Lactate, N-acetylaspartate, choline and creatine concentrations, and spin-spin relaxation in thalamic and occipito-parietal regions of developing human brain

Previous studies of the brains of normal infants demonstrated lower lactate (Lac)/choline (Cho), Lac/creatine (Cr), and Lac/ N-acetylaspartate (Naa) peak-area ratios in the thalamic region (predominantly gray matter) compared with occipitoparietal (mainly unmyelinated white matter) values. In the present study, thalamic Cho, Cr, and Naa concentrations between 32-42 weeks\u27 gestational plus postnatal age were greater than occipito-parietal: 4.6 +/- 0.8 (mean +/- SE), 10.5 +/- 2.0, and 9.0 +/- 0.7 versus 1.8 +/- 0.6, 5.8 +/- 1.5, and 3.4 +/- 1.1 mmol/kg wet weight, respectively: Lac concentrations were similar, 2.7 +/- 0.6 and 3.3 +/- 1.3 mmol/kg wet weight, respectively. In the thalamic region, Cho and Naa T2s increased, and Cho and Lac concentrations decreased, during development. Lower thalamic Lac peak-area ratios are principally due to higher thalamic concentrations of Cho, Cr, and Naa rather than less Lac. The high thalamic Cho concentration may relate to active myelination; the high thalamic Naa concentration may be due to advanced gray-matter development including active myelination. Lac concentration is higher in neonatal than in adult brain

Beyond Blobs in Percolation Cluster Structure: The Distribution of 3-Blocks at the Percolation Threshold

The incipient infinite cluster appearing at the bond percolation threshold can be decomposed into singly-connected ``links'' and multiply-connected ``blobs.'' Here we decompose blobs into objects known in graph theory as 3-blocks. A 3-block is a graph that cannot be separated into disconnected subgraphs by cutting the graph at 2 or fewer vertices. Clusters, blobs, and 3-blocks are special cases of $k$-blocks with $k=1$, 2, and 3, respectively. We study bond percolation clusters at the percolation threshold on 2-dimensional square lattices and 3-dimensional cubic lattices and, using Monte-Carlo simulations, determine the distribution of the sizes of the 3-blocks into which the blobs are decomposed. We find that the 3-blocks have fractal dimension $d_3=1.2\pm 0.1$ in 2D and $1.15\pm 0.1$ in 3D. These fractal dimensions are significantly smaller than the fractal dimensions of the blobs, making possible more efficient calculation of percolation properties. Additionally, the closeness of the estimated values for $d_3$ in 2D and 3D is consistent with the possibility that $d_3$ is dimension independent. Generalizing the concept of the backbone, we introduce the concept of a ``$k$-bone'', which is the set of all points in a percolation system connected to $k$ disjoint terminal points (or sets of disjoint terminal points) by $k$ disjoint paths. We argue that the fractal dimension of a $k$-bone is equal to the fractal dimension of $k$-blocks, allowing us to discuss the relation between the fractal dimension of $k$-blocks and recent work on path crossing probabilities.Comment: All but first 2 figs. are low resolution and are best viewed when printe

Organotypic sinonasal airway culture systems are predictive of the mucociliary phenotype produced by bronchial airway epithelial cells

