Non-contact low-frequency ultrasound therapy compared with UK standard of care for venous leg ulcers: a single-centre, assessor-blinded, randomised controlled trial

‘Hard-to-heal’ wounds are those which fail to heal with standard therapy in an orderly and timely manner and may warrant the use of advanced treatments such as non-contact low-frequency ultrasound (NLFU) therapy. This evaluator-blinded, single-site, randomised controlled trial, compared NLFU in addition to UK standard of care [SOC: (NLFU + SOC)] three times a week, with SOC alone at least once a week. Patients with chronic venous leg ulcers were eligible to participate. All 36 randomised patients completed treatment (17 NLFU + SOC, 19 SOC), and baseline demographics were comparable between groups. NLFU + SOC patients showed a −47% (SD: 38%) change in wound area; SOC, −39% (38%) change; and difference, −7·4% [95% confidence intervals (CIs) −33·4–18·6; P = 0·565]. The median number of infections per patient was two in both arms of the study and change in quality of life (QoL) scores was not significant (P = 0·490). NLFU + SOC patients reported a substantial mean (SD) reduction in pain score of −14·4 (14·9) points, SOC patients' pain scores reduced by −5·3 (14·8); the difference was −9·1 (P = 0·078). Results demonstrated the importance of high-quality wound care. Outcome measures favoured NLFU + SOC over SOC, but the differences were not statistically significant. A larger sample size and longer follow-up may reveal NLFU-related improvements not identified in this study

Expression of hepatocyte growth factor-like protein in human wound tissue and its biological functionality in human keratinocytes

Hepatocyte growth factor-like protein (HGFl) and its receptor, Recepteur d'Origine Nantais (RON), have been implicated in the development of wound chronicity. HGFl and RON expression was detected in acute wound tissue, chronic wound tissue and in normal skin using quantitative polymerase chain reaction (Q-PCR). HGFl and RON expression was also assessed in chronic healing and chronic non-healing wound tissues using Q-PCR and immunohistochemical staining. Expression was similarly detected in the HaCaT immortalized human keratinocyte cell line using reverse transcription polymerase chain reaction (RT-PCR). rhHGFl was used to assess the impact of this molecule on HaCaT cell functionality using in vitro growth assays and electric cell-substrate impendence sensing (ECIS) migration assays. HGFl and RON transcript expression were significantly increased in acute wound tissue compared to chronic wound tissue and were also elevated, though non-significantly, in comparison to normal skin. Minimal expression was seen in both healing and non-healing chronic wounds. Treatment of HaCaT cells with rhHGFl had no effect on growth rates but did enhance cell migration. This effect was abolished by the addition of a phospholipase C gamma (PLCγ) small molecule inhibitor. The increased expression of HGFl and RON in acute, healing wounds and the pro-migratory effect of HGFl in an in vitro human keratinocyte model, may indicate a role for HGFl in active wound healing

Diagnosing foot infection in diabetes

Infection represents the presence of an inflammatory response and tissue injury due to the interaction of the host with multiplying bacteria. The disease spectrum is a consequence of the variability in these interactions. Diabetes, because of its effects on the vascular, neurological, and immune systems, can compromise the local and systemic response to infection, potentially masking the typical clinical features and hindering diagnosis. The early recognition of infection, particularly osteomyelitis, is paramount in the management of diabetic foot disease. Careful clinical appraisal remains the cornerstone of the assessment. Hematologic, biochemical, and radiological investigations are important aids in assessing the severity of infection. Microbiological assessment, particularly in more severe infection, requires good-quality samples, combined with rapid transport in an appropriate medium and effective communication with the laboratory. A focused, systematic approach to the accurate diagnosis and treatment of infection, combined with careful monitoring, ensures the maintenance of optimal management

Role of HuR in keratinocyte migration and wound healing

Human antigen R (HuR) is a post-translational modifier of mRNAs rich in AU- and U-rich elements. These mRNAs typically code for proteins involved in cell growth and differentiation, signal transduction, transcriptional and translational control, apoptosis, nutrient transport and metabolism. Thus, HuR affects a variety of biological functions and processes. Via its effect on growth and cellular migration, HuR has been shown to enhance clinical progression of a number of cancers. Its role in wound healing remains unknown. In the present study, we evaluated HuR tissue expression in a cohort of chronic healed and non-healed leg ulcers. We also evaluated the effect of HuR knockdown on a number of cellular processes using the HaCaT human keratinocyte cell line. HuR was expressed in greater levels in the ‘chronic healed’ cohort of ulcers, compared to the ‘chronic non-healed’, although this failed to reach statistical significance (p=0.13). HuR knockdown resulted in greater cellular growth, faster progression through the cell cycle and reduced apoptosis. Furthermore, it reduced cellular adhesion rates without affecting migration. We, therefore, concluded that HuR promotes wound healing, primarily through its effect on cellular adhesion. It also slows cellular growth rate via its effect on both cell cycle progression and rates of apoptosis

Pattern of expression of CCN family members Cyr61, CTGF and NOV in human acute and chronic wounds

The CCN family is a group of extremely cysteine-rich proteins that are found within the extracellular matrix and are comprised of cysteine-rich 61 (Cyr61/CCN1), connective tissue growth factor (CTGF/CCN 2) and nephroblastoma overexpressed (NOV/CCN3). Collectively, these proteins stimulate mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration, and regulate angiogenesis, tumour growth, placentation, implantation, embryogenesis and endochondral ossification. Despite such diverse activity, CCN protein function has not been explored in human wounds and healing. In the present study, we investigated the expression of these proteins in samples of normal, acute and chronic wounds using immunohistochemical staining and real-time quantitative RT-PCR. Statistical analysis was performed using the Fisher's exact test. Our results showed that, although all CCN proteins were present in normal, acute and chronic wounds, their expression levels differed, particularly in the case of connective tissue growth factor (CTGF), for which significantly reduced levels were found in chronic wounds compared to acute wounds (p<0.002). Thus, the lack of CTGF in wound tissues may contribute to the abnormal healing of clinical wounds. This suggests that CCN proteins may play an important role in human tissue wound healing. This further suggests that human wound healing may be promoted by manipulating the levels of this protein

