE activity was measured using a colorimetric assay. Results: The mean AChE activity for the whole sample was 2.46 μmol/μml/min (SD 1.75). Higher AChE activity was associated with increased likelihood of hypoactive delirium rather than the hyperactive or mixed subtype (OR 1.98, CI 1.10-3.59). Conclusion: Higher AChE activity was associated with hypoactive delirium, but did not predict outcomes. Simple enhancement of cholinergic neurotransmission may not be sufficient to treat deliriu

Immortalized mouse caput epididymal epithelial (mECap18) cell line recapitulates the in-vivo environment

OnlinePublResiding between the testes and the vas deferens, the epididymis is a highly convoluted tubule whose unique luminal microenvironment is crucial for the functional maturation of spermatozoa. This microenvironment is created by the combined secretory and resorptive activity of the lining epididymal epithelium, including the release of extracellular vesicles (epididymosomes), which encapsulate fertility modulating proteins and a myriad of small non-coding RNAs (sncRNAs) that are destined for delivery to recipient sperm cells. To enable investigation of this intercellular communication nexus, we have previously developed an immortalized mouse caput epididymal epithelial cell line (mECap18). Here, we describe the application of label-free mass spectrometry to characterize the mECap18 cell proteome and compare this to the proteome of native mouse caput epididymal epithelial cells. We report the identification of 5,313 mECap18 proteins, as many as 75.8% of which were also identified in caput epithelial cells wherein they mapped to broadly similar protein classification groupings. Furthermore, key pathways associated with protein synthesis (e.g., EIF2 signaling) and cellular protection in the male reproductive tract (e.g., sirtuin signaling) were enriched in both proteomes. This comparison supports the utility of the mECap18 cell line as a tractable in-vitro model for studying caput epididymal epithelial cell function.Jess E. Mulhall, Natalie A. Trigg, Ilana R. Bernstein, Amanda L. Anderson, Heather C. Murray, Petra Sipilä, Tessa Lord, John E. Schjenken, Brett Nixon, David A. Skerrett-Byrn

Recommendations for clinical interpretation of variants found in non-coding regions of the genome

Background The majority of clinical genetic testing focuses almost exclusively on regions of the genome that directly encode proteins. The important role of variants in non-coding regions in penetrant disease is, however, increasingly being demonstrated, and the use of whole genome sequencing in clinical diagnostic settings is rising across a large range of genetic disorders. Despite this, there is no existing guidance on how current guidelines designed primarily for variants in protein-coding regions should be adapted for variants identified in other genomic contexts. Methods We convened a panel of nine clinical and research scientists with wide-ranging expertise in clinical variant interpretation, with specific experience in variants within non-coding regions. This panel discussed and refined an initial draft of the guidelines which were then extensively tested and reviewed by external groups. Results We discuss considerations specifically for variants in non-coding regions of the genome. We outline how to define candidate regulatory elements, highlight examples of mechanisms through which non-coding region variants can lead to penetrant monogenic disease, and outline how existing guidelines can be adapted for the interpretation of these variants. Conclusions These recommendations aim to increase the number and range of non-coding region variants that can be clinically interpreted, which, together with a compatible phenotype, can lead to new diagnoses and catalyse the discovery of novel disease mechanisms

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Cachexia, sarcopenia, inflammaging and outcomes in hospitalised Older people (the CaSIO study) study protocol and preliminary results

IntroductionOlder people admitted to hospital are vulnerable to adverse outcomes including prolonged length of stay, reduced mobility, admission to care homes. Cachexia, sarcopenia and inflammaging are age-related conditions associated with poor outcomes but are little characterised in older people admitted to hospital. The aim of this study was to describe in detail a cohort of hospitalised older people with focus on cachexia, sarcopenia, inflammaging and clinical outcomes.Materials and methodsCaSIO was a prospective, cohort study of hospitalised older women, with a follow-up time over 2 years. Participants were recruited from the Medicine for Older People wards at a university hospital in England. Detailed characterisation of cachexia, sarcopenia and the immune-endocrine axis occurred on admission, discharge and at 6 months post-discharge. Outcome data were collected on the length of hospital admission, discharge destination, and longer-term outcomes including functional status at six month follow-up. Mortality data were collected at 6, 12 and 24 months.Results145 female participants (58% of eligible patients) were recruited and survived the admission with an average age 86 years; baseline characteristics are provided. 103 (71%) were re-assessed 6 months after discharge (18 (12%) had died; 24 (17%) were lost to follow up); mortality data was ascertained at 12 and 24 months.ConclusionThis study has described cachexia, sarcopenia and inflammaging in relation to clinical outcomes in hospitalised older women with 6 month follow up and mortality data collected for 24 months. This will add to a greater understanding of these conditions within older people