Early events in the human airways determining whether exposure to Mycobacterium tuberculosis (Mtb) results in acquisition of infection are poorly understood. Epithelial cells are the dominant cell ...type in the lungs, but little is known about their role in tuberculosis. We hypothesised that human primary airway epithelial cells are part of the first line of defense against Mtb-infection and contribute to the protective host response in the human respiratory tract. We modelled these early airway-interactions with human primary bronchial epithelial cells (PBECs) and alveolar macrophages. By combining in vitro infection and transwell co-culture models with a global transcriptomic approach, we identified PBECs to be inert to direct Mtb-infection, yet to be potent responders within an Mtb-activated immune network, mediated by IL1β and type I interferon (IFN). Activation of PBECs by Mtb-infected alveolar macrophages and monocytes increased expression of known and novel antimycobacterial peptides, defensins and S100-family members and epithelial-myeloid interactions further shaped the immunological environment during Mtb-infection by promoting neutrophil influx. This is the first in depth analysis of the primary epithelial response to infection and offers new insights into their emerging role in tuberculosis through complementing and amplifying responses to Mtb.
Myocardial deformation is a key to clinical decision-making. Feature-tracking cardiovascular magnetic resonance (FT-CMR) provides quantification of motion and strain using standard steady-state in ...free-precession (SSFP) imaging, which is part of a routine CMR left ventricular (LV) study protocol. An accepted definition of a normal range is essential if this technique is to enter the clinical arena.
One hundred healthy individuals, with 10 men and women in each of 5 age deciles from 20 to 70 years, without a history of cardiovascular disease, diabetes, renal impairment, or family history of cardiovascular disease, and with a normal stress echocardiogram, underwent FT-CMR assessment of LV myocardial strain and strain rate using SSFP cines.Peak systolic longitudinal strain (Ell) was -21.3 ± 4.8%, peak systolic circumferential strain (Ecc) was -26.1 ± 3.8%, and peak systolic radial strain (Err) was 39.8 ± 8.3%. On Bland-Altman analyses, peak systolic Ecc had the best inter-observer agreement (bias 0.63 ± 1.29% and 95% CI -1.90 to 3.16) and peak systolic Err the least inter-observer agreement (bias 0.13 ± 6.41 and 95% CI -12.44 to 12.71). There was an increase in the magnitude of peak systolic Ecc with advancing age, which was greatest in subjects over the age of 50 years (R(2) = 0.11, P = 0.003). There were significant gender differences (P < 0.001) in peak systolic Ell, with a greater magnitude of deformation in females (-22.7%) than in males (-19.3%).
Normal values for myocardial strain measurements using FT-CMR are provided. All circumferential and longitudinal based variables had excellent intra- and inter-observer variability.
ABSTRACT
Reconstructions of palaeo‐sea level are vital for predicting future sea level change and constraining palaeo‐ice sheet reconstructions, as well as being useful for a wide array of ...applications across Quaternary Science. Previous reconstructions of the palaeo‐sea level of Britain and Ireland relied on a circular tuning of glacio‐isostatic models: input ice sheet thicknesses and extents were iteratively altered to fit relative sea level data. Here we break that circularity by utilizing new data from the BRITICE‐CHRONO project, which constrains the position of the British–Irish ice sheet margin through time, and we compare derived glacio‐isostatic modelling to the rich relative sea level record. We test a combination of plausible ice thickness scenarios which account for the uncertainty of ice margin position over the North Sea, demonstrating the region where regional sea level data could distinguish between different glaciation scenarios. Our optimal reconstruction is then combined with several global‐scale reconstructions. As the signal of the British–Irish Ice Sheet is constrained, we demonstrate how the relative sea level record of Britain and Ireland can be used to test reconstructions of far‐field ice sheets (e.g. Antarctica, Eurasia and the Laurentide). The derived palaeo‐topography data are likely to be useful for multiple disciplines. Finally, our improved method of sea level reconstruction impacts predictions of contemporary vertical land motion.
Summary
Background
We investigated whether metformin prevents tamoxifen‐induced endometrial changes and insulin resistance (IR) after a diagnosis of breast cancer.
