455 research outputs found
Mesenteric artery disease in the elderly
AbstractPurposeThe purpose of this study was to estimate the population-based prevalence of mesenteric artery stenosis (MAS) and occlusion among independent elderly Americans.MethodAs part of an ancillary investigation to the Cardiovascular Health Study (CHS), participants in the Forsyth County, NC cohort had visceral duplex sonography of the celiac arteries and superior mesenteric arteries (SMAs). Critical MAS was defined by celiac peak systolic velocity ≥2.0 m/s and/or SMA peak systolic velocity ≥2.7 m/s. Occlusion of either vessel was defined by lack of a Doppler-shifted signal within the imaged artery. Demographic data, blood pressures, and blood lipid levels were collected as part of the baseline CHS examination. Participants' weights were measured at baseline and before the duplex exam. Univariate tests of association were performed with two-way contingency tables, Student t tests, and Fisher exact tests. Multivariate associations were examined with logistic regression analysis.ResultsA total of 553 CHS participants had visceral duplex sonography technically adequate to define the presence or absence of MAS. The study group had a mean age of 77.2 ± 4.9 years and comprised 63% women and 37% men. Participant race was 76% white and 23% African-American. Ninety-seven participants (17.5%) had MAS. There was no significant difference in age, race, gender, body mass index, blood pressure, cholesterol, or low-density lipoproteins for participants with or without MAS. Forward stepwise variable selection found renal artery stenosis (P = .008; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.31, 6.21) and high-density lipoprotein >40 (P = .02; OR, 3.03; 95% CI, 1.17, 7.81) significantly associated with MAS in a multivariate logistic regression model. Eighty-three of the 97 participants with MAS (15.0% of the cohort) had isolated celiac stenosis. Seven participants (1.3% of the cohort) had combined celiac and SMA stenosis. Five participants (0.9% of the cohort) had isolated SMA stenosis. Two participants (0.4% of the cohort) had celiac occlusion. Considering all participants with MAS, there was no association with weight change. However, SMA stenosis and celiac occlusion demonstrated an independent association with annualized weight loss (P = .028; OR, 1.54; 95% CI, 1.05, 2.26) and with renal artery stenosis (P =.001; OR, 9.48; 95% CI, 2.62, 34.47).ConclusionThis investigation provides the first population-based estimate of the prevalence of MAS among independent elderly Americans. MAS existed in 17.5% of the study cohort. The majority had isolated celiac disease. SMA stenosis and celiac artery occlusion demonstrated a significant and independent association with weight loss and concurrent renal artery disease
Investigating Perceptual Congruence Between Data and Display Dimensions in Sonification
The relationships between sounds and their perceived meaning and connotations are complex, making auditory perception an important factor to consider when designing sonification systems. Listeners often have a mental model of how a data variable should sound during sonification and this model is not considered in most data:sound mappings. This can lead to mappings that are difficult to use and can cause confusion. To investigate this issue, we conducted a magnitude estimation experiment to map how roughness, noise and pitch relate to the perceived magnitude of stress, error and danger. These parameters were chosen due to previous findings which suggest perceptual congruency between these auditory sensations and conceptual variables. Results from this experiment show that polarity and scaling preference are dependent on the data:sound mapping. This work provides polarity and scaling values that may be directly utilised by sonification designers to improve auditory displays in areas such as accessible and mobile computing, process-monitoring and biofeedback
Canine \u3cem\u3eRD3\u3c/em\u3e Mutation Establishes Rod-Cone Dysplasia Type 2 (\u3cem\u3ercd2\u3c/em\u3e) as Ortholog of Human and Murine \u3cem\u3erd3\u3c/em\u3e
Rod-cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed and to fine map rcd2 to a 230-kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2 and is predicted to alter the last 61 codons of the normal open reading frame and further extend the open reading frame. Thus, combined meiotic linkage and LD mapping within a single canine breed can yield critical reduction of the disease interval when appropriate advantage is taken of within-breed population structure. This should permit a similar approach to tackle other hereditary traits that segregate in single closed populations
New paradoxical games based on Brownian ratchets
Based on Brownian ratchets, a counter-intuitive phenomenon has recently
emerged -- namely, that two losing games can yield, when combined, a
paradoxical tendency to win. A restriction of this phenomenon is that the rules
depend on the current capital of the player. Here we present new games where
all the rules depend only on the history of the game and not on the capital.
This new history-dependent structure significantly increases the parameter
space for which the effect operates.Comment: 4 pages, 3 eps figures, revte
Cell-intrinsic lysosomal lipolysis is essential for macrophage alternative activation
Alternative (M2) macrophage activation driven through interleukin 4 receptor α (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of fatty acids to support this metabolic program has not been clear. We show that the uptake of triacylglycerol substrates via CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation (OXPHOS), enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth, and blocked protective responses against this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation
Differentiation of constrictive pericarditis from restrictive cardiomyopathy by Doppler transesophageal echocardiographic measurements of respiratory variations in pulmonary venous flow
AbstractObjectives. The purpose of this study was to test the utility of measuring respiratory variation in pulmonary venous flow by transesophageal echocardiography.Background. Respiratory variation of atrioventricular and central venous flow velocities by Doppler echocardiography has been used to differentiate constrictive pericarditis from restrictive cardiomyopathy.Methods. We performed pulsed wave Doppler transesophageal echocardiography of the left or right pulmonary veins in 31 patients with diastolic dysfunction. Fourteen patients had constrictive pericarditis, and 17 had restrictive cardiomyopathy. We measured the pulmonary venous peak systolic and diastolic flow velocities and the systolic/diastolic flow ratio with transesophageal echocardiography during expiration and inspiration. The percent change in Doppler flow velocity from expiration to inspiration (%E) was calculated.Results. Pulmonary venous peak systolic flow in both inspiration and expiration was greater in constrictive pericarditis than in restrictive cardiomyopathy. The %E for peak systolic flow tended to be higher in constrictive pericarditis (19% vs. 10%, p = 0.09). In contrast, pulmonary venous peak diastolic flow during inspiration was lower in constrictive pericarditis than in restrictive cardiomyopathy. The %E for peak diastolic flow was larger in constrictive pericarditis (29% vs. 16%, p = 0.008). The pulmonary venous systolic/diastolic flow ratio was greater in constrictive pericarditis in both inspiration and expiration. The combination of pulmonary venous systolic/diastolic flow ratio ≥0.65 in inspiration and a %E for peak diastolic flow ≥40% correctly classified 86% of patients with constrictive pericarditis.Conclusions. The relatively larger pulmonary venous systolic/ diastolic flow ratio and greater respiratory variation in pulmonary venous systolic, and especially diastolic, flow velocities by transesophageal echocardiography can be useful signs in distinguishing constrictive pericarditis from restrictive cardiomyopathy
PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer
BACKGROUND: Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC). METHODS: Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage. RESULTS: Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed. CONCLUSIONS: The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01862003
Microbial ligand costimulation drives neutrophilic steroid-refractory asthma
Funding: The authors thank the Wellcome Trust (102705) and the Universities of Aberdeen and Cape Town for funding. This research was also supported, in part, by National Institutes of Health GM53522 and GM083016 to DLW. KF and BNL are funded by the Fonds Wetenschappelijk Onderzoek, BNL is the recipient of an European Research Commission consolidator grant and participates in the European Union FP7 programs EUBIOPRED and MedALL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD
Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription
AbstractBackground: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3.Results: SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3α in vitro, with Kis of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3β with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a β-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase.Conclusions: SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease
The state of the Martian climate
60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes
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