Background Tendon disease is a significant global healthcare burden whereby patients experience pain and disability; however, the mechanisms that underlie inflammation and pain are poorly understood. ...Herein, we investigated the role of prostaglandins as important mediators of inflammation and pain in tissues and cells derived from patients with tendinopathy. Methods We studied supraspinatus and Achilles tendon biopsies from symptomatic patients with tendinopathy or rupture. Tendon-derived stromal cells (CD45negCD34neg) isolated from tendons were cultured and treated with interleukin-1β (IL-1β) to investigate prostaglandin production. Results Diseased tendon tissues showed increased expression of prostacyclin receptor (IP) and enzymes catalyzing the biosynthesis of prostaglandins, including cyclooxygenase-1 (COX-1), COX-2, prostacyclin synthase (PGIS), and microsomal prostaglandin E synthase-1 (mPGES-1). PGIS co-localized with cells expressing Podoplanin, a marker of stromal fibroblast activation, and the nociceptive neuromodulator NMDAR-1. Treatment with IL-1β induced release of the prostacyclin metabolite 6-keto PGF1α in tendon cells isolated from diseased supraspinatus and Achilles tendons but not in cells from healthy comparator tendons. The same treatment induced profound prostaglandin E2 (PGE2) release in tendon cells derived from patients with supraspinatus tendon tears. Incubation of IL-1β treated diseased tendon cells with selective mPGES-1 inhibitor Compound III, reduced PGE2, and simultaneously increased 6-keto PGF1α production. Conversely, COX blockade with naproxen or NS-398 inhibited both PGE2 and 6-keto PGF1α production. Tendon biopsies from patients in whom symptoms had resolved showed increased PTGIS compared to biopsies from patients with persistent tendinopathy. Conclusions Our results suggest that PGE2 sustains inflammation and pain while prostacyclin may have a protective role in human tendon disease.
The aim of this study was to determine the long-term risk of undergoing knee arthroplasty in a cohort of patients with meniscal tears who had undergone arthroscopic partial meniscectomy (APM).
A ...retrospective national cohort of patients with a history of isolated APM was identified over a 20-year period. Patients with prior surgery to the same knee were excluded. The primary outcome was knee arthroplasty. Hazard ratios (HRs) were adjusted by patient age, sex, year of APM, Charlson comorbidity index, regional deprivation, rurality, and ethnicity. Risk of arthroplasty in the index knee was compared with the patient's contralateral knee (with
without a history of APM). A total of 834 393 patients were included (mean age 50 years; 37% female).
Of those with at least 15 years of follow-up, 13.49% (16 256/120 493; 95% confidence interval (CI) 13.30 to 13.69) underwent subsequent arthroplasty within this time. In women, 22.07% (95% CI 21.64 to 22.51) underwent arthroplasty within 15 years compared with 9.91% of men (95% CI 9.71 to 10.12), corresponding to a risk ratio (RR) of 2.23 (95% CI 2.16 to 2.29). Relative to the general population, patients with a history of APM were over ten times more likely (RR 10.27; 95% CI 10.07 to 10.47) to undergo arthroplasty rising to almost 40 times more likely (RR 39.62; 95% CI 27.68 to 56.70) at a younger age (30 to 39 years). In patients with a history of APM in only one knee, the risk of arthroplasty in that knee was greatly elevated in comparison with the contralateral knee (no APM; HR 2.99; 95% CI 2.95 to 3.02).
Patients developing a meniscal tear undergoing APM are at greater risk of knee arthroplasty than the general population. This risk is three-times greater in the patient's affected knee than in the contralateral knee. Women in the cohort were at double the risk of progressing to knee arthroplasty compared with men. These important new reference data will inform shared decision making and enhance approaches to treatment, prevention, and clinical surveillance. Cite this article:
2019;101-B:1071-1080.
