141 research outputs found
Sex-dependent Effects of Developmental Hypoxia on Cardiac Mitochondria from Adult Murine Offspring
Peptide Location Fingerprinting Reveals Tissue Region-Specific Differences in Protein Structures in an Ageing Human Organ
From MDPI via Jisc Publications RouterHistory: accepted 2021-09-14, pub-electronic 2021-09-27Publication status: PublishedFunder: Manchester Institute for Collaborative Research on Ageing; Grant(s): n/aFunder: Walgreens Boots Alliance; Grant(s): n/aIn ageing tissues, long-lived extracellular matrix (ECM) proteins are susceptible to the accumulation of structural damage due to diverse mechanisms including glycation, oxidation and protease cleavage. Peptide location fingerprinting (PLF) is a new mass spectrometry (MS) analysis technique capable of identifying proteins exhibiting structural differences in complex proteomes. PLF applied to published young and aged intervertebral disc (IVD) MS datasets (posterior, lateral and anterior regions of the annulus fibrosus) identified 268 proteins with age-associated structural differences. For several ECM assemblies (collagens I, II and V and aggrecan), these differences were markedly conserved between degeneration-prone (posterior and lateral) and -resistant (anterior) regions. Significant differences in peptide yields, observed within collagen I α2, collagen II α1 and collagen V α1, were located within their triple-helical regions and/or cleaved C-terminal propeptides, indicating potential accumulation of damage and impaired maintenance. Several proteins (collagen V α1, collagen II α1 and aggrecan) also exhibited tissue region (lateral)-specific differences in structure between aged and young samples, suggesting that some ageing mechanisms may act locally within tissues. This study not only reveals possible age-associated differences in ECM protein structures which are tissue-region specific, but also highlights the ability of PLF as a proteomic tool to aid in biomarker discovery
Optimising Large Animal Models of Sustained Atrial Fibrillation: Relevance of the Critical Mass Hypothesis
From Frontiers via Jisc Publications RouterHistory: collection 2021, received 2021-04-04, accepted 2021-05-24, epub 2021-06-15Publication status: PublishedBackground: Large animal models play an important role in our understanding of the pathophysiology of atrial fibrillation (AF). Our aim was to determine whether prospectively collected baseline variables could predict the development of sustained AF in sheep, thereby reducing the number of animals required in future studies. Our hypothesis was that the relationship between atrial dimensions, refractory periods and conduction velocity (otherwise known as the critical mass hypothesis) could be used for the first time to predict the development of sustained AF. Methods: Healthy adult Welsh mountain sheep underwent a baseline electrophysiology study followed by implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 50 Hz bursts of 30 s duration over an 8-week period whilst sheep were monitored for AF. Results: Eighteen sheep completed the protocol, of which 28% developed sustained AF. Logistic regression analysis showed only fibrillation number (calculated using the critical mass hypothesis as the left atrial diameter divided by the product of atrial conduction velocity and effective refractory period) was associated with an increased likelihood of developing sustained AF (Ln Odds Ratio 26.1 [95% confidence intervals 0.2–52.0] p = 0.048). A receiver-operator characteristic curve showed this could be used to predict which sheep developed sustained AF (C-statistic 0.82 [95% confidence intervals 0.59–1.04] p = 0.04). Conclusion: The critical mass hypothesis can be used to predict sustained AF in a tachypaced ovine model. These findings can be used to optimise the design of future studies involving large animals
Paediatric meningitis in the conjugate vaccine era and a novel clinical decision model to predict bacterial aetiology
Objectives
The aims of this study were to assess aetiology and clinical characteristics in childhood meningitis, and develop clinical decision rules to distinguish bacterial meningitis from other similar clinical syndromes.
Methods
Children aged <16 years hospitalised with suspected meningitis/encephalitis were included, and prospectively recruited at 31 UK hospitals. Meningitis was defined as identification of bacteria/viruses from cerebrospinal fluid (CSF) and/or a raised CSF white blood cell count. New clinical decision rules were developed to distinguish bacterial from viral meningitis and those of alternative aetiology.
