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Zahs K.R.,University of Minnesota | Ashe K.H.,University of Minnesota | Ashe K.H.,Geriatric Research Education Clinical Center
Neuron | Year: 2015

Mutations in presenilins are linked to familial autosomal dominant Alzheimer's disease. In this issue of Neuron, Xia etal. (2015) show that a disease-linked mutation leads to loss of γ-secretase function, cognitive decline, and neurodegeneration when knocked into the mouse genome. Mutations in presenilins are linked to familial autosomal dominant Alzheimer's disease. In this issue of Neuron, Xia etal. (2015) show that a disease-linked mutation leads to loss of γ-secretase function, cognitive decline, and neurodegeneration when knocked into the mouse genome. © 2015 Elsevier Inc.

Pehar M.,University of Wisconsin - Madison | Pehar M.,Medical University of South Carolina | Puglielli L.,University of Wisconsin - Madison | Puglielli L.,Geriatric Research Education Clinical Center
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2013

The Nε-amino group of lysine residues can be transiently modified by the addition of an acetyl group. Recognized functions of Nε-lysine acetylation include regulation of activity, molecular stabilization and conformational assembly of a protein. For more than forty years lysine acetylation was thought to occur only in the cytosol and nucleus. Targets included cytoskeletal-associated proteins as well as transcription factors, histone proteins and proteins involved in DNA recombination and repair. However, in 2007 we reported that a type I membrane protein involved in the pathogenesis of Alzheimer's disease was transiently acetylated on the ε amino group of seven lysine residues while transiting along the secretory pathway. Surprisingly, the acetylation occurred in the lumen of the endoplasmic reticulum (ER) forcing us to reconsider old paradigms. Indeed, if lysine acetylation can occur in the lumen of the ER, then all the essential biochemical elements of the reaction must be available in the lumen of the organelle. Follow-up studies revealed the existence of ER-based acetyl-CoA:lysine acetyltransferases as well as a membrane transporter that translocates acetyl-CoA from the cytosol into the ER lumen. Large-scale proteomics showed that the list of substrates of the ER-based acetylation machinery includes both transiting and resident proteins. Finally, genetic studies revealed that this machinery is tightly linked to human diseases. Here, we describe these exciting findings as well as recent biochemical and cellular advances, and discuss possible impact on both human physiology and pathology. © 2012 Elsevier B.V.

Kramer B.J.,Geriatric Research Education Clinical Center
Journal of general internal medicine | Year: 2011

To determine if the combined effects of patient-level (demographic and clinical characteristics) and organizational-level (structure and strategies to improve access) factors are uniformly associated with utilization of Indian Health Service (IHS) and/or Veterans Health Administration (VHA) by American Indian and Alaska Native (AIAN) Veterans to inform policy which promotes dual use. We estimated correlates and compared two separate multilevel logistic regression models of VHA-IHS dual versus IHS-only and VHA-IHS dual versus VHA-only in a sample of 18,892 AIAN Veterans receiving care at 201 VHA and IHS facilities during FY02 and FY03. Demographic, diagnostic, eligibility, and utilization data were drawn from administrative records. A survey of VHA and IHS facilities defined availability of services and strategies to enhance access to healthcare for AIAN Veterans. Facility level strategies that are generally associated with enhancing access to healthcare (e.g., population-based services and programs, transportation or co-location) were not significant factors associated with dual use. In both models the common variable of dual use was related to medical need, defined as the number of diagnoses per patient. Other significant demographic, medical need and organizational factors operated in opposing manners. For instance, age increased the likelihood of dual use versus IHS-only but decreased the likelihood of dual use versus VHA-only. Efforts to enhance access through population-based and consumer-driven strategies may add value but be less important to utilization than availability of healthcare resources needed by this population. Sharing health records and co-management strategies would improve quality of care while policies allow and promote dual use.

