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Satisfactory osseous tissue integration of the soft tissue graft with bone is the mainstay of healing following surgical reconstruction of the anterior cruciate ligament (ACL). However, tissue remodelling is slow and significantly impacts on quality of life by delaying return to work and sport and accelerating the onset of degenerative diseases such as osteoarthritis. Delivery of multipotent human mesenchymal stem cells (hMSCs) at surgery could enhance osseous tissue integration. We aim to use hMSCs derived from haemarthrosis fluid (HF) (the intra-articular bleed accrued post-trauma) which is aspirated and discarded as clinical waste. With the aim of improving our bioprocessing methodologies for clinical translation we have investigated the effect of low oxygen tension on the derivation and osteogenic potential of this novel HF-hMSC population. Mononuclear cells were isolated from HF aspirated samples and divided for derivation and culture under normal or low oxygen tension. HF-hMSCs were derived from 100 % of cultures under low oxygen tension compared to 71 % for normal oxygen tension; this was coupled with increased CFU-Fs. We investigated the osteogenic potential and cellular health of HF-hMSC populations following ex vivo expansion. HF-hMSC populations showed enhanced matrix mineralisation and cellular health when differentiated under low oxygen tension. This positive effect of low oxygen on osteogenesis and cellular health was reduced with prolonged culture. These data demonstrate that derivation and culture of HF-hMSC populations under low oxygen tension will enable the translation of a cellular therapy for the treatment of broad patient numbers with optimal osteogenic potency and cellular vitality.

Purpose Early knee replacement following arthroscopy may be perceived as a failure of the original treatment and thus a poor use of resources. Factors that may be associated with increased risk of early replacement were explored in this study. Methods All adult patients who underwent planned knee arthroscopy in a national cohort over a 6-month period in 2005 were extracted from the administrative hospital admissions database and linked to determine whether and when a knee replacement occurred on the same knee within the subsequent 5 years. A combination of survival analysis and mixed effect modelling was used to investigate risk factors for replacement. Results There were a total of 20,556 arthroscopies, of which 2,161 (10.6 %) subsequently underwent knee replacement. For patients under 60 years, female gender (62.1 % higher risk, p  < 0.001) and increasing age (12.7 % increased risk per increasing year of age, p  < 0.001) were significant associations for requiring knee replacement, after risk adjusting. Of those aged ≥60, 12.7 % (576) had undergone a replacement at 1 year following arthroscopy. Females (33 % higher risk), increasing age (7.3 % increased risk per increasing year of age, p  < 0.001) and hypertension (1,600 % higher risk, p  < 0.001) were significant predictors. The risk associated with increased age was not proportional for the older age group, with risk declining as time passed from arthroscopy, indicating other factors were influencing progression to knee replacement. Conclusions The predictors of early knee replacement following arthroscopy were female sex, age over 60 years and hypertension, irrespective of type of operation. This work may contribute to national recommendations regarding the provision of arthroscopy for patients over 60 years. Level of evidence III.

The causes of pain after an anterior cruciate ligament (ACL) reconstruction are numerous and may have complex origins. We present an unusual case in which pain after an ACL reconstruction developed secondary to a giant cell tumour of the bone occurring around a fixation screw in the distal femur, with an associated fracture through the femoral tunnel of a previously well-functioning reconstruction. We discuss the aetiology and the treatment of a complex clinical scenario.

A fit and well 36-year-old male presented to his general practitioner with a 10-day history of pain and swelling in his right leg following a football injury. He had sustained blunt trauma to the lateral aspect of his right thigh and described it as a “dead leg”. A clinical diagnosis of deep vein thrombosis (DVT) was made and the patient was advised to attend the DVT outpatient clinic. In line with hospital protocol, he was commenced on low molecular weight heparin (LMWH enoxaparin) as an outpatient pending urgent ultrasound scan. Following his second dose of enoxaparin, he developed worsening pain in his thigh and was admitted for urgent ultrasound scan which showed a large haematoma (15/5 cm) in the thigh (figure 1). A diagnosis of acute compartment syndrome was made and the patient was taken to theatre for an emergency right thigh fasciotomy and decompression of the haematoma.

