To examine the independent contributions and combined interactions of medial temporal lobe atrophy (MTA), cortical and subcortical atrophy, and white matter lesion (WML) volume in longitudinal ...cognitive performance.
A total of 477 subjects with age-related WML were evaluated with brain MRI and annual neuropsychological examinations in 3-year follow-up. Baseline MRI determinants of cognitive decline were analyzed with linear mixed models controlling for multiple confounders.
MTA and subcortical atrophy predicted significantly steeper rate of decline in global cognitive measures as well as compound scores for psychomotor speed, executive functions, and memory after adjusting for age, gender, education, lacunes/infarcts, and WML volume. Cortical atrophy independently predicted decline in psychomotor speed. WML volume remained significantly associated with cognitive decline even after controlling for the atrophy scores. Moreover, significant synergistic interactions were found between WML and atrophy measures in overall cognitive performance across time and the rate of cognitive decline. Synergistic effects were also observed between baseline lacunar infarcts and all atrophy measures on change in psychomotor speed. The main results remained robust after exclusion of subjects with clinical stroke or incident dementia, and after additional adjustments for progression of WML and lacunes.
Brain atrophy and WML are independently related to longitudinal cognitive decline in small vessel disease. MTA, subcortical, and cortical atrophy seem to potentiate the effect of WML and lacunes on cognitive decline.
Pregnane X receptor (PXR) is a major transcriptional regulator of xenobiotic metabolism and transport pathways in the liver and intestines, which are critical for protecting organisms against ...potentially harmful xenobiotic and endobiotic compounds. Inadvertent activation of drug metabolism pathways through PXR is known to contribute to drug resistance, adverse drug–drug interactions, and drug toxicity in humans. In both humans and rodents, PXR has been implicated in non-alcoholic fatty liver disease, diabetes, obesity, inflammatory bowel disease, and cancer. Because of PXR's important functions, it has been a therapeutic target of interest for a long time. More recent mechanistic studies have shown that PXR is modulated by multiple PTMs. Herein we provide the first investigation of the role of acetylation in modulating PXR activity. Through LC–MS/MS analysis, we identified lysine 109 (K109) in the hinge as PXR's major acetylation site. Using various biochemical and cell-based assays, we show that PXR's acetylation status and transcriptional activity are modulated by E1A binding protein (p300) and sirtuin 1 (SIRT1). Based on analysis of acetylation site mutants, we found that acetylation at K109 represses PXR transcriptional activity. The mechanism involves loss of RXRα dimerization and reduced binding to cognate DNA response elements. This mechanism may represent a promising therapeutic target using modulators of PXR acetylation levels. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
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•p300 acetylates pregnane X receptor (PXR) at lysine (K) 109.•Acetylation at K109 negatively regulates DNA binding and transcriptional activity.•Acetylation acts to fine-tune PXR activity.
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Current database technology and computer hardware allow us to gather, store, access, and manipulate massive volumes of raw data in an efficient and inexpensive manner. In addition, the amount of data ...collected and warehoused in all industries is growing every year at a phenomenal rate. Nevertheless, our ability to discover critical, non-obvious nuggets of useful information in data that could influence or help in the decision making process, is still limited. Knowledge discovery (KDD) and Data Mining (DM) is a new, multidisciplinary field that focuses on the overall process of information discovery from large volumes of data. The field combines database concepts and theory, machine learning, pattern recognition, statistics, artificial intelligence, uncertainty management, and high-performance computing. To remain competitive, businesses must apply data mining techniques such as classification, prediction, and clustering using tools such as neural networks, fuzzy logic, and decision trees to facilitate making strategic decisions on a daily basis. Knowledge Discovery for Business Information Systems contains a collection of 16 high quality articles written by experts in the KDD and DM field from the following countries: Austria, Australia, Bulgaria, Canada, China (Hong Kong), Estonia, Denmark, Germany, Italy, Poland, Singapore and USA.
Does Vascular Calcification Accelerate Inflammation? Joshi, Francis R., MBBS; Rajani, Nikil K., MA; Abt, Markus, PhD ...
