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A study of fatigue behaviour in an Fe-28Al-3Cr-Ce (at.%) based alloy was carried out on compact tension (CT) specimens 5 mm in thickness. The specimens were loaded in tension at 20, 300 and 500 °C with 10 Hz frequency and R in the range from 0.05 to 0.1. The fatigue crack growth rate was measured by the potential method. The number of cycles to failure decreases rapidly with temperature. The fatigue crack propagation rate at RT and elevated temperatures is different. The slope of v(ΔK) curves is much steeper at RT, while it remains almost the same at 300 and 500 °C. The fatigue crack growth rate at 500 °C is nearly two orders higher than at 300 °C. Fractographic analysis showed that at room temperature (RT) fatigue crack growth is controlled by several mechanisms. The main failure mechanism is transgranular cleavage, crack growth by the brittle or ductile striation mechanism is localized only in several areas along the crack front. [Copyright &y& Elsevier]

Aim: To describe the relationship between loss of control events in preschoolers with asthma and persistence of disease., Methods: We reviewed medical records of children <6 years diagnosed with asthma in 2018 to assess loss of control events during three years of follow-up. Asthma persistency was defined by redeem of short-acting β2-agonist or asthma controllers within one year after the end of follow-up. Logistic regression models were applied to analyse the association between loss of control events and persistence of asthma., Results: We included 172 patients (median age 1.8 years), whereof 126 (73.3%) experienced a loss of control event and 87 (50.6%) had asthma one year after the end of follow-up. Any loss of control event was associated with persistence of asthma adjusted for controller treatment at inclusion, prior exacerbations, atopic comorbidity and caesarean section: aOR, 10.9 (95% CI, 3.9-34.6), p < 0.001. This was also significant restricted to events in the first year of follow-up: 3.52 (1.50-8.67), p < 0.01 and among children only experiencing one event: 6.4 (1.7-27.3), p = 0.01., Conclusion: Loss of control events during a 3-year period among preschoolers with asthma are closely related to disease persistency, which may aid clinicians to assess risk of persistent asthma in young children., (© 2022 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Non-adherence to asthma controllers increases morbidity among school-aged children. This study aimed to determine non-adherence risk factors in preschool children with asthma. We investigated 172 children <6 years diagnosed with asthma in 2018 and analyzed baseline characteristics and loss of control events extracted from the medical records for four years following diagnosis. At end of follow-up, 79 children had a prescription of inhaled corticosteroids (ICS) and were included in the analyses. Adherence was assessed in a two-year period through pharmacy claims using percentage of days covered (PDC) analyzed dichotomously with non-adherence defined as PDC < 80% and using adherence ratio (AR) defined as days with medical supply divided by days without. Of the 79 children, 59 (74.7%) were classified as non-adherent. In analyses adjusted for sex, age and exacerbations prior to inclusion, adherence was positively associated with having had a loss of control event requiring a step-up in asthma controller (aAR:2.34 [1.10;4.98], p = 0.03), oral corticosteroids (aAR:2.45 [1.13;5.34], p = 0.026) or redeeming a short-acting b2-agonist prescription (aAR:2.91 [1.26;6.74], p = 0.015). Further, atopic comorbidity was associated with increased adherence (aAR:1.18 [1.01;1.37], p = 0.039), whereas having a first degree relative with asthma was associated with worse adherence (aAR:0.44 [0.23;0.84], p = 0.015). This study found poor adherence to ICS among three quarters of preschool children with asthma. Increasing adherence was associated with atopic comorbidity and loss of control events, whereas lower adherence was associated with atopic predisposition. These findings should be considered to improve adherence in preschool children with asthma.

The vitamin D receptor as well as its ligand have been localized to various immune tissues and cells. These observations have led researchers to hypothesize a role for vitamin D in the immune system. However, a specific role for vitamin D in immunity has yet to be clearly delineated. The work in this report was undertaken to determine if mounting an antibody response is altered in the face of vitamin D-deficiency or when the signaling pathway is eliminated by removal of the nuclear receptor. This investigation provides direct evidence vitamin D is not necessary for producing antibodies, a process paramount for optimal attack against many foreign organisms. The idea that vitamin D plays a significant role in immunity has been proposed repeatedly for many years. To address this important idea we have carried out studies in mice to determine if vitamin D plays a significant role in antibody production. Two animal models were utilized: mice depleted of vitamin D and mice devoid of the vitamin D receptor. Further, a possible role of hypocalcemia resulting from vitamin D deficiency in antibody production was determined. Neither the absence of vitamin D or the vitamin D receptor nor hypocalcemia affected the ability of mice to mount an antibody response to an antigen challenge. Thus, we found no evidence that vitamin D or normal serum calcium is required for this major form of immunity., Competing Interests: Author JS was employed by DiaSorin Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Plum, Blaser, Peter, Prahl, Seeman and DeLuca.)

