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

Cholinergic Deficiency Hypothesis in Delirium: A Synthesis of Current Evidence

Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. This review examines current understanding of the cholinergic deficiency hypothesis in delirium by synthesizing evidence on potential pathophysiological pathways. Acetylcholine synthesis involves various precursors, enzymes, and receptors, and dysfunction in these components can lead to delirium. Insults to the brain, like ischemia and immunological stressors, can precipitously alter acetylcholine levels. Imbalances between cholinergic and other neurotransmitter pathways may result in delirium. Furthermore, genetic, enzymatic, and immunological overlaps exist between delirium and dementia related to the cholinergic pathway. Important areas for future research include identifying biomarkers, determining genetic contributions, and evaluating response to cholinergic drugs in delirium. Understanding how the cholinergic pathway relates to delirium may yield innovative approaches in the diagnosis, prevention, and treatment of this common, costly, and morbid condition

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

Relationship between physician and patient assessment of performance status and survival in a large cohort of patients with haematologic malignancies

Background: Few studies have investigated the relationship between physician and patient-assessed performance status (PS) in blood cancers. Methods: Retrospective analysis among 1418 patients with haematologic malignancies seen at Dana-Farber Cancer Institute between 2007 and 2014. We analysed physician-patient agreement of Eastern Cooperative Oncology Group PS using weighted kappa-statistics and survival analysis. Results: Mean age was 58.6 years and average follow-up was 38 months. Agreement in PS was fair/moderate (weighted kappa = 0.41, 95% CI 0.37-0.44). Physicians assigned a better functional status (lower score) than patients (mean 0.60 vs 0.81), particularly when patients were young and the disease was aggressive. Both scores independently predicted survival, but physician scores were more accurate. Disagreements in score were associated with poorer survival when physicians rated PS better than patients, and were modified by age, sex and severity of disease. Conclusions: Physician-patient disagreements in PS score are common and have prognostic significance.MSTAR Program (American Federation for Aging Research/NIH) [T35AG038027-05]; National Institute on Aging [T32AG000158]; Hartford Center of Excellence Award; Mary P. Murphy Fund for Hematologic Malignancies Research; Veterans' Administration Merit Review Award12 Month Embargo.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Cognitive and Brain Reserve and the Risk of Postoperative Delirium in Older Patients

BACKGROUND: Cognitive and brain reserve theories suggest that aspects of neural architecture or cognitive processes modify the impact of neuropathological processes on cognitive outcomes. While frequently studied in the context of dementia, reserve in delirium is relatively understudied. METHODS: We examined the association of three markers of brain reserve (head circumference, MRI-derived brain volume, and leisure time physical activity) and five markers of cognitive reserve (education, vocabulary, cognitive activities, cognitive demand of lifetime occupation, and interpersonal demand of lifetime occupation) and the risk of postoperative delirium in a prospective observational study of 566 older adults free of dementia undergoing scheduled surgery. FINDINGS: Twenty four percent of patients (135/566) developed delirium during the postoperative hospitalization period. Of the reserve markers examined, only the Wechsler Test of Adult Reading (WTAR) was significantly associated with the risk of delirium. A one-half standard deviation better performance on the WTAR was associated with a 38% reduction in delirium risk (P = 0.01); adjusted relative risk of 0.62, 95% confidence interval 0.45-0.85. INTERPRETATION: In this relatively large and well-designed study, most markers of reserve fail to predict delirium risk. The exception to this is the WTAR. Our findings suggest that the reserve markers that are important for delirium may be different from those considered to be important for dementia

Relationship between physician and patient assessment of performance status and survival in a large cohort of patients with haematologic malignancies

Background: Few studies have investigated the relationship between physician and patient-assessed performance status (PS) in blood cancers. Methods: Retrospective analysis among 1418 patients with haematologic malignancies seen at Dana-Farber Cancer Institute between 2007 and 2014. We analysed physician-patient agreement of Eastern Cooperative Oncology Group PS using weighted kappa-statistics and survival analysis. Results: Mean age was 58.6 years and average follow-up was 38 months. Agreement in PS was fair/moderate (weighted kappa = 0.41, 95% CI 0.37-0.44). Physicians assigned a better functional status (lower score) than patients (mean 0.60 vs 0.81), particularly when patients were young and the disease was aggressive. Both scores independently predicted survival, but physician scores were more accurate. Disagreements in score were associated with poorer survival when physicians rated PS better than patients, and were modified by age, sex and severity of disease. Conclusions: Physician-patient disagreements in PS score are common and have prognostic significance.MSTAR Program (American Federation for Aging Research/NIH) [T35AG038027-05]; National Institute on Aging [T32AG000158]; Hartford Center of Excellence Award; Mary P. Murphy Fund for Hematologic Malignancies Research; Veterans' Administration Merit Review Award12 Month Embargo.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]