Journal of the American College of Cardiology,
01/2016, Letnik:
67, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract Background Atherosclerosis is an inflammatory condition with calcification apparent late in the disease process. The extent and progression of coronary calcification predict cardiovascular ...events. Relatively little is known about noncoronary vascular calcification. Objectives This study investigated noncoronary vascular calcification and its influence on changes in vascular inflammation. Methods A total of 130 participants in the dal-PLAQUE (Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) study underwent fluorodeoxyglucose positron emission tomography/computed tomography at entry and at 6 months. Calcification of the ascending aorta, arch, carotid, and coronary arteries was quantified. Cardiovascular risk factors were related to arterial calcification. The influences of baseline calcification and drug therapy (dalcetrapib vs. placebo) on progression of calcification were determined. Finally, baseline calcification was related to changes in vascular inflammation. Results Age >65 years old was consistently associated with higher baseline calcium scores. Arch calcification trended to progress more in those with calcification at baseline (p = 0.055). There were no significant differences between progression of vascular calcification with dalcetrapib compared to that with placebo. Average carotid target-to-background ratio indexes declined over 6 months if carotid calcium was absent (single hottest slice p = 0.037, mean of maximum target-to-background ratio p = 0.010, and mean most diseased segment p < 0.001), but did not significantly change if calcification was present at baseline. Conclusions Across multiple arterial regions, higher age is consistently associated with higher calcium scores. The presence of vascular calcification at baseline is associated with progressive calcification; in the carotid arteries, calcification appears to influence vascular inflammation. Dalcetrapib therapy did not affect vascular calcification.
Objective
To determine trends in demographics and treatment for inpatient upper urinary tract calculi in the USA using a population‐based cohort.
Patients and Methods
All patients with a primary or ...secondary diagnosis of kidney or ureteric calculus between 1999 and 2009 in the US Nationwide Inpatient Sample were extracted and weighted.
Temporal trend analyses were used to determine trends in gender, race and age presentation, as well as utilization rates of interventions.
Temporal trends were quantified using the estimated annual percent change (EAPC) using least squares linear regression analysis.
Results
Overall, 2 109 455 patients were hospitalized with upper urinary tract calculi over the 11‐year period. The majority of admissions were for ureteric calculi (63.4%).
Admissions for renal calculus increased by 12.1% during the study period (EAPC + 0.92%, P = 0.039, 95% CI: 0.17–1.66), whilst discharges for ureteric calculus remained stable.
A significant increase (25.4%) in hospitalizations for women was found (EAPC + 2.21%, P < 0.001, 95% CI: 1.40–3.03); by 2006, more women than men were admitted to hospital (95 953 vs. 94 556, respectively).
There were significant increases in hospitalization for black, Hispanic and older patients.
Significant changes in the use of all studied interventions were found except for ureteroscopy, extracorporeal shockwave lithotripsy and nephrectomy.
Conclusions
In this nationally representative sample of inpatient discharges, significant increases were found in admissions for renal compared with ureteric calculi, and for black, Hispanic and older patients.
With regard to surgical intervention, the largest increase was found in the use of procedures for kidney calculi.
Women now comprise the majority in the inpatient management of stone disease.
ADITYA-L1 is India's first dedicated mission to observe the Sun and its atmosphere from a halo orbit around L1 point. Visible emission line coronagraph (VELC) is the primary payload on board ...Aditya-L1 to observe the Sun’s corona. VELC is designed as an internally occulted reflective coronagraph to meet the observational requirements of wide wavelength band and the field of view close to the solar limb (1.05 RSun). Images of the solar corona in continuum and spectra in three emission lines 5303 Å Fe xiv, 7892 Å Fe xi and 10747 Å Fe xiii obtained with high cadence are to be analyzed using software algorithms automatically. A reasonable part of these observations will be made in a synoptic mode in which the data are processed through a standard pipeline and the resulting products will be made available for public use. The procedure involves the calibration of instrument and detectors, converting the images into the FITS format, correcting the images and spectra for the instrumental effects, and aligning the images (in terms of position angles and image scales) etc. Then, develop image processing algorithms to detect the occurrence of energetic events using continuum images. Also derive physical parameters, such as temperature and velocity structure of solar corona using emission line observations. Here, we describe the calibration of detectors and the development of software algorithms to detect the occurrence of CMEs and analyze the spectroscopic data.
