NSAIDs inhibit bone healing through the downregulation of TGF-ß3 expression during endochondral ossification.

INTRODUCTION & AIMS: Non Steroidal Anti-Inflammatory drugs (NSAIDs) are potent inhibitors of post-traumatic pain. Several studies have highlighted that NSAIDs could exert a negative effect on bone healing process possibly by down-regulating chondrogenesis and endochondral ossification. The aim of the study is to explore the potential mechanism though which NSAIDs can affect chondrogenesis. M&M: Trabecular bone from the fracture site was isolated from 10 patients suffering from long bone fractures. Mesenchymal Stem Cells (MSCs) were isolated following collagenase digestion and functional assays to assess the effect of diclofenac sodium on chondrogenesis were performed. Gene expression analysis of 84 key molecules was performed. RESULTS: Diclofenac sodium inhibits chondrogenic differentiation and induces a strong inhibition of prostaglandin E-2 (PGE-2) production during chondrogenic differentiation. Replenishment of PGE-2 did not reverse this negative effect. Chondrogenic inhibition is similar in cells treated only for the first week of chondrogenic differentiation or continuously for 3 weeks. Gene analysis shows a strong downregulation of TGF-ß3 and FGF-1 while TNF was upregulated. CONCLUSION: NSAIDs seem to affect the transition phase of mesenchymal stem cells towards functional chondrocytes. This effect is unrelated to the endogenous production of PGE-2. The downregulation of the expression of key molecules like TGF-ß3 seem to be the underlying mechanism.

Anatomical and functional outcomes following switching from aflibercept to ranibizumab in neovascular age-related macular degeneration in Europe: SAFARI study.

BACKGROUND/AIMS: Prospective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity. METHODS: SAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed. RESULTS: One hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of -30.75 µm (95% CI -59.50,-20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0-≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified. CONCLUSION: Switching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.

Inflammatory Profile and Osteogenic Potential of Fracture Haematoma in Humans.

Fracture haematoma forms immediately after fracture and is considered essential for the bone healing process. Its molecular composition has been briefly investigated with our current understanding being based on animal studies. This study aims to analyse the inflammatory cytokine content of fracture haematoma in humans and determine its effect on osteoprogenitor cells. Twenty-three patients were recruited following informed consent. Peripheral blood, fracture haematoma and bone were collected. A Luminex assay on the levels of 34 cytokines was performed and autologous peripheral blood samples served as control. Mesenchymal Stem Cells (MSCs) were isolated following collagenase digestion and functional assays were performed. Gene expression analysis of 84 key osteogenic molecules was performed. Thirty-three inflammatory cytokines were found to be significantly raised in fracture haematoma when compared to peripheral serum (p < 0.05). Amongst the most raised molecules were IL-8, IL-11 and MMP1, -2 and -3. Fracture haematoma did not significantly affect MSC proliferation, but ALP activity and calcium deposition were significantly increased in the MSCs undergoing osteogenic differentiation. Medium supplementations with fracture haematoma resulted in a statistically significant upregulation of osteogenic genes including the EGF, FGF2 and VEGFA. This seems to be the pathway involved in the osteogenic effect of fracture haematoma on bone cells. In conclusion, fracture haematoma is found to be a medium rich in inflammatory and immunomodulatory mediators. At the same time, it contains high levels of anti-inflammatory molecules, regulates osteoclastogenesis, induces angiogenesis and the production of the extracellular matrix. It appears that fracture haematoma does not affect osteoprogenitor cells proliferation as previously thought, but induces an osteogenic phenotype.

Action on neovascular age-related macular degeneration (nAMD): recommendations for management and service provision in the UK hospital eye service.

This report by a group of UK retina specialists and health professionals considers best practice recommendations for the management of sight-threatening neovascular age-related macular degeneration (nAMD), based on collective experience and expertise in routine clinical practice. The authors provide an update for ophthalmologists, allied healthcare professionals and commissioners on practice principles for optimal patient care and service provision standards. Refinement of care pathways for nAMD has improved access to intravitreal anti-vascular endothelial growth factor therapy but there are still variations in care and reported outcomes between clinic centres. Innovative organisational models of service provision allow providers to better match capacity with increasing demand. The authors review the recent NICE guideline for diagnosis and management of AMD, considerations for switching therapies and stopping treatment and need for regular monitoring of non-affected fellow eyes in patients with unilateral nAMD. Actions for delivery of high-quality care and to improve long-term patient outcomes are discussed. Local pathways need to detail nAMD target time to treat, maintenance of review intervals to ensure proactive treatment regimens are delivered on time and appropriate discharge for patients deemed low risk or no longer benefiting from treatment. Actual visual acuity outcomes achieved and maintenance of the level of vision when disease stability is achieved are considered good measures for judging the quality of care in the treatment of patients with nAMD. Robust community referral pathways must be in place for suspected reactivation of choroidal neovascularisation and rapid referral for second eye involvement. Practical considerations for intravitreal injection therapy are outlined.

The cytokines and micro-environment of fracture haematoma: Current evidence.