Methods
This was a single‐centre, ...randomized, double‐blind, placebo‐controlled, parallel group trial. Postmenopausal women with hormone receptor‐positive breast cancer taking tamoxifen were randomly allocated to metformin 850 mg or identical placebo, twice daily, for 52 weeks. Outcome measures included double endometrial thickness (ET) measured by transvaginal ultrasound, fasting insulin, glucose and IR estimated by the homeostasis model of assessment (HOMA‐IR).
Results
A total of 112 women were screened and 102 randomized. Results are presented as median (range). The 101 women who took at least one dose of medication were aged 56 (43‐72) years, with 5(0.5‐28) years postmenopause, and had taken tamoxifen for 28.9 (0‐367.4) weeks. The baseline ET was 2.9 mm (1.4‐21.9) for the placebo group (n = 52) and 2.5 mm (1.3‐14.8) for the metformin group (n = 50). At 52 weeks, the median ET was statistically significantly lower for the metformin (n = 36) than for the placebo group (n = 45) (2.3 mm (1.4‐7.8) vs 3.0 (1.2‐11.3); P = 0.05). 13.3% allocated to placebo had an ET greater than 4 mm vs 5.7% for metformin (P = 0.26). There was no endometrial atypia or cancer. Compared with placebo, metformin resulted in significantly greater baseline‐adjusted reductions in weight (P < 0.001), waist circumference (0.03) and HOMA‐IR (P < 0.001).
Conclusions
Metformin appears to inhibit tamoxifen‐induced endometrial changes and has favourable metabolic effects. Further research into the adjuvant use of metformin after breast cancer and to prevent EH and cancer is warranted.
There is a robust inverse graded association between glomerular filtration rate (GFR) and cardiovascular risk, but proof of causality is lacking. Emerging data suggest living kidney donation may be ...associated with increased cardiovascular mortality although the mechanisms are unclear. We hypothesized that the reduction in GFR in living kidney donors is associated with increased left ventricular mass, impaired left ventricular function, and increased aortic stiffness. This was a multicenter, parallel group, blinded end point study of living kidney donors and healthy controls (n=124), conducted from March 2011 to August 2014. The primary outcome was a change in left ventricular mass assessed by magnetic resonance imaging (baseline to 12 months). At 12 months, the decrease in isotopic GFR in donors was -30±12 mL/min/1.73m(2). In donors compared with controls, there were significant increases in left ventricular mass (+7±10 versus -3±8 g; P<0.001) and mass:volume ratio (+0.06±0.12 versus -0.01±0.09 g/mL; P<0.01), whereas aortic distensibility (-0.29±1.38 versus +0.28±0.79×10(-3) mm Hg(-1); P=0.03) and global circumferential strain decreased (-1.1±3.8 versus +0.4±2.4%; P=0.04). Donors had greater risks of developing detectable highly sensitive troponin T (odds ratio, 16.2 95% confidence interval, 2.6-100.1; P<0.01) and microalbuminuria (odds ratio, 3.8 95% confidence interval, 1.1-12.8; P=0.04). Serum uric acid, parathyroid hormone, fibroblast growth factor-23, and high-sensitivity C-reactive protein all increased significantly. There were no changes in ambulatory blood pressure. Change in GFR was independently associated with change in left ventricular mass (R(2)=0.28; P=0.01). These findings suggest that reduced GFR should be regarded as an independent causative cardiovascular risk factor.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01028703.
Fibroblastic foci represent the cardinal pathogenic lesion in idiopathic pulmonary fibrosis (IPF) and comprise activated fibroblasts and myofibroblasts, the key effector cells responsible for ...dysregulated extracellular matrix deposition in multiple fibrotic conditions. The aim of this study was to define the major transcriptional programmes involved in fibrogenesis in IPF by profiling unmanipulated myofibroblasts within fibrotic foci in situ by laser capture microdissection.
The challenges associated with deriving gene calls from low amounts of RNA and the absence of a meaningful comparator cell type were overcome by adopting novel data mining strategies and by using weighted gene co-expression network analysis (WGCNA), as well as an
-based approach to identify transcriptional signatures, which correlate with fibrillar collagen gene expression.