Curcumin (1, 7-bis (4-hydroxyl-3-methoxyphenyl)-1, 6 heptadiene-3, 5-dione) is a potent natural anti oxidant and anti-inflammatory agent, which mediates its effects mainly by inhibiting the activity ...of enzymes like cyclooxygenase, lipooxygenases and phospholipase A2. Here we examined the possibility of curcumin affecting the production of matrix metalloproteinases (MMPs) by peripheral blood mononuclear cells (PBMCs), which play an important role in inflammation. Zymographic analysis and ELISA showed that curcumin significantly inhibited the activity and level of MMPs produced by PBMCs isolated from human and inflammation-induced rabbit in a concentration dependent manner. The administration of curcumin to inflammation-induced rabbits also caused downregulation of MMP-9. Kinetic analysis showed that the effect of curcumin was a delayed one indicating inhibition of de novo protein synthesis. RT-PCR and immunoblot analysis showed inhibition of the production of MMP-9 mRNA and protein respectively by human PBMCs, which were activated in vitro by Artocarpus Lakoocha agglutinin (ALA) lectin. EMSA and super shift showed activation of classical NFκB in in vitro activated PBMCs and treatment with curcumin inhibited activation of NFκB. Immunoblot analysis suggested that ALA-induced activation of NFκB leading to the upregulation of MMP-9 was due to the degradation of IκB-α. Curcumin inhibited the degradation of IκB-α, which inhibited the ALA mediated activation of NFκB and upregulation of MMP-9. These results indicated that anti-inflammatory effect of curcumin also involves inhibition of the production of MMP-9 in PBMCs.
•Optimal Test Assembly is a reproducible and replicable method to create shorter forms and reduce burden on respondents.•This manuscript is the first paper to externally validate a measure developed ...through optimal test assembly methods.•In our validation of the Patient Health Questionnaire 4-item shortened form, we found that the same cutoff maximized diagnostic accuracy.•We found that sensitivity was non-inferior to that of the full-length form, but the specificity was slightly reduced.
Shortened versions of self-reported questionnaires may be used to reduce respondent burden. When shortened screening tools are used, it is desirable to maintain equivalent diagnostic accuracy to full-length forms. This manuscript presents a case study that illustrates how external data and individual participant data meta-analysis can be used to assess the equivalence in diagnostic accuracy between a shortened and full-length form. This case study compares the Patient Health Questionnaire-9 (PHQ-9) and a 4-item shortened version (PHQ-Dep-4) that was previously developed using optimal test assembly methods. Using a large database of 75 primary studies (34,698 participants, 3,392 major depression cases), we evaluated whether the PHQ-Dep-4 cutoff of ≥ 4 maintained equivalent diagnostic accuracy to a PHQ-9 cutoff of ≥ 10. Using this external validation dataset, a PHQ-Dep-4 cutoff of ≥ 4 maximized the sum of sensitivity and specificity, with a sensitivity of 0.88 (95% CI 0.81, 0.93), 0.68 (95% CI 0.56, 0.78), and 0.80 (95% CI 0.73, 0.85) for the semi-structured, fully structured, and MINI reference standard categories, respectively, and a specificity of 0.79 (95% CI 0.74, 0.83), 0.85 (95% CI 0.78, 0.90), and 0.83 (95% CI 0.80, 0.86) for the semi-structured, fully structured, and MINI reference standard categories, respectively. While equivalence with a PHQ-9 cutoff of ≥ 10 was not established, we found the sensitivity of the PHQ-Dep-4 to be non-inferior to that of the PHQ-9, and the specificity of the PHQ-Dep-4 to be marginally smaller than the PHQ-9.
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