The stem cells that safeguard synovial joints in adulthood are undefined. Studies on mesenchymal stromal/stem cells (MSCs) have mainly focused on bone marrow. Here we show that lineage tracing of Gdf5-expressing joint interzone cells identifies in adult mouse synovium an MSC population largely negative for the skeletal stem cell markers Nestin-GFP, Leptin receptor and Gremlin1. Following cartilage injury, Gdf5-lineage cells underpin synovial hyperplasia through proliferation, are recruited to a Nestin-GFPhigh perivascular population, and contribute to cartilage repair. The transcriptional co-factor Yap is upregulated after injury, and its conditional ablation in Gdf5-lineage cells prevents synovial lining hyperplasia and decreases contribution of Gdf5-lineage cells to cartilage repair. Cultured Gdf5-lineage cells exhibit progenitor activity for stable chondrocytes and are able to self-organize three-dimensionally to form a synovial lining-like layer. Finally, human synovial MSCs transduced with Bmp7 display morphogenetic properties by patterning a joint-like organ in vivo. Our findings further the understanding of the skeletal stem/progenitor cells in adult life.
Following platelet adhesion and primary activation at sites of vascular injury, secondary platelet activation is induced by soluble platelet agonists, such as ADP, ATP, thrombin and thromboxane. Zinc ions are also released from platelets and damaged cells and have been shown to act as a platelet agonist. However, the mechanism of zinc-induced platelet activation is not well understood. Here we show that exogenous zinc gains access to the platelet cytosol and induces full platelet aggregation that is dependent on platelet protein tyrosine phosphorylation, PKC and integrin αIIbβ3 activity and is mediated by granule release and secondary signalling. ZnSO4 increased the binding affinity of GpVI, but not integrin α2β1. Low concentrations of ZnSO4 potentiated platelet aggregation by collagen-related peptide (CRP-XL), thrombin and adrenaline. Chelation of intracellular zinc reduced platelet aggregation induced by a number of different agonists, inhibited zinc-induced tyrosine phosphorylation and inhibited platelet activation in whole blood under physiologically relevant flow conditions. Our data are consistent with a transmembrane signalling role for zinc in platelet activation during thrombus formation.
ObjectiveWe aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction.MethodsSynovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap–Tead reporter cells and Yap–Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells.ResultsYap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Pdgfrα-expressing SF during AIA, with predominant expansion of the Gdf5-lineage SF subpopulation descending from the embryonic joint interzone. Gdf5-lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen−), invading cartilage and bone. Conditional ablation of Yap in Gdf5-lineage cells or Pdgfrα-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1β, Jak-dependently activated Yap and induced Yap–Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA.ConclusionsOur findings uncover the IL-6–Yap–Snail signalling axis in pathogenic SF in inflammatory arthritis.
l‐glutamine was approved by the U.S. Food and Drug Administration (FDA) for sickle cell disease (SCD) in 2017. A vaso‐occlusive crisis (VOC) occurs in persons with SCD and is associated with acute pain episodes. This systematic review summarizes the evidence for l‐glutamine in the prevention of VOC and associated pain in patients with SCD. Medline, Embase, and International Pharmaceutical Abstracts were searched for records reporting on l‐glutamine use in persons with SCD. Eligibility criteria identified primary reports of investigations conducted in humans who were administered l‐glutamine, reported on outcomes related to VOC or associated pain, published in English, and were available as full text. All relevant efficacy, safety, participant demographic data, and study method characteristics were extracted and documented. Risk‐of‐bias assessments were conducted using the Risk of Bias in Non‐Randomized Studies‐of Interventions (ROBINS‐I) tool and the revised Cochrane risk‐of‐bias tool for randomized studies. Three studies assessing the effect of exogenous l‐glutamine administration in patients with SCD met eligibility criteria: one prospective nonrandomized controlled study and two prospective randomized controlled trials. Rate of VOC and related hospitalizations were reduced in patients receiving l‐glutamine, although some conflicting results were noted between studies. l‐glutamine was generally well tolerated. Limitations of one or more of the eligible studies included small sample size, nonblinding, and study groups that differed at baseline. l‐glutamine has limited high‐quality evidence supporting its use. Although l‐glutamine is FDA approved for the prevention of frequent episodes of VOC pain, only one randomized controlled trial has strong evidence to support this indication. Based on the results of a systematic review, l‐glutamine may be considered for patients unable to receive hydroxyurea or in addition to hydroxyurea for reduction in VOC and associated pain.