We present the stable carbon and nitrogen isotope compositions of 204 plants and 99 soils from South Africa's Fynbos and Succulent Karoo biomes, from which we assess variability in δ13C and δ15N ...within and between the biomes. Higher foliar δ13C in the Succulent Karoo (−22.4 ± 4.7‰) primarily reflects a greater abundance of CAM photosynthesis relative to Fynbos (−25.7 ± 3.5‰). For C3 plants within the Fynbos Biome, there is no statistically significant relationship between δ13C and climate, suggesting that within the present sampling framework, local-scale variability masks expected climatic controls on C3 plant δ13C. Soil and foliar δ15N are highly variable, but foliar δ15N is significantly higher in the Succulent Karoo (7.7 ± 3.9‰) compared to the Fynbos (4.4 ± 3.3‰). Soil and foliar δ15N correlate, with soils 3 ± 1‰ more enriched in 15N. Both soil and foliar δ15N show stronger correlations with climate than δ13C, and they accord with the previously observed tendency for higher δ15N with greater aridity. The relationship between δ15N and mean annual rainfall is, however, relatively steep (2.4 ± 0.6‰ per 100 mm rainfall), potentially implying additional controls on δ15N variability. These data provide a benchmarking of contemporary isotopic variability, anticipated to support future archaeological, palaeoenvironmental and C and N cycling research.
•Foliar and soil δ13C distinct between biomes•Foliar δ13C for C3 plants in the Fynbos biome is un-correlated with climate•Foliar δ15N is highly variable at the plot scale•Plot average soil and foliar δ15N negatively correlated with rainfall•Foliar isotopic signatures are mirrored in associated soils
•Systematic study of leaf wax n-alkanes in an arid environment.•Succulent plants can provide a very high n-alkane yield.•n-Alkane distributions were variable but biomes were on average ...distinct.•Distribution changes reflect both climate response and turnover of plant type.•High yield from succulents has implications for compound specific isotope analysis.
The environmental controls on leaf wax n-alkane distributions and associated interpretation of such distributions in geological archives have long remained rather enigmatic. Studies of contemporary vegetation often conflate changing environmental conditions and species differences between biomes, making it difficult to assess the extent to which variation is driven by plant adaptation to prevailing environmental conditions and/or more fixed chemotaxonomic patterns. We present a case study of arid and semi-arid regions of South Africa that considers these issues. We anticipate that such conditions may impart strong controls upon leaf wax synthesis.
Leaf wax n-alkane data from 215 plants and 93 soils from the Succulent Karoo and Fynbos biomes of South Africa revealed yield and distributions to be highly variable. While many plants exhibited concentrations comparable with previous reports, several succulent plants produced n-alkane yield up to 100× the modal n-alkane concentration for their biome. The data demonstrate that, on average, leaf wax n-alkane distributions in the Succulent Karoo are different from those of the Fynbos biome, with the former associated with longer maximum chain length, less dispersed distributions and stronger odd numbered chain length preference. The patterns were closely mirrored in the soils. Average chain length was weakly correlated with climate and this is interpreted to be a function of multiple factors. We hypothesise that a key control is the shifting proportion of plant functional type between biomes, with a greater abundance of succulent growth forms in the more arid Succulent Karoo (which tended to produce longer and less dispersed n-alkane chain length distributions), differentiating this biome from the Fynbos, in which woody shrubs are more dominant. Inter-biome variability was also apparent, with some same taxonomic or functional groups common to both biomes tending to produce longer chain length n-alkane distributions under more arid conditions. There was, however, considerable individual plant variability and we observed both insensitivity to environmental conditions (i.e. consistent n-alkane distributions) and marked variability in chain length distributions.
A key finding is the high yield of n-alkanes from multiple succulent plants, many of which use the CAM photosynthetic pathway. Compound specific δ13C/δD analyses (e.g. estimates of C3 and C4 biomass) for regions with potential succulent plant contributions should therefore be carried out cautiously.
Abstract
Objectives
Osteoarthritis (OA) is increasingly recognised as a whole joint disease, with an important role for synovium. However, the repertoire of immune cells and fibroblasts that ...constitute OA synovium remains understudied. This study aims to characterise the cellular composition of advanced OA synovium and to explore potential correlations between different cell types and patient demographics or clinical scores.
Methods
Synovium, collected from 10 patients with advanced OA during total knee replacement surgery, was collagenase-digested, and cells were stained for flow cytometry analysis. Formalin-fixed paraffin-embedded synovium was sectioned, stained with immunofluorescence, and imaged using the multiplex Cell DIVE platform. Patient demographics and clinical scores were also collected.