Tumour endothelial marker-8 in wound healing and its impact on the proliferation and migration of keratinocytes

Chronic wound management represents a significant burden on healthcare systems and negatively impacts on the quality of patient life. New strategies to understand and identify wounds that will not heal in a normal manner are required. Tumour endothelial marker‑8 (TEM‑8) has been implicated in the wound healing and angiogenesis processes. TEM‑8 expression was examined at the transcript level in a cohort of acute (n=10) and chronic (n=14) wounds and in normal skin (n=10). Protein analysis of TEM‑8 was also undertaken for this cohort using immunohistochemistry (IHC). TEM‑8 impact on keratinocyte cell growth and migration was assessed following TEM‑8 ribozyme transgene transfection of human HaCaT keratinocytes using cell growth and electric cell‑substrate impedance sensing (ECIS)‑based assays. Expression of TEM‑8 was observed to be increased in acute wounds compared to chronic wounds and normal skin using quantitative polymerase chain reaction transcript analysis and IHC staining of wound tissues. Knockdown of TEM‑8 in HaCaT cells, using two independent ribozyme transgenes, resulted in significant decreases in cell growth as well as reductions in the rate of migration assessed using an ECIS‑based system. TEM‑8 may be differentially expressed between wound types and loss of this molecule impacts HaCaT growth and migration, potentially implicating this molecule as a factor involved in successful progression of wound healing

Identification of Cross-Country Skiing Movement Patterns Using Micro-Sensors

This study investigated the potential of micro-sensors for use in the identification of the main movement patterns used in cross-country skiing. Data were collected from four elite international and four Australian athletes in Europe and in Australia using a MinimaxX™ unit containing accelerometer, gyroscope and GPS sensors. Athletes performed four skating techniques and three classical techniques on snow at moderate velocity. Data from a single micro-sensor unit positioned in the centre of the upper back was sufficient to visually identify cyclical movement patterns for each technique. The general patterns for each technique were identified clearly across all athletes while at the same time distinctive characteristics for individual athletes were observed. Differences in speed, snow condition and gradient of terrain were not controlled in this study and these factors could have an effect on the data patterns. Development of algorithms to process the micro-sensor data into kinematic measurements would provide coaches and scientists with a valuable performance analysis tool. Further research is needed to develop such algorithms and to determine whether the patterns are consistent across a range of different speeds, snow conditions and terrain, and for skiers of differing ability

Improving the cost-effectiveness of photographic screening for diabetic macular oedema: a prospective, multi-centre, UK study

Background/aims: Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. Methods: Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. Results: 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England’s scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland’s had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30 000 per quality adjusted life years (QALY) gained, Scotland’s scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England’s scheme, but was not cost effective, at the study’s operating point, compared with Scotland’s. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. Conclusions: Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies

Dressing-related pain in patients with chronic wounds: an international patient perspective

This cross-sectional international survey assessed patients’ perceptions of their wound pain. A total of 2018 patients (57% female) from 15 different countries with a mean age of 68.6 years (SD = 15.4) participated. The wounds were categorised into ten different types with a mean wound duration of 19.6 months (SD = 51.8). For 2018 patients, 3361 dressings/compression systems were being used, with antimicrobials being reported most frequently (n = 605). Frequency of wound-related pain was reported as 32.2%, ‘never’ or ‘rarely’, 31.1%, ‘quite often’ and 36.6%, ‘most’ or ‘all of the time’, with venous and arterial ulcers associated with more frequent pain (P = 0.002). All patients reported that ‘the wound itself’ was the most painful location (n = 1840). When asked if they experienced dressing-related pain, 286 (14.7%) replied ‘most of the time’ and 334 (17.2%) reported pain ‘all of the time’; venous, mixed and arterial ulcers were associated with more frequent pain at dressing change (P , 0<001). Eight hundred and twelve (40.2%) patients reported that it took ,1 hour for the pain to subside after a dressing change, for 449 (22.2%) it took 1–2 hours, for 192 (9.5%) it took 3–5 hours and for 154 (7.6%) patients it took more than 5 hours. Pain intensity was measured using a visual analogue scale (VAS) (0–100) giving a mean score of 44.5 (SD = 30.5, n = 1981). Of the 1141 who reported that they generally took pain relief,21% indicated that they did not feel it was effective. Patients were asked to rate six symptoms associated with living with a chronic wound; ‘pain’ was given the highest mean score of 3.1 (n = 1898). In terms of different types of daily activities, ‘overdoing things’ was associated with the highest mean score (mean = 2.6, n = 1916). During the stages of the dressing change procedure; ‘touching/handling the wound’ was given the highest mean score of 2.9, followed by cleansing and dressing removal (n = 1944). One thousand four hundred and eighty-five (80.15%) patients responded that they liked to be actively involved in their dressing changes, 1141 (58.15%) responded that they were concerned about the long-term side-effects of medication, 790 (40.3%) of patient indicated that the pain at dressing change was the worst part of living with a wound. This study adds substantially to our knowledge of how patients experience wound pain and gives us the opportunity to explore cultural differences in more detail