WGCNA identified prominent clusters of genes associated with cell cycle, inflammation/differentiation, translation and cytoskeleton/cell adhesion. Collagen eigengene analysis revealed that transforming growth factor β1 (TGF-β1), RhoA kinase and the TSC2/RHEB axis formed major signalling clusters associated with collagen gene expression. Functional studies using CRISPR-Cas9 gene-edited cells demonstrated a key role for the TSC2/RHEB axis in regulating TGF-β1-induced mechanistic target of rapamycin complex 1 activation and collagen I deposition in mesenchymal cells reflecting IPF and other disease settings, including cancer-associated fibroblasts.
These data provide strong support for the human tissue-based and bioinformatics approaches adopted to identify critical transcriptional nodes associated with the key pathogenic cell responsible for fibrogenesis in situ and further identify the TSC2/RHEB axis as a potential novel target for interfering with excessive matrix deposition in IPF and other fibrotic conditions.
To compare changes in gait kinematics and walking speed 24 months after conventional (C-MLS) and minimally invasive (MI-MLS) multilevel surgery for children with diplegic cerebral palsy (CP).
A ...retrospective analysis of 19 children following C-MLS, with mean age at surgery of 12 years five months (seven years ten months to 15 years 11 months), and 36 children following MI-MLS, with mean age at surgery of ten years seven months (seven years one month to 14 years ten months), was performed. The Gait Profile Score (GPS) and walking speed were collected preoperatively and six, 12 and 24 months postoperatively. Type and frequency of procedures as part of MLS, surgical adverse events, and subsequent surgery were recorded.
In both groups, GPS improved from the preoperative gait analysis to the six-month assessment with maintenance at 12 and 24 months postoperatively. While reduced at six months in both groups, walking speed returned to preoperative speed by 12 months. The overall pattern of change in GPS and walking speed was similar over time following C-MLS and MI-MLS. There was a median of ten procedures per child as part of both C-MLS (interquartile range (IQR) 8.0 to 11.0) and MI-MLS (IQR 7.8 to 11.0). Surgical adverse events occurred in seven (37%) and 13 (36%) children, with four (21%) and 13 (36%) patients requiring subsequent surgery following C-MLS and MI-MLS, respectively.
This study indicates similar improvements in gait kinematics and walking speed 24 months after C-MLS and MI-MLS for children with diplegic CP. Cite this article:
2021;103-B(1):192-197.
The introduction of invasive Spartina grasses (C4 plant) into previously C3‐dominated saltmarshes of western Europe complicates the reconstruction of past relative sea‐level (RSL) using sediment ...geochemistry‐based approaches. We apply a Bayesian mixing model (SIAR – Stable Isotope Analysis in R) to identify organic carbon (Corg) source contributions to saltmarsh sediment and correct δ13C values for the contaminating influence of C4 vegetation. We first assess the performance of SIAR by simulation, producing synthetic saltmarsh sediment samples with variable contributions from three organic matter sources (C3 plants, C4 plants and particulate organic matter (POM)) and then comparing these known contributions to those determined by SIAR. For each source type, SIAR 68% credible intervals include true source contribution in 70% of calculations (n = 60) and all three sources were incorporated within credible intervals for 45% of sediment samples (n = 20). SIAR improves the mean absolute error of source contribution predictions by up to 26% compared to a conventional ternary mixing model approach. We then apply SIAR to real sediment samples recovered along transects spanning the intertidal zones at two contrasting saltmarshes in the inner and outer Shannon estuary, western Ireland. SIAR identified decreasing Corg contributions from POM with increasing elevation in the intertidal zone, reflecting differences in tidal inundation with height. Sediment δ13C values across the intertidal zones varied by 4.4‰ in the inner estuary and 9.4‰ in the outer estuary. Removal of the invasive C4 signatures reduced these differences to 0.5‰ and to 2.4‰ in the inner and outer estuary, respectively, with the larger range due to increased deposition of marine POM. Although subtle, when used in combination with additional proxies, these geochemical gradients can assist in RSL reconstruction. This will be most effective when POM from marine sources is a significant carbon source.
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