Published online: 10 November 2022Differentiated air-liquid interface models are the current standard to assess the mucociliary phenotype using clinically-derived samples in a controlled environment. However, obtaining basal progenitor airway epithelial cells (AEC) from the lungs is invasive and resource-intensive. Hence, we applied a tissue engineering approach to generate organotypic sinonasal AEC (nAEC) epithelia to determine whether they are predictive of bronchial AEC (bAEC) models. Basal progenitor AEC were isolated from healthy participants using a cytological brushing method and differentiated into epithelia on transwells until the mucociliary phenotype was observed. Tissue architecture was assessed using H&E and alcian blue/Verhoeff-Van Gieson staining, immunofluorescence (for cilia via acetylated α-tubulin labelling) and scanning electron microscopy. Differentiation and the formation of tight-junctions were monitored over the culture period (day 1-32) by quantifying trans-epithelial electrical resistance. End point (day 32) tight junction protein expression was assessed using Western blot analysis of ZO-1, Occludin-1 and Claudin-1. Reverse transcription qPCR-array was used to assess immunomodulatory and autophagy-specific transcript profiles. All outcome measures were assessed using R-statistical software. Mucociliary architecture was comparable for nAEC and bAEC-derived cultures, e.g. cell density P = 0.55, epithelial height P = 0.88 and cilia abundance P = 0.41. Trans-epithelial electrical resistance measures were distinct from day 1-14, converged over days 16-32, and were statistically similar over the entire culture period (global P  0.05). Transcript analysis for inflammatory markers demonstrated significant variation between nAEC and bAEC epithelial cultures, and favoured increased abundance in the nAEC model (e.g. TGFβ and IL-1β; P < 0.05). Conversely, the abundance of autophagy-related transcripts were comparable and the range of outcome measures for either model exhibited a considerably more confined uncertainty distribution than those observed for the inflammatory markers. Organotypic air-liquid interface models of nAEC are predictive of outcomes related to barrier function, mucociliary architecture and autophagy gene activity in corresponding bAEC models. However, inflammatory markers exhibited wide variation which may be explained by the sentinel immunological surveillance role of the sinonasal epithelium.Juliette Delhove, Moayed Alawami, Matthew Macowan, Susan E. Lester, Phan T. Nguyen, Hubertus P. A. Jersmann, Paul N. Reynolds and Eugene Rosciol

¿Legalización de la Marihuana recreativa en Colombia, una propuesta de ley viable?

Ensayo II Congreso Internacional COFACESEn el presente ensayo se hará referencia a la posibilidad de legalizar el comercio, la producción y el consumo del cannabis para uso recreativo en adultos en Colombia. Para lograr esto se debe hacer una modificación a la constitución política, y rebatir todos los argumentos que se tienen sobre el consumo de está, ya que es considerada una sustancia, adictiva, nociva y que representa un problema de salud pública.RESUMEN INTRODUCCIÓN DESARROLLO CONCLUSIONES BIBLIOGRAFÍAEspecializaciónEspecialista en Formulación y Evaluación Social y Económica de Proyecto

Pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The prevalence of NAFLD has risen rapidly in parallel with the dramatic rise in obesity and diabetes, and is rapidly becoming the most common cause of liver disease in Western countries. Indeed, NAFLD is now recognized to be the aetiology in many cases previously labelled as cryptogenic cirrhosis

Efficacy of azithromycin in severe asthma from the AMAZES randomised trial

Background:Low-dose azithromycin is an effective therapy for persistent asthma; however, its benefit in severe asthma is not defined. Methods:Participants with severe asthma were identified from the AMAZES randomised, placebo-controlled trial of long-term (48 weeks) low-dose azithromycin. Participants who met one of the following severe asthma definitions were included: 1) Global Initiative for Asthma step 4 treatment with poor asthma control (asthma control questionnaire score ≥0.75); 2) International Severe Asthma Registry definition; 3) American Thoracic Society and European Respiratory Society severe asthma definitions. The rate of total exacerbations was calculated for each subgroup and efficacy of azithromycin compared with placebo. Asthma-related quality of life was assessed before and after treatment along with adverse effects. Results:Azithromycin significantly reduced asthma exacerbations in each group. In patients meeting the American Thoracic Society and European Respiratory Society task force definition of severe asthma (n=211), the rate of exacerbations with treatment was 1.2 per person-year, which was significantly less than for placebo (2.01 per person-year), giving an incidence rate ratio (95% CI) of 0.63 (0.41, 0.96). The proportion of participants experiencing at least one asthma exacerbation was reduced by azithromycin from 64% to 49% (p=0.021). A similar beneficial treatment effect was seen in participants poorly controlled with Global Initiative for Asthma step 4 treatment and those with International Severe Asthma Registry-defined severe asthma. Azithromycin also significantly improved the quality of life in severe asthma (p<0.05). Treatment was well tolerated, with gastrointestinal symptoms being the main adverse effect. Conclusion:Long-term, low-dose azithromycin reduced asthma exacerbations and improved the quality of life in patients with severe asthma, regardless of how this was defined. These data support the addition of azithromycin as a treatment option for patients with severe asthma.Peter G. Gibson, Ian A. Yang, John W. Upham, Paul N. Reynolds, Sandra Hodge, Alan L. James ... et al

Stateful Contracts for Affine Types

Abstract. Affine type systems manage resources by preventing some values from being used more than once. This offers expressiveness and performance benefits, but difficulty arises in interacting with components written in a conventional language whose type system provides no way to maintain the affine type system’s aliasing invariants. We propose and implement a technique that uses behavioral contracts to mediate between code written in an affine language and code in a conventional typed language. We formalize our approach via a typed calculus with both affine-typed and conventionally-typed modules. We show how to preserve the guarantees of both type systems despite both languages being able to call into each other and exchange higher-order values.

