Serum Cholesterol and Cognitive Performance in the Framingham Heart Study

Objective: The objective of this study was to examine the relationship between total cholesterol (TC) and cognitive performance within the context of the Framingham Heart Study, a large, community-based, prospective investigation of cardiovascular risk factors. Methods: Participants were 789 men and 1105 women from the Framingham Heart Study original cohort who were free of dementia and stroke and who received biennial TC determinations over a 16- to 18-year surveillance period. Cognitive tests were administered 4 to 6 years subsequent to the surveillance period and consisted of measures of learning, memory, attention/ concentration, abstract reasoning, concept formation, and organizational abilities. Statistical models were adjusted for multiple demographic and biological covariates. Results: There was a significant positive linear association between TC and measures of verbal fluency, attention/concentration, abstract reasoning, and a composite score measuring multiple cognitive domains. Performance levels for three clinically defined groups were examined. Participants with “desirable” TC levels (/dL) performed less well than participants with borderline-high TC levels (200–239 mg/dL) and participants with high TC levels (∃240 mg/dL). Conclusions: Lower naturally occurring TC levels are associated with poorer performance on cognitive measures, which place high demands on abstract reasoning, attention/concentration, word fluency, and executive functioning

Essential Role for Cathepsin S in MHC Class II–Associated Invariant Chain Processing and Peptide Loading

AbstractDestruction of Ii by proteolysis is required for MHC class II molecules to bind antigenic peptides, and for transport of the resulting complexes to the cell surface. The cysteine protease cathepsin S is highly expressed in spleen, lymphocytes, monocytes, and other class II–positive cells, and is inducible with interferon-γ. Specific inhibition of cathepsin S in B lymphoblastoid cells prevented complete proteolysis of Ii, resulting in accumulation of a class II–associated 13 kDa Ii fragment in vivo. Consequently, the formation of SDS-stable complexes was markedly reduced. Purified cathepsin S, but not cathepsin B, H, or D, specifically digested Ii from αβIi trimers, generating αβ–CLIP complexes capable of binding exogenously added peptide in vitro. Thus, cathepsin S is essential in B cells for effective Ii proteolysis necessary to render class II molecules competent for binding peptides

Measuring what matters: A proposal for reframing how we evaluate and improve experience in healthcare

The conversation on measuring experience has been a long and thoughtful one. It has reflected a dynamic tension between measures used as a lever for action in some health systems and as a mechanism to determine reimbursable dollars in others. Yet underlying all the conversation, the question of what we measure, to what end we measure and what truly matters to those who experience care remains. Through a series of conversations over the last two years senior experience leaders across healthcare organizations determined it is time to assess the current landscape of patient experience measurement, to acknowledge what the existing system of measurement has inspired in effort and outcomes and to look forward to what could really make a difference in providing actionable insight and sustainable improvement in the future. While there are policy requirements for what organizations measure and report along with financial implications, this need not be the universal means by which patient feedback is captured and issues are addressed. This is paralleled by a global call for a clear, simple, comparable and actionable system of measurement to both understand and improve experience efforts in healthcare. This article reflects those conversations and frames the opportunity we have. It acknowledges all that the current system of measurement has helped us do, offers a new view on what measurement can be and presents a call to action to convene a diverse range of voices to shape experience measurement for the future. Experience Framework This article is associated with the Policy & Measurement lens of The Beryl Institute Experience Framework. (https://www.theberylinstitute.org/ExperienceFramework). Access other PXJ articles related to this lens. Access other resources related to this lens

Direct frequency-comb spectroscopy of a dipole-forbidden clock transition in trapped 40Ca+ ions

We demonstrate direct frequency-comb (FC) spectroscopy of the dipole-forbidden 4

Stability of methylation markers in head and neck squamous cell carcinoma

BackgroundAs cancer progresses, methylation patterns change to promote the tumorigenic phenotype. However, stability of methylation markers over time and the extent that biopsy samples are representative of larger tumor specimens are unknown. This information is critical for clinical use of such biomarkers.MethodsNinety‐eight patients with tumor specimens from 2 timepoints were measured for DNA methylation in the promoter regions across 4 genes.ResultsThere were no significant differences in overall methylation of CCNA1 (cyclin A1), NDN (necdin), deleted in colorectal carcinoma (DCC), and cluster of differentiation 1a (CD1A) within paired specimens (p values = .56, .17, .66, and .58, respectively). All genes showed strong correlations between paired specimens across time. Methylation was most consistent for CCNA1 and NDN over time.ConclusionThis report provides the first evidence that methylation markers measured in biopsy samples are representative of gene methylation in later specimens and suggests that biopsy markers could be representative biomarkers for use in defining personalized treatment utilizing epigenetic changes. © 2015 Wiley Periodicals, Head Neck 38: E1325–E1331, 2016Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137576/1/hed24223.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137576/2/hed24223_am.pd