Results
The proportion of immune cells in OA synovium varied between patients (8–38% of all cells). Macrophages and T cells were the dominant immune cell populations, together representing 76% of immune cells. Age positively correlated with the proportion of macrophages, and negatively correlated with T cells. CCR6+ T cells were found in 6/10 patients; these patients had a higher mean Kellgren-Lawrence grade across the three knee compartments. Immunofluorescence staining showed that macrophages were present in the lining as well as distributed throughout the sublining, while T and B cells were mainly localised near vessels in the sublining. Fibroblast subsets (CD45−PDPN+) based on the expression of CD34/CD90 or FAP/CD90 were identified in all patient samples, and some populations correlate with the percentage of immune cells or clinical scores. Immunofluorescence staining showed that FAP expression was particularly strong in the lining layer, but also present throughout the sublining layer. CD90 expression was exclusively found around vessels in the sublining, while CD34 was mostly found in the sublining but also occasionally in the lining layer.
Conclusions
There are significant differences in the relative proportions and subsets of immune cells in OA synovium; exploratory correlative analyses suggest that these differences might be correlated with age, clinical scores, or fibroblast subsets. Additional studies are required to understand how different cell types affect OA pathobiology, and if the presence or proportion of cell subsets relates to disease phenotypes.
Australian State governments have maintained overseas trade and diplomatic engagements, a practice known as 'paradiplomacy' for well over a century. In 2020 the Federal Government abruptly moved to ...restrict the practice, establishing oversight and creating a Ministerial veto power. Why did this sudden shift occur? This article reviews the under-studied history and contemporary practice of paradiplomacy in Australia. It explains and analyses the 2020 shift as a response to fears of weaponised interdependence within an evolving strategic environment. The article shows the legislation has advantages yet is insufficient to resolve the political challenges and reflects an unprecedented desire for control. The article then argues the lack of scholarship on paradiplomacy reflects a prevailing 'methodological nationalism' and argues this should be re-considered to help think through how the new strategic environment is shaping Australia's national institutions and policies.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the effects of gestational age (GA) and postnatal age on skin barrier integrity by comparing premature infants at full-term corrected age with infants born at term.
Parallel comparison of ...chest skin in 36 premature infants with 39 full-term infants using daily measures of transepidermal water loss (TEWL), skin pH, erythema and rash, over 2 weeks.
Chest skin pH was significantly lower for premature infants, indicating that acid mantle formation had occurred in the premature versus full-term infants. Chest TEWL was significantly higher for premature versus full-term infants over 2 weeks, suggesting that even 7-8 weeks after birth, skin integrity is poorer in premature infants.
Skin barrier properties of premature infants at adjusted full-term age differ from full-term infants, suggesting that epidermal barrier development depends on GA and time from birth. These maturational differences may influence premature infant response to topical agents.
Background:
Platelet-rich plasma (PRP) has been proposed to augment tendon healing through improving tissue structure during the initial repair phase.
Purpose:
To investigate both the clinical and ...tissue effects of the coapplication of PRP injection with arthroscopic acromioplasty (AA) in patients with chronic rotator cuff tendinopathy.
Design:
Randomized controlled trial; Level of evidence, 1.
Methods:
The study comprised 60 randomized patients diagnosed with rotator cuff tendinopathy (55% women) aged between 35 and 75 years. Patients were randomized to AA alone or in combination with an injection of autologous PRP into the subacromial bursa (AA + PRP). Efficacy of treatment was assessed by analysis of patient-reported outcomes up to 2 years after treatment (Oxford Shoulder Score OSS) and by analysis of tendon biopsy specimens taken 12 weeks after treatment.
Results:
There was no significant difference in the OSS between AA alone and AA + PRP at any time point in the study. From 12 weeks onward, there was a significant increase in the OSS for both groups compared with their baseline scores (P < .001). Bonar scoring determined no significant change in tissue structure with the coapplication of PRP compared with surgery alone. The number of blood vessels and tendon cellularity were significantly decreased in tissue biopsy specimens taken from PRP-treated patients. The expression of p53-positive apoptotic cells increased after AA + PRP but decreased after AA alone.
Conclusion:
Arthroscopic acromioplasty significantly improves long-term clinical outcomes up to 2 years. The coapplication of PRP did not affect clinical outcomes. PRP significantly alters the tissue characteristics in tendons after surgery with reduced cellularity and vascularity and increased levels of apoptosis.
Clinical Relevance:
The coapplication of PRP did not improve clinical outcomes and may have potential deleterious effects on healing tendons.
Registry Number:
ISRCTN 10464365
Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA ...pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and synovial fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptor A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with anti-IL-17A monoclonal antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Future studies should further investigate the role of IL-17A in the OA joint to establish whether anti-IL-17 treatment could be a potential therapeutic option in OA patients with an inflammatory phenotype.
PDF