Results
The cohort included 3002 children (median age 2·4 months); 1101/3002 (36·7%) had meningitis, including 180 bacterial, 423 viral and 280 with no pathogen identified. Enterovirus was the most common pathogen in those aged <6 months and 10–16 years, with Neisseria meningitidis and/or Streptococcus pneumoniae commonest at age 6 months to 9 years. The Bacterial Meningitis Score had a negative predictive value of 95·3%. We developed two clinical decision rules, that could be used either before (sensitivity 82%, specificity 71%) or after lumbar puncture (sensitivity 84%, specificity 93%), to determine risk of bacterial meningitis.
Conclusions
Bacterial meningitis comprised 6% of children with suspected meningitis/encephalitis. Our clinical decision rules provide potential novel approaches to assist with identifying children with bacterial meningitis.
Funding
This study was funded by the Meningitis Research Foundation, Pfizer and the NIHR Programme Grants for Applied Research
Anti-group B Streptococcus antibody in infants born to mothers with human immunodeficiency virus (HIV) infection.
BACKGROUND: HIV-exposed uninfected infants have increased infection risk and mortality compared to HIV-unexposed infants. HIV-exposed infants may be at increased risk of invasive GBS disease due to reduced maternal antibody against GBS. METHODS: We quantified antibodies that bind to the surface of whole Group B Streptococcus (GBS) of serotypes Ia, Ib, II, III and V using novel flow cytometry assays in South African HIV-infected and non-infected mothers and their uninfected infants. Antibody-mediated complement C3b/iC3b deposition onto GBS of these serotypes was also quantified by a novel flow cytometry assay. RESULTS: Geometric mean concentration (GMC) of both surface-binding anti-GBS antibody and antibody-mediated complement deposition onto GBS were reduced in HIV-infected women (n=46) compared to HIV-uninfected women (n=58) for ST1a (surface-binding: 19.3 vs 29.3; p=0.003; complement deposition: 2.9 vs 5.3 SU/mL; p=0.003), STIb (24.9 vs 47.6; p=0.003; 2.6 vs 4.9 SU/mL; p=0.003), STII (19.8 vs 50.0; p=0.001; 3.1 vs 6.2 SU/mL; p=0.001), STIII (27.8 vs 60.1; p=0.001; 2.8 vs 5.3 SU/mL; p=0.001) and STV (121.9 vs 185.6 SU/mL; p<0.001) and in their infants for STIa (complement deposition 9.4 vs 27.0 SU/mL; p=0.02), STIb (13.4 vs 24.5 SU/mL; p=0.02), STII (14.6 vs 42.7 SU/mL; p=0.03), STIII (26.6 vs 62.7 SU/mL; p=0.03) and STV (90.4 vs 165.8 SU/mL; p=0.04). Median transplacental transfer of antibody from HIV-infected women to their infants was reduced compared to HIV-uninfected women for GBS serotypes II (0.42 [IQR 0.22-0.59] vs 1.0 SU/mL [0.42-1.66]; p<0.001), III (0.54 [0.31-1.03] vs 0.95 SU/mL [0.42-3.05], p=0.05) and V (0.51 [0.28-0.79] vs 0.75 SU/mL [0.26-2.9], p=0.04). The differences between infants remained significant at 16 weeks of age. CONCLUSIONS: Maternal HIV infection was associated with lower anti-GBS surface binding antibody concentration and antibody-mediated C3b/iC3b deposition onto GBS bacteria of serotypes Ia, Ib, II, III and V. This may render these infants more susceptible to early and late onset GBS disease
Author Correction: Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia
From Springer Nature via Jisc Publications RouterHistory: registration 2021-11-25, collection 2021-12, pub-electronic 2021-12-08, online 2021-12-08Publication status: Publishe
Response to correspondence on Reproducibility of CRISPR-Cas9 Methods for Generation of Conditional Mouse Alleles: A Multi-Center Evaluation
Spatial disruption and enhanced degradation of collagen with the transition from compensated ventricular hypertrophy to symptomatic congestive heart failure
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