Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD.

Significance Statement: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment.

Outpatient neurology diagnostic coding: a proposed scheme for standardised implementation.

Clinical coding uses a classification system to assign standard codes to clinical terms and so facilitates good clinical practice through audit, service design and research. However, despite clinical coding being mandatory for inpatient activity, this is often not so for outpatient services, where most neurological care is delivered. Recent reports by the UK National Neurosciences Advisory Group and NHS England's 'Getting It Right First Time' initiative recommend implementing outpatient coding.

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

Aims: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period.

Methods And Results: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy.

Investigating modifications to participant information materials to improve recruitment into a large randomized trial.

Background: Large randomized trials are the best method to test the efficacy and safety of treatments expected to have moderate effects. We observed a significant decline in potential participants' response to mailed invitations to participate in such trials over a 10-year period and investigated possible reasons behind this and potential modifications to the invitation process to mitigate it.

Methods: Participants who declined to participate in the HPS2-THRIVE trial were asked to give a reason.

Morvan Syndrome: A Case Report With Patient Narrative and Video.

A 74-year-old gentleman was admitted to the regional neurosciences center with encephalopathy, myokymia, and dysautonomia. Chest imaging had previously identified an incidental mass in the anterior mediastinum, consistent with a primary thymic tumor. Antivoltage-gated potassium channel (anti-VGKC) antibodies were positive (titer 1273 pmol/L) and he was hypokalemic.

Screening for problem drinking in older people referred to a mental health service: a comparison of CAGE and AUDIT.

The aim of the study was to evaluate the validity of the Alcohol Use Disorders Identification Test (AUDIT), the five-item version (AUDIT-5) and the CAGE as screening tests for problem drinking in mentally ill older people. The study was of prospective cross-sectional design with questionnaire survey and interview and included all consecutive referrals to an old age psychiatry service fulfilling inclusion criteria. Sensitivity, specificity and positive predictive values and areas under the receiver operating characteristic curves (AUROC) for the AUDIT, AUDIT-5, and CAGE were the primary outcome measures.

Apolipoprotein E (apoE) uptake and distribution in mammalian cell lines is dependent upon source of apoE and can be monitored in living cells.

As part of investigations of the cellular uptake of apolipoprotein E (apoE) relevant to Alzheimer's disease we have found that different preparations of apoE are handled differently by cells expressing the LDL-receptor. Comparing recombinant, cellular and native apoE, complexed with different preparations of lipid we find that only cellular and native apoE enter a vesicular compartment. Some, but not all of these apoE containing vesicles are lysosomes.

Dynamic properties of APC-decorated microtubules in living cells.

The adenomatous polyposis coli (APC) tumour suppressor protein is a component of the Wnt signalling pathway in which it plays a major role in controlling nuclear accumulation of beta-catenin and hence in the modulation of beta-catenin-regulated gene transcription. APC also associates with microtubules at the ends of cytoplasmic extensions in epithelial cells, a distribution that can be reproduced in COS cells ectopically expressing APC. To examine the effect of APC on microtubule properties, we monitored directly the behaviour of APC and of APC-decorated microtubules by time-lapse imaging of cytoplasmic extensions in live COS cells expressing APC tagged with a green fluorescent protein.

Truncated apoE forms tangle-like structures in a neuronal cell line.

Apolipoprotein E is the predominant brain lipoprotein and polymorphic variation in the APOE gene the major genetic susceptibly factor for late onset Alzheimer's disease (AD). Recently it was reported that carboxyl-truncated ApoE fragments induce tangle-like structures in neurons. We confirm the finding: in mouse neuroblastoma cells truncated apoE fragments lacking the carboxyterminus induce structures that have the appearance of neurofibrillary tangles.

Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells.

The inherited form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has been attributed to mutations in the tau gene. Pathologically, affected FTDP-17 brains share tau aggregates with other tauopathies, the most common being Alzheimer's disease. FTDP-17 mutations may therefore affect tau function leading to tau aggregation and cell loss.

Neurofibrillary tangles and tau phosphorylation.

Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer's disease (AD). They are composed of a highly-phosphorylated form of the microtubule-associated protein tau. We are investigating the relationship between NFTs and microtubule stability and how tau phosphorylation and function is affected in transgenic models and by co-expression with beta-amyloid precursor protein and presenilins.

Sites of phosphorylation in tau and factors affecting their regulation.

The microtubule-associated protein, tau, is the principal component of paired helical filaments (PHFs) in Alzheimer's disease. PHF-tau is highly phosphorylated and a total of 25 sites of phosphorylation have so far been identified. Many of these sites are serine or threonine residues that are immediately followed in the sequence by proline residues, and hence are candidate phosphorylation sites for proline-directed kinases.

Apolipoprotein E gene and Alzheimer's disease: is tau the link?

The finding that APOE (the gene encoding apolipoprotein E) polymorphic variation was associated with an altered risk of developing Alzheimer's disease (AD) was a significant advance and immediately prompted a search for the mechanisms responsible for this alteration. Some 6 years later, a number of different hypotheses remain that might account for this influence on pathogenesis with no single mechanism being unequivocally accepted. The different approaches to understanding these mechanisms can be broadly categorized as: those suggesting a remote effect, such as different rates of vascular risk factors in those with the different APOE alleles; those proposing altered neuronal vulnerability, perhaps due to apolipoprotein E (ApoE)-isoform-specific differences in local cholesterol transport; and those hypotheses postulating an ApoE interaction with the two key lesions of AD, plaques and tangles.

Does dysregulation of the Notch and wingless/Wnt pathways underlie the pathogenesis of Alzheimer's disease?

Alzheimer's disease is characterized by the presence of neurofibrillary tangles and senile neuritic plaques in the brain. Tangles are aggregates of paired helical filaments composed of the microtubule-associated protein, tau, in a hyperphosphorylated state. Senile plaques have a core of amyloid beta-peptide derived by proteolysis of the amyloid precursor protein.

The function of the microtubule-associated protein tau is variably modulated by graded changes in glycogen synthase kinase-3beta activity.

The microtubule-associated protein tau favors microtubule nucleation and stabilization and plays a role in the elongation of axons. We have investigated the ability of glycogen synthase kinase-3beta (GSK-3beta) to control tau-induced processes outgrowth. Tau-transfected Chinese hamster ovary (CHO) cells developed processes containing microtubule bundles after cytochalasin treatment, but a significant reduction in the number of cells harboring processes was observed in tau/GSK-3beta-co-transfected cells.

Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation.

In vitro evidence has suggested a change in the ability of tau bearing mutations associated with fronto-temporal dementia to promote microtubule assembly. We have used a cellular assay to quantitate the effect of both isoform differences and mutations on the physiological function of tau. Whilst all variants of tau bind to microtubules, microtubule extension is reduced in cells transfected with 3-relative to 4-repeat tau.