New Norms for a New Generation: Cognitive Performance in the Framingham Offspring Cohort

A previous publication presented normative data on neuropsychological tests stratified by age, gender, and education based on the Original Cohort of the Framingham Heart Study. Many contemporary investigations include subject samples with higher levels of education, a factor known to affect cognitive performance. Secular change in education prompted the reexamination of norms in the children of the Original Cohort. The study population consisted of 853 men and 988 women from the Offspring Study, free of clinical neurological disease, who underwent a neuropsychological examination, which included tests given to their parents in 1974 to 1976 as well as additional newer tests to provide a more comprehensive battery. The Offspring population overall was more evenly distributed by gender and better educated. Their performance on cognitive tests was superior to that of the Original Cohort. Multivariable analyses revealed that more years of education explained only a part of the cohort differences. These findings suggest that continued surveillance of each generation is necessary to document the impact that unique social and economic variables have on cognitive function. Here, the authors provide updated normative data

Family history of cancer and head and neck cancer survival

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137774/1/lary26524_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137774/2/lary26524.pd

Baseline White Matter Hyperintensities and Hippocampal Volume are Associated With Conversion From Normal Cognition to Mild Cognitive Impairment in the Framingham Offspring Study.

INTRODUCTION: We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up. METHODS: Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified. RESULTS: Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion from normal cognition to MCI at 6.5-year follow-up. Annualized change rates in total cerebral brain volume and hippocampal volume were associated with conversion from normal cognition to MCI to follow-up. DISCUSSION: Baseline WMH and hippocampal volume are markers that are both associated with conversion from normal cognition to MCI, highlighting the role of both vascular lesions and neurodegeneration in MCI

A theoretical study of the structural phases of Group 5B - 6B metals and their transport properties

In order to predict the stable and metastable phases of the bcc metals in the block of the Periodic Table defined by groups 5B to 6B and periods 4 to 6, as well as the structure dependence of their transport properties, we have performed full potential computations of the total energies per unit cell as a function of the c/a ratio at constant experimental volume. In all cases, a metastable body centered tetragonal (bct) phase was predicted from the calculations. The total energy differences between the calculated stable and metastable phases ranged from 0.09 eV/cell (vanadium) to 0.39 eV/cell (tungsten). The trends in resistivity as a function of structure and atomic number are discussed in terms of a model of electron transport in metals. Theoretical calculations of the electrical resistivity and other transport properties show that bct phases derived from group 5B elements are more conductive than the corresponding bcc phases, while bct phases formed from group 6B elements are less conductive than the corresponding bcc phases. Special attention is paid to the phases of tantalum where we show that the frequently observed beta phase is not a simple tetragonal distortion of bcc tantalum

Bioactive Recombinant Human Oncostatin M for NMR-Based Screening in Drug Discovery

Oncostatin M (OSM) is a pleiotropic, interleukin-6 family inflammatory cytokine that plays an important role in inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, and cancer progression and metastasis. Recently, elevated OSM levels have been found in the serum of COVID-19 patients in intensive care units. Multiple anti-OSM therapeutics have been investigated, but to date no OSM small molecule inhibitors are clinically available. To pursue a high-throughput screening and structure-based drug discovery strategy to design a small molecule inhibitor of OSM, milligram quantities of highly pure, bioactive OSM are required. Here, we developed a reliable protocol to produce highly pure unlabeled and isotope enriched OSM from E. coli for biochemical and NMR studies. High yields (ca. 10 mg/L culture) were obtained in rich and minimal defined media cultures. Purified OSM was characterized by mass spectrometry and circular dichroism. The bioactivity was confirmed by induction of OSM/OSM receptor signaling through STAT3 phosphorylation in human breast cancer cells. Optimized buffer conditions yielded 1H, 15N HSQC NMR spectra with intense, well-dispersed peaks. Titration of 15N OSM with a small molecule inhibitor showed chemical shift perturbations for several key residues with a binding affinity of 12.2 ± 3.9 μM. These results demonstrate the value of bioactive recombinant human OSM for NMR-based small molecule screening