Genome-wide association studies have consistently shown that the alpha-synuclein locus is significantly associated with Parkinson's disease. The mechanism by which this locus modulates the disease pathology and etiology remains largely under-investigated. This is due to the assumption that SNCA is the only driver of the functional aspects of several single nucleotide polymorphism (SNP) risk-signals at this locus. Recent evidence has shown that the risk associated with the top GWAS-identified variant within this locus is independent of SNCA expression, calling into question the validity of assigning function to the nearest gene, SNCA . In this review, we examine additional genes and risk variants present at the SNCA locus and how they may contribute to Parkinson's disease. Using the SNCA locus as an example, we hope to demonstrate that deeper and detailed functional validations are required for high impact disease-linked variants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Prahl and Coetzee.)

Aim: The aim of this study was to investigate the diagnostic workup in children with asthma hypothesising that objective confirmation of the diagnosis is associated with improved treatment adherence and patient outcomes., Methods: We reviewed medical records of children aged 5-18 years diagnosed with asthma at the Department of Paediatric and Adolescent Medicine, Herlev-Gentofte Hospital, Denmark, in 2018. Objective confirmation of the diagnosis was based on either (1) lung function, (2) bronchodilator response, (3) bronchial hyperresponsiveness and/or (4) elevated FeNO and was associated with treatment adherence (proportion of days covered, PDC), lung function development and exacerbations during a two-year follow-up period., Results: A total of 88 children were included. Asthma was objectively confirmed in 67 (76%). Children with objective confirmation of the diagnosis were more likely to redeem short-acting beta-2-agonist prescriptions: at least once, aOR = 1.3 (95% CI, 1.1-13.1), p = 0.036, and were more adherent to inhaled corticosteroid treatment: PDC>80%, aOR = 10.4 (1.8-201.1), p = 0.033. Further, objective confirmation was associated with improved lung function and reduced bronchodilator response, but not with exacerbations., Conclusion: Objective confirmation of the asthma diagnosis in children is associated with an increased treatment adherence and improved lung function, which underlines the importance of conducting objective tests in the diagnostic workup in paediatric asthma management., (© 2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

As researchers grapple with the mechanisms and implications of alpha-synuclein (α-syn) in neuropathology, it is often forgotten that the function(s) of α-syn in healthy cells remain largely elusive. Previous work has relied on observing α-syn localization in the cell or using knockout mouse models. Here, we address the specific role of α-syn in human dopaminergic neurons by disrupting its gene (SNCA) in the human dopaminergic neuron cell line, LUHMES. SNCA-null cells were able to differentiate grossly normally and showed modest effects on gene expression. The effects on gene expression were monodirectional, resulting primarily in the significant decrease of expression for 401 genes, implicating them as direct, or indirect positive targets of α-syn. Gene ontological analysis of these genes showed enrichment in terms associated with proliferation, differentiation, and synapse activity. These results add to the tapestry of α-syn biological functions. SIGNIFICANCE STATEMENT: The normal functions of α-syn have remained controversial, despite its clear importance in Parkinson's Disease pathology, where it accumulates in Lewy bodies and contributes to neurodegeneration. Its name implies synaptic and nuclear functions, but how it participates at these locations has not been resolved. Via knock-out experiments in dopaminergic neurons, we implicate α-syn as a functional participant in synapse activity and in proliferation/differentiation, the latter being novel and provide insight into α-syn's role in neuronal development., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Genetic risk for complex diseases very rarely reflects only Mendelian-inherited phenotypes where single-gene mutations can be followed in families by linkage analysis. More commonly, a large set of low-penetrance, small effect-size variants combine to confer risk; they are normally revealed in genome-wide association studies (GWAS), which compare large population groups. Whereas Mendelian inheritance points toward disease mechanisms arising from the mutated genes, in the case of GWAS signals, the effector proteins and even general risk mechanism are mostly unknown. Instead, the utility of GWAS currently lies primarily in predictive and diagnostic information. Although an amazing body of GWAS-based knowledge now exists, we advocate for more funding towards the exploration of the fundamental biology in post-GWAS studies; this research will bring us closer to causality and risk gene identification. Using Parkinson's Disease as an example, we ask, how, where, and when do risk loci contribute to disease?, Competing Interests: Competing InterestsThe authors declare no competing interests., (© The Author(s) 2020.)