A fit and well 36-year-old male presented to his general practitioner with a 10-day history of pain and swelling in his right leg following a football injury. He had sustained blunt trauma to the lateral aspect of his right thigh and described it as a “dead leg”. A clinical diagnosis of deep vein thrombosis (DVT) was made and the patient was advised to attend the DVT outpatient clinic. In line with hospital protocol, he was commenced on low molecular weight heparin (LMWH enoxaparin) as an outpatient pending urgent ultrasound scan. Following his second dose of enoxaparin, he developed worsening pain in his thigh and was admitted for urgent ultrasound scan which showed a large haematoma (15/5 cm) in the thigh (figure 1). A diagnosis of acute compartment syndrome was made and the patient was taken to theatre for an emergency right thigh fasciotomy and decompression of the haematoma.

The causes of pain after an anterior cruciate ligament (ACL) reconstruction are numerous and may have complex origins. We present an unusual case in which pain after an ACL reconstruction developed secondary to a giant cell tumour of the bone occurring around a fixation screw in the distal femur, with an associated fracture through the femoral tunnel of a previously well-functioning reconstruction. We discuss the aetiology and the treatment of a complex clinical scenario.

Background Cohesin is a major regulator of three-dimensional genome organization and gene expression. Cohesin associates with DNA and dynamically extrudes a DNA loop, often bringing two cis -regulatory elements physically close together. Extruding cohesin molecules can be stalled or stabilized when they encounter a CTCF insulator protein on DNA, thereby anchoring a DNA loop. However, many enhancer-promoter loops that are bound by cohesin lack CTCF and it is not clear how cohesin is stabilized at or recruited to these sites in the genome. Results Here, we investigated the localization of cohesin with common chromatin regulators and transcription factors on the mouse embryonic stem cell genome. The SP1 and NFYA transcription factors are ubiquitously expressed proteins known to regulate expression of genes associated with a variety of cellular processes, while WDR5 is a ubiquitous core component of multiple chromatin regulatory complexes. We found that cohesin co-bound promoters and enhancers with WDR5, with SP1, or with NFYA in mESCs. Cohesin physically interacted with and colocalized with WDR5, with SP1, or with NFYA on the same molecule of chromatin. Strikingly, depletion of WDR5, SP1, or NFYA caused a decrease in cohesin binding at shared binding sites, while depletion of cohesin did not alter binding of WDR5, SP1, or NFYA on the genome. Conclusions These results indicate that common transcription factors and chromatin regulators stabilize cohesin at specific sites in chromatin and may thereby serve as structural regulators of enhancer-promoter loops via the stabilization of cohesin.

Stress responses are controlled by specialized stress-responsive proteostasis transcription factors that rapidly upregulate protein quality components to re-establish protein homeostasis and safeguard survival. Here we show that the zinc finger transcription factor PQM-1 is crucial for stress survival in response to thermal and oxidative challenges. We provide mechanistic insight into the regulation of PQM-1 during stress that depends on ILS-DAF-16 signaling, as well as phosphorylation on threonine residue 268 that is located within a conserved AKT motif. Our data show that in reproductively mature adults and during well-fed conditions, PQM-1 induction requires DAF-16 and occurs during the recovery period post heat shock. Moreover, PQM-1 co-localizes with DAF-16 in the nucleus during the stress recovery phase. This regulatory dependency on DAF-16 is bypassed under dietary restriction, allowing PQM-1 to promote stress resilience independent of the ILS pathway. During both conditions, PQM-1 is crucial for the upregulation of cytosolic and endoplasmic reticulum stress response genes required for organismal recovery and stress resilience. Our transcriptional and bioinformatic analysis reveals that PQM-1 regulates a distinct set of target genes during the stress recovery phase, suggesting that PQM-1 may be involved in vital secondary wave stress response. Thus, our findings uncover a previously unrecognized mechanism of stress-dependent PQM-1 activation that integrates multiple environmental cues to ensure proteostasis and organismal survival.

Tight control over cell identity gene expression is necessary for proper adult form and function. The opposing activities of Polycomb and trithorax complexes determine the ON/OFF state of targets like the Hox genes. Trithorax encodes a methyltransferase specific to histone H3 lysine-4 (H3K4). However, there is no direct evidence that H3K4 regulates Polycomb group target genes . Here, we demonstrate two key roles for replication-dependent histone H3.2K4 in target control. We find that H3.2K4 antagonizes Polycomb group catalytic activity and that it is required for proper target gene activation. We conclude that H3.2K4 directly regulates expression of Polycomb targets.