Naidech A.M.,Northwestern University | Beaumont J.L.,Northwestern University | Rosenberg N.F.,Northwestern University | Maas M.B.,Northwestern University | And 5 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Rationale: The prognostic significance of delirium symptoms in intensive care unit (ICU) patients with focal neurologic injury is unclear. Objectives: To determine the relationship between delirium symptoms and subsequent functional outcomes and quality of life (QOL) after intracerebral hemorrhage. Methods: We prospectively enrolled 114 patients. Delirium symptoms were routinely assessed twice daily using the Confusion Assessment Method for the ICU by trained nurses. Functional outcomes were recorded with modified Rankin Scale (scored from 0 [no symptoms] to 6 [dead]), and QOL outcomes with Neuro-QOL at 28 days, 3 months, and 12 months. Measurements and Main Results: Thirty-one (27%) patients had delirium symptoms ("ever delirious"), 67 (59%) were never delirious, and the remainder (14%) had persistent coma. Delirium symptoms were nearly always hypoactive, were detected mean 6 days after intracerebral hemorrhage presentation, and were associated with longer ICU length of stay (mean 3.5 d longer in ever vs. never delirious patients; 95% confidence interval, 1.5-8.3; P = 0.004) after correction for age, admit National Institutes of Health (NIH) Stroke Scale, and any benzodiazepine exposure. Delirium symptoms were associated with increased odds of poor outcome at 28 days (odds ratio, 8.7; 95%confidence interval, 1.4-52.5; P =0.018) after correction for admission NIH Stroke Scale and age, and with worse QOL in the domains of applied cognition-executive function and fatigue after correcting for the NIH Stroke Scale, age, benzodiazepine exposure, and time of follow-up. Conclusions: After focal neurologic injury, delirium symptoms were commondespitelowrates of infectionandsedationexposure,andwere predictive of subsequent worse functional outcomes and lower QOL. Copyright © 2013 by the American Thoracic Society.

Carrothers K.M.,Cynosure | Barr J.,Stanford University | Spurlock B.,Cynosure | Susan Ridgely M.,RAND Corporation | And 4 more authors.
Critical Care Medicine | Year: 2013

Objective: This pilot study was designed to identify which contextual factors facilitate/hinder the implementation of the awakening, breathing, coordination, delirium, and early mobility (ABCDE) bundle for guidance in future studies. Design: The sources of data for this study included document review, planned site visits (including interviews and observations), a brief online contextual factors survey, and self-reported process and outcome data. Patients: All patients in the four participating SF Bay Area ICUs were eligible to be included in this pilot study. Setting: This study took place in the four San Francisco Bay Area ICUs participating in the ICU Clinical Impact Interest Group, funded by the Gordon and Betty Moore Foundation from January 2012 through June 2013. Interventions: This was a pilot evaluation study to identify factors that facilitated/hindered the implementation of the ABCDE bundle, interventions designed to decrease the prevalence of ICU-acquired delirium and muscle weakness. The ABCDE bundle consists of spontaneous awakening trials, spontaneous breathing trials, coordination of awakening and breathing trials, choice of sedation, delirium screening and treatment, and early progressive mobility. MEASUREMENTS:: Process data related to bundle element compliance were collected at baseline and monthly during the intervention period. Outcome data (average ICU length of stay and average days on mechanical ventilation) were collected at baseline and quarterly during the intervention period. Hospital-specific results of the online contextual factors survey and information gathered through interviews and observations during site visits also contributed to the analysis. MAIN Results: Factors related to structural characteristics of the ICU, an organizational-wide patient safety culture, an ICU culture of quality improvement, implementation planning, training/support, and prompts/ documentation are believed to have facilitated the rate and success of ABCDE bundle implementation. Excessive turnover (both in project and ICU leadership), staff morale issues, lack of respect among disciplines, knowledge deficits, and excessive use of registry staff are believed to have hindered implementation. Conclusions: Successful implementation of the elements of the ABCDE bundle can result in significant improvements in ICU patient care. The results of this study highlight specific structural and cultural elements of ICUs and hospitals that can positively and negatively influence the implementation of complex care bundles like the ABCDE bundle. Further research is needed to assess the influence of these contextual factors across a broader variety of ICUs and hospitals. © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.

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