Apolipoprotein E: Isoform Specific Differences in Tertiary Structure and Interaction with Amyloid-β in Human Alzheimer Brain

We applied a novel application of FLIM-FRET to in situ measurement and quantification of protein interactions to explore isoform specific differences in Aβ-ApoE interaction and ApoE tertiary conformation in senile plaques in human Alzheimer brain. ApoE3 interacts more closely with Aβ than ApoE4, but a greater proportion of Aβ molecules within plaques are decorated with ApoE4 than ApoE3, lending strong support to the hypothesis that isoform specific differences in ApoE are linked with Aβ deposition. We found an increased number of ApoE N-terminal fragments in ApoE4 plaques, consistent with the observation that ApoE4 is more easily cleaved than ApoE3. In addition, we measured a small but significant isoform specific difference in ApoE domain interaction. Based on our in situ data, supported by traditional biochemical data, we propose a pathway by which isoform specific conformational differences increase the level of cleavage at the hinge region of ApoE4, leading to a loss of ApoE function to mediate clearance of Aβ and thereby increase the risk of AD for carriers of the APOEε4 allele

The international normalized ratio does not reflect bleeding risk in esophageal variceal hemorrhage

Background/Aims: The international normalized ratio (INR) has not been validated as a predictor of bleeding risk in cirrhotics. The aim of this study was to determine whether elevation in the INR correlated with risk of esophageal variceal hemorrhage and whether correction of the INR prior to endoscopic therapy affects failure to control bleeding. Patients and Methods: Patient records were retrospectively reviewed from January 1, 2000 to December 31, 2010. Cases were cirrhotics admitted to the hospital due to bleeding esophageal varices. Controls were cirrhotics with a history of non-bleeding esophageal varices admitted with ascites or encephalopathy. All variceal bleeders were treated with octreotide, antibiotics, and band ligation. Failure to control bleeding was defined according to the Baveno V criteria. Results: We analyzed 74 cases and 74 controls. The mean INR at presentation was lower in those with bleeding varices compared to non-bleeders (1.61 vs 1.74, P = 0.03). Those with bleeding varices had higher serum sodium (136.1 vs 133.8, P = 0.02), lower hemoglobin (9.59 vs 11.0, P < 0.001), and lower total bilirubin (2.47 vs 5.50, P < 0.001). Multivariable logistic regression showed total bilirubin to inversely correlate with bleeding (OR = 0.74). Bleeders received a mean of 1.14 units of fresh frozen plasma (FFP) prior to endoscopy (range 0-11 units). Of the 14 patients (20%) with failure to control bleeding, median INR (1.8 vs 1.5, P = 0.02) and median units of FFP transfused (2 vs 0, P = 0.01) were higher than those with hemostasis after the initial endoscopy. Conclusions: The INR reflects liver dysfunction, not bleeding risk. Correction of INR with FFP has little effect on hemostasis

From research to bedside: Incorporation of a CGA‐based frailty index among multiple comanagement services

The comprehensive geriatric assessment (CGA) is the core tool used by geriatricians across diverse clinical settings to identify vulnerabilities and estimate physiologic reserve in older adults. In this paper, we demonstrate the iterative process at our institution to identify and develop a feasible, acceptable, and sustainable bedside CGA‐based frailty index tool (FI‐CGA) that not only quantifies and grades frailty but also provides a uniform way to efficiently communicate complex geriatric concepts such as reserve and vulnerability with other teams. We describe our incorporation of the FI‐CGA into the electronic health record (EHR) and dissemination among clinical services. We demonstrate that an increasing number of patients have documented FI‐CGA in their initial assessment from 2018 to 2020, while additional comanagement services were established (Figure 2). The acceptability and sustainability of the FI‐CGA, and its routine use by geriatricians in our division, were demonstrated by a survey where the majority of clinicians report using the FI‐CGA when assessing a new patient and that the FI‐CGA informs their clinical management. Finally, we demonstrate how we refined and updated the FI‐CGA, we provide examples of applications of the FI‐CGA across the institution and describe areas of ongoing process improvement and challenges for the use of this tailored yet standardized tool across diverse inpatient and outpatient services. The process outlined can be used by other geriatric departments to introduce and incorporate an FI‐CGA.See related editorial by Callahan in this issue.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171594/1/jgs17446_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171594/2/jgs17446.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171594/3/jgs17446-sup-0001-supinfo.pd