Fracture haematoma formation is the first and foremost important stage of fracture healing. It orchestrates the inflammatory and cellular processes leading to the formation of callus and the restoration of the continuity of the bone. Evidence suggests that blocking this initial stage could lead to an impairment of the overall bone healing process. This review aims to analyse the existing evidence of molecular contributions to bone healing within fracture haematoma and to determine the potential to modify the molecular response to fracture in the haematoma with the aim of improving union times. A comprehensive search of literature documenting fracture haematoma cytokine content was performed. Suitable papers according to prespecified criteria were identified and analysed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 89 manuscripts formed the basis of this analysis. Low oxygen tension, high acidity, and high calcium characterised initially the fracture haematoma micro-environment. In addition, a number of cytokines have been measured with concentrations significantly higher than those found in peripheral circulation. Growth factors have also been isolated, with an observed increase in bone morphogenetic proteins, platelet-derived growth factor, and transforming growth factor. Although molecular modification of fracture haematoma has been attempted, more research is required to determine a suitable biological response modifier leading to therapeutic effects. The cytokine content of fracture haematoma gives insight into processes occurring in the initial stages of fracture healing. Manipulation of signalling molecules represents a promising pathway to target future therapies aiming to upregulate the osteogenesis.

Aflibercept treatment for neovascular AMD beyond the first year: consensus recommendations by a UK expert roundtable panel, 2017 update.

National recommendations on continued administration of aflibercept solution for injection after the first year of treatment for neovascular age-related macular degeneration (nAMD) have been developed by an expert panel of UK retina specialists, based on clinician experience and treatment outcomes seen in year 2. The 2017 update reiterates that the treatment goal is to maintain or improve the macular structural and functional gains achieved in year 1 while attempting to reduce or minimize the treatment burden, recognizing the need for ongoing treatment. At the end of year 1 (ie, the decision visit at month 11), two treatment options should be considered: do not extend the treatment interval and maintain fixed 8-weekly dosing, or extend the treatment interval using a treat-and-extend regimen up to a maximum 12 weeks. Criteria for considering not extending the treatment interval are persistent macular fluid with stable vision, recurrent fluid, decrease in vision in the presence of fluid, macular hemorrhage, new choroidal neovascularization or any other sign(s) of exudative disease activity considered vision threatening in the opinion of the treating clinician. Treatment extension is recommended for eyes with a dry macula (ie, without macular fluid) and stable vision. Under both options, the treatment interval may be shortened if visual and/or anatomic outcomes deteriorate. Monitoring without treatment may be considered for eyes with a fluid-free macula for a minimum duration of 48 weeks. A patient completing one full year of monitoring without requiring injections may be considered for discharge from clinic. The treatment algorithm incorporates return to fixed 8-weekly dosing for disease reactivation during treatment extension and reinstatement of treatment for disease recurrence following discontinuation or discharge. For bilateral nAMD, either the eye requiring the more intensive treatment or the eye with the better vision, guided by local clinical practice, should determine the retreatment schedule overall.

Safety of Epidural Corticosteroid Injections.

BACKGROUND AND OBJECTIVE: Epidural corticosteroid injections (ESIs) have been used for several decades and now represent the most common intervention performed for the management of back pain with a radicular component. However, several reports have presented devastating complications and adverse effects, which fuelled concerns over the risk versus clinical effectiveness. The authors offer a comprehensive review of the available literature and analyse the data derived from studies and case reports. METHODS: Studies were identified by searching PubMed MEDLINE, Ovid MEDLINE, EMBASE, Scopus, Google Scholar and the Cochrane Library to retrieve all available relevant articles. Publications from the last 20 years (September 1994 to September 2014) were considered for further analysis. Studies selected were English-language original articles publishing results on complications related to the technique used for cervical and lumbar ESIs. The studies had to specify the approach used for injection. All studies that did not fulfil these eligibility criteria were excluded from further analysis. RESULTS: Overall, the available literature supports the view that serious complications following injections of corticosteroid suspensions into the cervical and lumbar epidural space are uncommon, but if they occur they can be devastating. CONCLUSIONS: The true incidence of such complications remains unclear. Direct vascular injury and/or administration of injectates intra-arterially represent a major concern and could account for the vast majority of the adverse events reported. Accurate placement of the needle, use of a non-particulate corticosteroid, live fluoroscopy, digital subtraction angiography, and familiarisation of the operator with contrast patterns on fluoroscopy should minimise these risks. The available literature has several limitations including incomplete documentation, unreported data and inherent bias. Large registries and well-structured observational studies are needed to determine the true incidence of adverse events and address the safety concerns.

Resolution of choroidal neovascularization secondary to punctate inner choroidopathy (PIC) with intravitreal anti-VEGF agents: a case series.

Case series of four patients with CNVM secondary to PIC treated solely with anti VEGF in three cases and in combination with PDT in the other. This series reveals long term follow up (3 months to 28 months) which is currently not described in the literature.

Treatment of chronic hepatitis C in Canadian prison inmates.

PURPOSE: To assess sustained viral response rate and adherence to standard interferon alpha-2b and ribavirin therapy in inmates with chronic hepatitis C (HCV) in Canadian penitentiaries in the Pacific region. METHODS: A retrospective chart review of all inmates with chronic HCV who were treated with standard interferon alpha-2b and ribavirin therapy between March 2001 and October 2002. RESULTS: A total of 90 male inmates were treated. The mean age at time of treatment was 40 years. There were 49 inmates with HCV genotype 1, 11 with HCV genotype 2 and 30 with HCV genotype 3. Eight inmates discontinued treatment because of intolerance to side effects. Nine inmates were stopped by the physician because of nonresponse at an average of 27 weeks. All inmates achieved at least 80% adherence of interferon and ribavirin therapy. The overall sustained virological response (SVR) was 55.9%. SVR was 31.6% for genotype 1, 100% for genotype 2 and 71.4% for genotype 3. CONCLUSION: There was excellent SVR and adherence to treatment with interferon and ribavirin. This experience highlights an important opportunity to treat a population with a high prevalence of HCV-positive persons who may otherwise not seek treatment.