Gastroesophageal reflux and antacid therapy in IPF: analysis from the Australia IPF Registry

BACKGROUND AND OBJECTIVE:Gastroesophageal reflux disease (GORD) is highly prevalent in idiopathic pulmonary fibrosis (IPF) and may play a role in its pathogenesis. Recent IPF treatment guidelines suggest that all patients with IPF be considered for antacid therapy. However, emerging evidence suggests that antacid therapy does not improve IPF patient outcomes and may increase the risk of pulmonary infection. METHODS:Using prospectively collected data from the Australian IPF Registry including use of antacid therapy, GORD diagnosis and GORD symptoms, the relationship of these GORD variables to survival and disease progression was assessed. The severity of GORD symptoms using the frequency scale for symptoms of GORD (FSSG) and its relationships to outcomes was also assessed for the first time in an IPF cohort. RESULTS:Five hundred eighty-seven (86%) of the 684 patients in the Australian IPF Registry were eligible for inclusion. Patients were mostly male (69%), aged 71.0 ± 8.5 years with moderate disease (FVC 81.7 ± 21.5%; DLco 48.5 ± 16.4%). Most patients were taking antacids (n = 384; 65%), though fewer had a diagnosis of GORD (n = 243, 41.4%) and typical GORD symptoms were even less common (n = 171, 29.1%). The mean FSSG score was 8.39 ± 7.45 with 43% (n = 251) having a score > 8. Overall, there was no difference in survival or disease progression, regardless of antacid treatment, GORD diagnosis or GORD symptoms. CONCLUSIONS:Neither the use of antacid therapy nor the presence of GORD symptoms affects longer term outcomes in IPF patients. This contributes to the increasing evidence that antacid therapy may not be beneficial in IPF patients and that GORD directed therapy should be considered on an individual basis to treat the symptoms of reflux.Helen E. Jo, Tamera J. Corte, Ian Glaspole, Christopher Grainge, Peter M. A. Hopkins ... Peter A. Bampton ... et al

Quantitative computed tomography predicts outcomes in idiopathic pulmonary fibrosis

First published: 25 July 2022Background and objective: Prediction of disease course in patients with progressive pulmonary fibrosis remains challenging. The purpose of this study was to assess the prognostic value of lung fibrosis extent quantified at computed tomography (CT) using data-driven texture analysis (DTA) in a large cohort of well-characterized patients with idiopathic pulmonary fibrosis (IPF) enrolled in a national registry. Methods: This retrospective analysis included participants in the Australian IPF Registry with available CT between 2007 and 2016. CT scans were analysed using the DTA method to quantify the extent of lung fibrosis. Demographics, longitudinal pulmonary function and quantitative CT metrics were compared using descriptive statistics. Linear mixed models, and Cox analyses adjusted for age, gender, BMI, smoking history and treatment with anti-fibrotics were performed to assess the relationships between baseline DTA, pulmonary function metrics and outcomes. Results: CT scans of 393 participants were analysed, 221 of which had available pulmonary function testing obtained within 90 days of CT. Linear mixed-effect modelling showed that baseline DTA score was significantly associated with annual rate of decline in forced vital capacity and diffusing capacity of carbon monoxide. In multivariable Cox proportional hazard models, greater extent of lung fibrosis was associated with poorer transplant-free survival (hazard ratio [HR] 1.20, p < 0.0001) and progression-free survival (HR 1.14, p < 0.0001). Conclusion: In a multi-centre observational registry of patients with IPF, the extent of fibrotic abnormality on baseline CT quantified using DTA is associated with outcomes independent of pulmonary function.Stephen M. Humphries, John A. Mackintosh, Helen E. Jo, Simon L. F. Walsh, Mario Silva, Lucio Calandriello, Sally Chapman, Samantha Ellis, Ian Glaspole, Nicole Goh, Christopher Grainge, Peter M. A. Hopkins, Gregory J. Keir, Yuben Moodley, Paul N. Reynolds, E. Haydn Walters, David Baraghoshi, Athol U. Wells, David A. Lynch, Tamera J. Cort