Detecting Delirium: A Systematic Review of Identification Instruments for Non-ICU Settings

BACKGROUND/OBJECTIVES: Delirium manifests clinically in varying ways across settings. More than 40 instruments currently exist for characterizing the different manifestations of delirium. We evaluated all delirium identification instruments according to their psychometric properties and frequency of citation in published research. DESIGN: We conducted the systematic review by searching Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Library, Excerpta Medica Database (Embase), PsycINFO, PubMed, and Web of Science from January 1, 1974, to January 31, 2020, with the keywords delirium and instruments, along with their known synonyms. We selected only systematic reviews, meta-analyses, or narrative literature reviews including multiple delirium identification instruments. MEASUREMENTS: Two reviewers assessed the eligibility of articles and extracted data on all potential delirium identification instruments. Using the original publication on each instrument, the psychometric properties were examined using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) framework. RESULTS: Of 2,542 articles identified, 75 met eligibility criteria, yielding 30 different delirium identification instruments. A count of citations was determined using Scopus for the original publication for each instrument. Each instrument underwent methodological quality review of psychometric properties using COSMIN definitions. An expert panel categorized key domains for delirium identification based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM)-III through DSM-5. Four instruments were notable for having at least two of three of the following: citation count of 200 or more, strong validation methodology in their original publication, and fulfillment of DSM-5 criteria. These were, alphabetically, Confusion Assessment Method, Delirium Observation Screening Scale, Delirium Rating Scale-Revised-98, and Memorial Delirium Assessment Scale. CONCLUSION: Four commonly used and well-validated instruments can be recommended for clinical and research use. An important area for future investigation is to harmonize these measures to compare and combine studies on delirium

List of cases used for the FLIM-FRET study.

<p>The genotype, age of the patient at death, sex and postmortem interval (PMI) is given where available from ADRC records. The check marks show which of the three experiments in which the brain was used. Some brains were used in more than one comparison depending on availability of tissue. For each of the 6 comparisons, the total number of plaques imaged (‘n’) is also given.</p

FLIM-FRET study of ApoE conformation and Aβ-ApoE interaction reveals multiple aspects of ApoE4 associated plaque pathology.

<p>Inter-epitope distances are normalized to the Förster radius. a) A dense core senile plaque from the cortex of a patient homozygous for ApoEε3. Aβ (green) and ApoE NT (red) are extremely well co-localized which illustrates that the plaque is decorated with ApoE. b) Schematic showing the three FLIM-FRET measurements that were made. We independently measured the interacting fraction and distance between Aβ and both ApoE terminal domains as well between the two ApoE domains. c) ApoE CT is in closer apposition to Aβ than ApoE NT, consistent with the assumption that the hydrophobic lipid binding region interacts with Aβ. The difference in distance is small enough to suggest that ApoE envelops Aβ in a similar fashion than it is known to interact with lipids. d) A significantly greater proportion of Aβ is bound to ApoE in the case of ApoE4. The data suggest a reduced capacity of ApoE4 to induce clearance of Aβ. e) ApoE4 has a slightly tighter terminal interaction. This is surprising because a large difference in inter-terminal interaction is expected from the <i>in vitro</i> data. f) ApoE shows a significantly lower numbers of interacting terminal domains. These data are proof that ApoE4 undergoes a greater amount of cleavage either before or after binding to Aβ. Differential cleavage may mediate Aβ clearance or deposition.</p