A needs assessment determined Oregon community college staff knowledge of (a) accessible information technology (IT) guidelines, (b) IT-related disability laws, (c) legal obligations regarding Web accessibility, and (d) perceived level of current Web accessibility. Training needs were assessed and training suggestions were solicited. IT staff demonstrated higher levels of Web accessibility guidelines knowledge, and disability/student services staff best understood disability laws. At most schools, knowledge of disability issues and IT were not integrated. Needs identified included provision of: comprehensive resources about accessible Web design, hands-on trainings in accessible technology topics, strategies for fulfilling legal accessibility obligations, training for students and staff regarding their responsibilities in the area of accessible IT, and a Web site accessibility testing service.
Objectives:The objectives of this study were to identify sonographic changes of the endometrium following endometrial biopsy (EB) and correlate these with IVF pregnancy outcomes. Methods: In this prospective controlled study, unselected infertile women were randomised to undergo a Pipelle endometrial biopsy or no procedure during the mid-luteal phase of the cycle directly preceding IVF. Following EB, all participants underwent IVF using standard local protocols. A transvaginal ultrasound scan (TVUS) was performed at oocyte retrieval (OR) and embryo transfer (ET). 2D, 3D and Doppler ultrasound data were acquired (Voluson E8, GE Healthcare). Clinical pregnancy rates were the primary outcome. Student's t-test and Chi 2 statistics were used as appropriate. Research Ethics Committee approval was obtained. Results: A total of 151 women were recruited and randomised: 76 to the biopsy group and 75 to the control group. TVUS data of adequate quality were available for 49 and 50 of these women respectively. Mean age was 33.7±4.0 and 32.8±4.3 years in the treatment and control group, respectively (P=0.21). Both clinical groups were matched for duration of infertility, BMI, AMH, and cycle number (P<0.05). At OR, 19/49 (38.8%) women in the biopsy group and 10/50 (20.0%) control subjects had a triple endometrial pattern (P=0.04). There were no statistically significant differences in other TVUS markers (P>0.05). The clinical pregnancy rates were 31/49(63.3%) and 27/50(54.0%) in the treatment and control group, respectively (P=0.35). Women whom achieved pregnancy were more likely to have a triple pattern endometrium at OR (P=0.035). There were no statistically significant differences in other TVUS markers at ET. Conclusions: In conclusion, a mid-luteal EB may influence endometrial response during the peri-ovulatory phase of a subsequent cycle, as evident by an ultrasound appearance of a triple pattern at the time of OR. Molecular and histological studies are required to provide clues to the underlying mechanisms. Objectives: To compare the performance of oocyte retrieval with and without follicular flushing on the reproductive outcomes in women undergoing IVF. Methods: Only RCTs were included in this review (PROSPERO CRD42016037960); the searches were run in PubMed and Scopus. The evaluation of the risk of bias within each study was structured using the Cochrane risk of bias and the overall quality of the body of evidence was assessed through the GRADE criteria. Results: Ten studies encompassing 910 women were included. There was no evidence of a difference for live birth (RR = 1.04 [0.83, 1.30], I 2 = 0%, 7 RCTs, moderate quality evidence of no effect, downgraded by imprecision); clinical pregnancy (RR = 1.05 [0.80, 1.37], I 2 = 27%, 6 RCTs, moderate quality evidence of no effect, downgraded by imprecision); miscarriage (RR = 1.13 [0.66, 1.95], I 2 = 0%, 5 RCTs, low quality evidence of no effect, downgraded two-levels by imprecision); or for the number of oocytes retrieved (high quality evidence of no effect -Fig 1). We obser...
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