In genome-wide association studies of complex diseases, many risk polymorphisms are found to lie in non-coding DNA and likely confer risk through allele-dependent differences in gene regulatory elements. However, because distal regulatory elements can alter gene expression at various distances on linear DNA, the identity of relevant genes is unknown for most risk loci. In Parkinson's disease, at least some genetic risk is likely intrinsic to a neuronal subpopulation of cells in the brain regions affected. In order to compare neuron-relevant methods of pairing risk polymorphisms to target genes as well as to further characterize a single-cell model of a neurodegenerative disease, we used the portionally-dopaminergic, neuronal, mesencephalic-derived cell line LUHMES to dissect differentiation-specific mechanisms of gene expression. We compared genome-wide gene expression in undifferentiated and differentiated cells with genome-wide histone H3K27ac and CTCF-bound regions. Whereas promoters and CTCF binding were largely consistent between differentiated and undifferentiated cells, enhancers were mostly unique. We matched the differentiation-specific appearance or disappearance of enhancers with changes in gene expression and identified 22,057 enhancers paired with 6388 differentially expressed genes by proximity. These enhancers are enriched with at least 13 transcription factor response elements, driving a cluster of genes involved in neurogenesis. We show that differentiated LUHMES cells, but not undifferentiated cells, show enrichment for PD-risk SNPs. Candidate genes for these loci are largely unrelated, though a subset is linked to synaptic vesicle cycling and transport, implying that PD-related disruption of these pathways is intrinsic to dopaminergic neurons., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Sarcoidosis patients often have myocardial involvement, however, very few have clinically significant cardiac disease and ventricular tachycardia as the initial presentation is exceedingly rare. We report the case of a middle-aged male with symptomatic but clinically stable ventricular tachycardia. Chest radiograph, computed tomography, and positron emission tomography demonstrated pulmonary and mediastinal abnormalities but no definitive etiology for his arrhythmia. Transthoracic echocardiogram revealed the nonspecific cardiac abnormalities of right ventricular dilation and septal flattening. Cardiac magnetic resonance demonstrated delayed enhancement and akinesia of the right ventricular free and inferior walls--virtually diagnostic of an infiltrative myocardial disease. The diagnosis was then verified with transbronchial biopsy showing noncaseating granulomas consistent with sarcoidosis. In conclusion, this case illustrates an unusual presentation of sarcoidosis and demonstrates how the diagnosis can be made using cardiac magnetic resonance alongside transbronchial biopsy., (Reprint & Copyright © 2013 Association of Military Surgeons of the U.S.)

This report investigates the use of electromagnetic articulography (EMA) to compare basic speech patterns between a patient with traditional dentures to those of a normally dentate person. The goal is to assess the efficacy of traditional dentures in order to generate clinical data and works towards the improvement of denture design. Kinematic and acoustic data were acquired for these two subjects using a variety of repetitive vowel-consonant-vowel tasks. Spatiotemporal parameters indicating dynamic properties of the tongue blade and jaw movements, and timing coordination of the movements between them and with the output acoustic signal, were measured and compared within and between the participants. The results show significant differences in both spatial and temporal patterns and variation between individual tasks within each subject's data, as well as a difference in the two subjects' performance of the same task (cross-subject) for select calculated kinematic and latency parameters. It is concluded that there is more variation in spatiotemporal parameters in speech patterns for patients with dentures than without; in particular, latencies of the tongue blade and jaw movements and acoustic landmarks of the consonants, show strategies of movements timing coordination, typical of the speaker with denture.

Besides its role in regulating serum levels of calcium and phosphorus, 1alpha, 25-dihydroxyvitamin D3 (1,25-(OH)2D3) has potent effects on the immune system and suppresses disease in several animal models of autoimmune disorders including experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. While the amount of 1,25-(OH)2D3 needed to prevent EAE is dependent on the gender of the mouse and amount of calcium available in the diet, the minimum levels of 1,25-(OH)2D3 sufficient to prevent disease cause hypercalcemia. To test if hypercalcemia independent of high levels of 1,25-(OH)2D3 can suppress EAE, we used a 25-hydroxyvitamin D3-1alpha-hydroxylase (1alpha-hydroxylase) knockout mouse strain. Because these 1alpha-hydroxylase knockout mice lack the parathyroid hormone (PTH)-regulated enzyme that synthesizes 1,25-(OH)2D3, hypercalcemia from increased bone turnover was created by continuous administration of PTH without changing the circulating levels of 1,25-(OH)2D3. This PTH-mediated hypercalcemia generated after EAE induction prevented disease in female mice but not male mice. When hypercalcemia was prevented by diet manipulation, PTH administration no longer prevented EAE. We conclude that hypercalcemia is able to prevent EAE after disease induction in female mice.