Non-invasive imaging reveals conditions that impact distribution and persistence of cells after in vivo administration.

BACKGROUND: Cell-based regenerative medicine therapies are now frequently tested in clinical trials. In many conditions, cell therapies are administered systemically, but there is little understanding of their fate, and adverse events are often under-reported. Currently, it is only possible to assess safety and fate of cell therapies in preclinical studies, specifically by monitoring animals longitudinally using multi-modal imaging approaches. Here, using a suite of in vivo imaging modalities to explore the fate of a range of human and murine cells, we investigate how route of administration, cell type and host immune status affect the fate of administered cells. METHODS: We applied a unique imaging platform combining bioluminescence, optoacoustic and magnetic resonance imaging modalities to assess the safety of different human and murine cell types by following their biodistribution and persistence in mice following administration into the venous or arterial system. RESULTS: Longitudinal imaging analyses (i) suggested that the intra-arterial route may be more hazardous than intravenous administration for certain cell types, (ii) revealed that the potential of a mouse mesenchymal stem/stromal cell (MSC) line to form tumours depended on administration route and mouse strain and (iii) indicated that clinically tested human umbilical cord (hUC)-derived MSCs can transiently and unexpectedly proliferate when administered intravenously to mice. CONCLUSIONS: In order to perform an adequate safety assessment of potential cell-based therapies, a thorough understanding of cell biodistribution and fate post administration is required. The non-invasive imaging platform used here can expose not only the general organ distribution of these therapies, but also a detailed view of their presence within different organs and, importantly, tumourigenic potential. Our observation that the hUC-MSCs but not the human bone marrow (hBM)-derived MSCs persisted for a period in some animals suggests that therapies with these cells should proceed with caution.

Vancomycin Povidone-Iodine Protocol Improves Survivorship of Periprosthetic Joint Infection Treated With Irrigation and Debridement.

BACKGROUND: Irrigation and debridement with modular component and liner exchange (IDLE) is a low morbidity procedure for treatment of periprosthetic joint infection (PJI) with reported failure rates exceeding 50%. Dilute povidone-iodine lavage has been shown to be safe and effective in decreasing acute PJI in primary total joint arthroplasty. Vancomycin powder has also shown to be effective in preventing infection in spine surgery. We hypothesize that a vancomycin povidone-iodine protocol (VIP) used in conjunction with IDLE can increase infection-free survivorship after acute PJI. METHODS: This is a single institution retrospective review of all PJIs treated with IDLE and VIP since March 2014. A consecutive matched control group of patients treated with IDLE for PJI for 2 years prior to March 2014 was also included for analysis. Primary outcome was failure, defined as return to operating room for an infection-related problem. Secondary outcome was chronic suppression with antibiotics at final follow-up. Minimum follow-up was 1 year. RESULTS: A total of 36 patients in the VIP group and 38 patients in control group were identified. In the VIP group, 16.7% (6/36) failed at final follow-up compared to 37% failure rate (14/38) in the control group (P < .05). Three patients in the VIP group were on chronic antibiotic suppression at final follow-up. There were no medical complications secondary to the VIP. CONCLUSIONS: The VIP group demonstrated a significant reduction in reinfection and failure rate following IDLE. The authors believe that a VIP is an effective adjunct for treating PJI with irrigation and debridement.

Reduction of anterior glenohumeral dislocations: a new closed reduction technique.

OBJECTIVE: A new closed reduction technique for anterior glenohumeral dislocations and tuberosity fracture dislocations is introduced. METHODS: Forty-one consecutive patients with an acute anterior glenohumeral dislocation or tuberosity fracture dislocation underwent closed reduction by an orthopaedic surgeon employing this new method. RESULTS: Closed reduction was successful in 88% of patients using the reduction maneuver. Associated fracture with glenohumeral dislocation did not influence the success rate of the reduction maneuver. An assistant was needed in 15% of cases. No complications related to the reduction maneuver were noted amongst the cohort. CONCLUSION: This novel reduction technique is safe demonstrating excellent success rates both for anterior shoulder dislocations and tuberosity fracture-dislocations.

Imaging technologies for monitoring the safety, efficacy and mechanisms of action of cell-based regenerative medicine therapies in models of kidney disease.

