Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved

A PGD-based multiscale formulation for non-linear solid mechanics under small deformations

Model reduction techniques have became an attractive and a promising field to be applied in multiscale methods. The main objective of this work is to formulate a multiscale procedure for non-linear problems based on parametrized microscale models. The novelty of this work relies in the implementation of the model reduction technique known as Proper Generalized Decomposition for solving the high dimensional parametrized problem resulting from the microscale model. The multiscale framework here proposed is formulated to non-linear problems, specifically to material non-linearities, where material response is governed by a strain dependent evolution law. Two strategies to deal with this kind of problem under small deformations are detailed in this work. Both strategies based on parametrized microscale models solved by PGD have been applied to a problem with a rate-dependent isotropic damage model. First, a procedure where the problem is solved by uncoupling the equilibrium equation to the state variable expression has been explored. In order, to alleviate the parametrized microscale problem, a second strategy for problems with material non-linearity has been proposed, incorporating a parametrized microscale problem at each macroscale increment (FE-PGD). The basis of those procedures are described and compared, highlighting the solution accuracy and computer time consumption in comparison to a traditional finite element analysis

Defining adenoma detection rate benchmarks in average-risk male veterans

Background and Aims Veterans have higher prevalence of colorectal neoplasia than non-veterans; however, it is not known whether specific Veterans Affairs (VA) adenoma detection rate (ADR) benchmarks are required. We compared ADRs of a group of endoscopists for colonoscopies performed at a VA to their ADRs at a non-VA academic medical center. Methods This was a retrospective review of screening colonoscopies performed by endoscopists who practice at the Indianapolis VA and Indiana University (IU). Patients were average-risk males aged 50 years or older. ADR, proximal adenoma detection rate, advanced adenoma detection rate, and adenomas per colonoscopy were compared between IU and the VA groups. Results Six endoscopists performed screening colonoscopies at both locations during the study period (470 at IU vs 608 at the VA). The overall ADR was not significantly different between IU and the VA (58% vs 61%; p =0.21). Advanced neoplasia detection rate (13% vs 17%; p=0.46), proximal adenoma detection rate (46% vs 47%; p=0.31), and adenoma per colonoscopy (1.59 vs 1.84; p=0.24) were not significantly different. There were no significant differences in cecal intubation rate (100% vs 99%; p=0.13) or withdrawal time (10.9 vs 11.1 min; p=0.28). In regression analysis, there was significant correlation between the attending-specific ADRs at IU and the VA (p=0.041, r-square=0.69). Conclusions In this study of average-risk males undergoing screening colonoscopies by the same group of endoscopists, the ADRs of VA and non-VA colonoscopies were not significantly different. This suggests that a VA-specific ADR target is not required for endoscopists with high ADR

An investigation of the efficiency of South Africa’s sector education and training authorities (SETA’s)

The performance of South African Sector Education and Training Authorities (SETA’s) has been increasingly questioned. On this premise, the paper investigated the efficiency of the SETAs with respect to their utilization of funds in order to promote a range of education and training outputs was investigated. More specifically, the study investigated the quantity and quality of five training and education outputs, set by the National Skills Development Strategy (NSDS), in relation to the funding received. Furthermore, the study examined the amount of money spend on administrative expenditure by the various SETAs, as well as the SETAs management of financial reserves. In order to guide the study, as well as analyze the data, a conceptual framework to measure efficiency was based on an input-output model developed by Gupta and Verhoeven (2001). Data were obtained from the published accounting and annual reports for the period 2006 – 2009. The results indicated only two of the SETA’s were efficient with respect to their utilization of funds and that only five SETA’s consistently met their own targets. The study also shows that if the SETA’ s funds had been applied to education and training outputs, rather than for investment purposes, training outputs could have been considerably increased. The paper has implications for the use of public funds with respect to the critical skills shortage confronting the economy

Statistical mechanics of transcription-factor binding site discovery using Hidden Markov Models

Hidden Markov Models (HMMs) are a commonly used tool for inference of transcription factor (TF) binding sites from DNA sequence data. We exploit the mathematical equivalence between HMMs for TF binding and the "inverse" statistical mechanics of hard rods in a one-dimensional disordered potential to investigate learning in HMMs. We derive analytic expressions for the Fisher information, a commonly employed measure of confidence in learned parameters, in the biologically relevant limit where the density of binding sites is low. We then use techniques from statistical mechanics to derive a scaling principle relating the specificity (binding energy) of a TF to the minimum amount of training data necessary to learn it.Comment: 25 pages, 2 figures, 1 table V2 - typos fixed and new references adde

Satisfaction of patients on chronic haemodialysis and peritoneal dialysis

BACKGROUND: In contrast to quality of life, patient satisfaction on chronic haemodialysis (HD) and peritoneal dialysis (PD) has only rarely been studied. PATIENTS AND METHODS: All chronic HD and PD patients of the 19 centres located in western Switzerland were asked to complete a specific questionnaire, assessing dialysis centre characteristics, treatment modalities, and information received before and during dialysis treatment. Comparison between satisfaction with PD and HD was carried out on the patients in the nine centres offering both treatment modalities. RESULTS: Of the 558 questionnaires distributed to chronic HD patients, 455 were returned (response rate 82%). Fifty of 64 PD patients (78%) returned the questionnaire. The two groups were similar in age, gender, and duration of dialysis treatment. Completion rates were >90% for a majority of questions, with the lowest rate for information on sexuality (49% in HD and 54% in PD respectively). The lowest scores were recorded for information received about complications and costs of dialysis, and impact of end-stage kidney disease on sexuality. Satisfaction was lower in anonymous questionnaires. Satisfaction of PD patients was significantly better in 50% of the questions, particularly session tolerance (p<0.001), information about dialysis sessions (p=0.007), and complications (p=0.006). CONCLUSIONS: PD patients were on average more satisfied with their treatment than HD patients. Satisfaction could be improved with more information about potential adverse treatment effects

Fibulin-4 is essential for maintaining arterial wall integrity in conduit but not muscular arteries.

Homozygous or compound heterozygous mutations in fibulin-4 (FBLN4) lead to autosomal recessive cutis laxa type 1B (ARCL1B), a multisystem disorder characterized by significant cardiovascular abnormalities, including abnormal elastin assembly, arterial tortuosity, and aortic aneurysms. We sought to determine the consequences of a human disease-causing mutation in FBLN4 (E57K) on the cardiovascular system and vascular elastic fibers in a mouse model of ARCL1B. Fbln4E57K/E57K mice were hypertensive and developed arterial elongation, tortuosity, and ascending aortic aneurysms. Smooth muscle cell organization within the arterial wall of large conducting vessels was abnormal, and elastic fibers were fragmented and had a moth-eaten appearance. In contrast, vessel wall structure and elastic fiber integrity were normal in resistance/muscular arteries (renal, mesenteric, and saphenous). Elastin cross-linking and total elastin content were unchanged in large or small arteries, whereas elastic fiber architecture was abnormal in large vessels. While the E57K mutation did not affect Fbln4 mRNA levels, FBLN4 protein was lower in the ascending aorta of mutant animals compared to wild-type arteries but equivalent in mesenteric arteries. We found a differential role of FBLN4 in elastic fiber assembly, where it functions mainly in large conduit arteries. These results suggest that elastin assembly has different requirements depending on vessel type. Normal levels of elastin cross-links in mutant tissue call into question FBLN4\u27s suggested role in mediating lysyl oxidase-elastin interactions. Future studies investigating tissuespecific elastic fiber assembly may lead to novel therapeutic interventions for ARCL1B and other disorders of elastic fiber assembly. 2017 © The Authors, some rights reserved