Bench to Bedside: Modelling Inflammatory Arthritis.

Inflammatory arthritides such as rheumatoid arthritis are a major cause of disability. Pre-clinical murine models of inflammatory arthritis continue to be invaluable tools with which to identify and validate therapeutic targets and compounds. The models used are well-characterised and, whilst none truly recapitulates the human disease, they are crucial to researchers seeking to identify novel therapeutic targets and to test efficacy during preclinical trials of novel drug candidates. The arthritis parameters recorded during clinical trials and routine clinical patient care have been carefully standardised, allowing comparison between centres, trials, and treatments. Similar standardisation of scoring across in vivo models has not occurred, which makes interpretation of published results, and comparison between arthritis models, challenging. Here, we include a detailed and readily implementable arthritis scoring system, that increases the breadth of arthritis characteristics captured during experimental arthritis and supports responsive and adaptive monitoring of disease progression in murine models of inflammatory arthritis. In addition, we reference the wider ethical and experimental factors researchers should consider during the experimental design phase, with emphasis on the continued importance of replacement, reduction, and refinement of animal usage in arthritis research.

Progressing the care, husbandry and management of ageing mice used in scientific studies.

Driven by the longer lifespans of humans, particularly in Westernised societies, and the need to know more about 'healthy ageing', ageing mice are being used increasingly in scientific research. Many departments and institutes involved with ageing research have developed their own systems to determine intervention points for potential refinements and to identify humane end points. Several good systems are in use, but variations between them could contribute to poor reproducibility of the science achieved. Working with scientific and regulatory communities in the UK, we have reviewed the clinical signs observed in ageing mice and developed recommendations for enhanced monitoring, behaviour assessment, husbandry and veterinary interventions. We advocate that the default time point for enhanced monitoring should be 15 months of age, unless prior information is available. Importantly, the enhanced monitoring should cause no additional harms to the animals. Where a mouse strain is well characterised, the onset of age-related enhanced monitoring may be modified based on knowledge of the onset of an expected age-related clinical sign. In progeroid models where ageing is accelerated, enhanced monitoring may need to be brought forward. Information on the background strain must be considered, as it influences the onset of age-related clinical signs. The range of ageing models currently used means that there will be no 'one-size fits all' solution. Increased awareness of the issues will lead to more refined and consistent husbandry of ageing mice, and application of humane end points will help to reduce the numbers of animals maintained for longer than is scientifically justified.

Outcome of Minimally Invasive Distal Metatarsal Metaphyseal Osteotomy (DMMO) for Lesser Toe Metatarsalgia.

BACKGROUND: As in all fields of surgery, advances in orthopaedic surgery develop toward less invasive surgical techniques. The advantages of smaller incisions include minimal soft tissue dissection allowing procedures to be performed as outpatient surgery. There is the assumption that this leads to a quicker recovery time permitting an earlier return to work. As with any new surgical technique, there is an associated learning curve. This study looked into the outcome of minimally invasive distal metatarsal metaphyseal osteotomy (DMMO) performed at a University Hospital. METHODS: Thirty patients underwent minimally invasive surgery for DMMO. There were 13 males and 17 females with an average age of 60 years. More than one metatarsal osteotomy was done in all cases to facilitate the moulding of the metatarsal head to the correct alignment with full weight bearing. The outcome was measured with the Manchester-Oxford Foot Questionnaire (MOXFQ), patient-reported outcome (PRO), and visual analog scale (VAS) pain score. Minimum follow up was 1 year. RESULTS: At the final review, the average MOXFQ score was an excellent 31. Average improvement in VAS score was 3.5, which ranged from 10 to -7. The VAS was affected by 2 patients whose pain worsened after the operation. There were 4 complications, one each of nonunion, malunion, transfer metatarsalgia, and soft tissue ossification. CONCLUSION: The 3 most common complications of foot and ankle surgery are infection, wound dehiscence, and skin ulcer or blister. Intra-articular metatarsal osteotomies are commonly associated with stiffness due to scarring and consequently hammertoes. By reducing the soft tissue injury in minimally invasive surgery, these risks can be potentially minimized. Minimally invasive DMMO produced good patient satisfaction, functional improvement, and low complication rates in most cases. LEVEL OF EVIDENCE: Level IV, retrospective case series.

NK cell function is markedly impaired in patients with chronic lymphocytic leukaemia but is preserved in patients with small lymphocytic lymphoma.

Chronic lymphocytic leukemia (B-CLL) and small lymphocytic lymphoma (SLL) are part of the same disease classification but are defined by differential distribution of tumor cells. B-CLL is characterized by significant immune suppression and dysregulation but this is not typical of patients with SLL. Natural killer cells (NK) are important mediators of immune function but have been poorly studied in patients with B-CLL/SLL. Here we report for the first time the NK cell phenotype and function in patients with B-CLL and SLL alongside their transcriptional profile. We show for the first time impaired B-CLL NK cell function in a xenograft model with reduced activating receptor expression including NKG2D, DNAM-1 and NCRs in-vitro. Importantly, we show these functional differences are associated with transcriptional downregulation of cytotoxic pathway genes, including activating receptors, adhesion molecules, cytotoxic molecules and intracellular signalling molecules, which remain intact in patients with SLL. In conclusion, NK cell function is markedly influenced by the anatomical site of the tumor in patients with B-CLL/SLL and lymphocytosis leads to marked impairment of NK cell activity. These observations have implications for treatment protocols which seek to preserve immune function by limiting the exposure of NK cells to tumor cells within the peripheral circulation.

Repeated ultraviolet exposure affords the same protection against DNA photodamage and erythema in human skin types II and IV but is associated with faster DNA repair in skin type IV.

We have investigated the photoprotective properties of induced pigmentation using erythema and epidermal DNA photodamage as endpoints. Previously unexposed buttock skin of 12 young, healthy adults (six skin type II and six skin type IV) was exposed daily (Monday to Friday) for 2 wk (days 1-12) with 0.65 minimal erythema dose of solar simulated radiation. Mean skin type IV minimal erythema dose was 1.8-fold greater than for skin type II. Compared to skin type II, solar simulated radiation treatments produced less erythema and more tanning in skin type IV. To assess DNA photodamage, biopsies were taken and prepared for paraffin sections that were stained with a monoclonal antibody for thymine dimers. Thymine dimers were quantified by image analysis. The single exposure data (0.65 and 2 minimal erythema dose) showed that DNA damage was related to physical dose (J per cm2) independent of skin type. Our data also showed that DNA photodamage accumulates in both skin types with repeated, suberythemal doses of solar simulated radiation. On day 12, there were more thymine dimers in skin type IV than skin type II, again indicating that physical rather than biologic dose determines the level of DNA damage. Comparisons on days 12 and 19, however, showed a much greater loss of thymine dimers in skin type IV, suggesting better thymine dimer repair. Protection factors for erythema and thymine dimers were calculated and shown to be about 2 in both skin types. This provides further indirect evidence that DNA is a chromophore for erythema, but also suggests that a tan may not be the major factor in natural photoprotection.