The incidence of end stage kidney disease is rising annually and it is now a global public health problem. Current treatment options are dialysis or renal transplantation, which apart from their significant drawbacks in terms of increased morbidity and mortality, are placing an increasing economic burden on society. Cell-based Regenerative Medicine Therapies (RMTs) have shown great promise in rodent models of kidney disease, but clinical translation is hampered due to the lack of adequate safety and efficacy data. Furthermore, the mechanisms whereby the cell-based RMTs ameliorate injury are ill-defined. For instance, it is not always clear if the cells directly replace damaged renal tissue, or whether paracrine effects are more important. Knowledge of the mechanisms responsible for the beneficial effects of cell therapies is crucial because it could lead to the development of safer and more effective RMTs in the future. To address these questions, novel in vivo imaging strategies are needed to monitor the biodistribution of cell-based RMTs and evaluate their beneficial effects on host tissues and organs, as well as any potential adverse effects. In this review we will discuss how state-of-the-art imaging modalities, including bioluminescence, magnetic resonance, nuclear imaging, ultrasound and an emerging imaging technology called multispectral optoacoustic tomography, can be used in combination with various imaging probes to track the fate and biodistribution of cell-based RMTs in rodent models of kidney disease, and evaluate their effect on renal function.

UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis.

The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic ductal adenocarcinoma (PDAC) and other cancers. However, the control of Nrf2 expression and activity in cancer is not fully understood. We previously reported the absence of Keap1, a pivotal regulator of Nrf2, in ∼70% of PDAC cases. Here we describe a novel mechanism whereby the epigenetic regulator UHRF1 suppresses Keap1 protein levels. UHRF1 expression was observed in 20% (5 of 25) of benign pancreatic ducts compared to 86% (114 of 132) of pancreatic tumours, and an inverse relationship between UHRF1 and Keap1 levels in PDAC tumours (n = 124) was apparent (p = 0.002). We also provide evidence that UHRF1-mediated regulation of the Nrf2 pathway contributes to the aggressive behaviour of PDAC. Depletion of UHRF1 from PDAC cells decreased growth and enhanced apoptosis and cell cycle arrest. UHRF1 depletion also led to reduced levels of Nrf2-regulated downstream proteins and was accompanied by heightened oxidative stress, in the form of lower glutathione levels and increased reactive oxygen species. Concomitant depletion of Keap1 and UHRF1 restored Nrf2 levels and reversed cell cycle arrest and the increase in reactive oxygen species. Mechanistically, depletion of UHRF1 reduced global and tumour suppressor promoter methylation in pancreatic cancer cell lines, and KEAP1 gene promoter methylation was reduced in one of three cell lines examined. Thus, methylation of the KEAP1 gene promoter may contribute to the suppression of Keap1 protein levels by UHRF1, although our data suggest that additional mechanisms need to be explored. Finally, we demonstrate that K-Ras drives UHRF1 expression, establishing a novel link between this oncogene and Nrf2-mediated cellular protection. Since UHRF1 over-expression occurs in other cancers, its ability to regulate the Keap1-Nrf2 pathway may be critically important to the malignant behaviour of these cancers.

Revision of Failed Hip Resurfacing and Large Metal-on-Metal Total Hip Arthroplasty Using Dual-Mobility Components.

Revision of metal-on-metal (MoM) total hip arthroplasty (THA) or hip resurfacing is associated with high complication rates. The authors propose dual-mobility components as a surgical option and present short- to mid-term results of MoM hips revised with dual-mobility components. Eighteen consecutive hips that underwent revision of MoM THA or hip resurfacing using dual-mobility components were identified. At final follow-up (mean, 17.5 months), the visual analog scale, modified Harris Hip Score, and SF-12 scores had all improved (P<.05, P<.01, and P<.05, respectively). There were no dislocations or other complications. Revision of failed MoM THA or hip resurfacing using a dual-mobility device is an effective strategy.

Anatomic variant of the inferior lateral cutaneous branch of the radial nerve during the posterior approach to the humerus: a case report.

Iatrogenic injury during the posterior approach to the humerus during operative fixation is not an uncommon occurrence. A comprehensive understanding of the normal anatomy and its variants is of paramount importance in order to avoid such injury. Typically, the inferior lateral cutaneous branch of the radial nerve originates towards the distal end of the humerus at the inferior portion of the spiral groove. Here, we report an important variant of this nerve, which originated significantly more proximal than expected, further emphasizing the importance of identification, dissection and protection of the radial nerve and its major branches.

Arthroscopic treatment of labral tears and concurrent avascular necrosis of the femoral head in young adults.

Avascular necrosis (AVN) of the femoral head is a progressive disease affecting young adults that results in collapse of the femoral head and subsequent degenerative joint disease. Although precollapse stages of AVN can be successfully treated with core decompression, making the diagnosis is often difficult given alternative sources of hip pain in this age group. We propose that arthroscopic-assisted core decompression of the femoral head offers an effective method of addressing AVN of the femoral head as well as coexistent hip disorders in the same operation. This article describes in detail the technique used to perform an arthroscopic-assisted core decompression of the femoral head, and a companion video demonstrating the procedure is included. Our experience suggests that arthroscopic-assisted core decompression can be used as an alternative to open core decompression, while simultaneously addressing other sources of hip pain, with successful outcomes.