Proteomics in chronic wound research : potentials in healing and health

Chronic wounds, such as venous and diabetic leg ulcers, represent a significant health and financial burden to individuals and healthcare systems. In worst case scenarios this condition may require the amputation of an affected limb, with significant impact on patient quality of life and health. Presently there are no clinical biochemical analyses used in the diagnosis and management of this condition; moreover few biochemical therapies are accessible to patients. This presents a significant challenge in the efficient and efficacious treatment of chronic wounds by medical practitioners. A number of protein-centric investigations have analysed the wound environment and implicated a suite of molecular species predicted to be involved in the initiation or perpetuation of the condition. However, comprehensive proteomic investigation is yet to be engaged in the analysis of chronic wounds for the identification of molecular diagnostic/prognostic markers of healing or therapeutic targets. This review examines clinical chronic wound research and recommends a path towards proteomic investigation for the discovery of medically significant targets. Additionally, the supplementary documents associated with this review provide the first comprehensive summary of protein-centric, small molecule and elemental analyses in clinical chronic wound research.

Predicting the likelihood of non-healing : a venous leg ulcer risk assessment tool

This project developed, validated and tested reliability of a risk assessment tool to predict the risk of failure to heal of patients with venous leg ulcers within 24 weeks. The risk assessment tool will allow clinicians to be able to determine realistic outcomes for their patients, promote early healing and potentially avoid weeks of inappropriate therapy. The tool will also assist in addressing specific risk factors and guide decisions on early, alternative, tailored interventions.

The Leg Club model in the Australian context

Leg Clubs are an innovative approach to the holistic treatment of leg ulcers. They are run in a social context by community nurses who deliver ongoing support and treatment for a wide spectrum of lower limb pathology. This article looks at how the Leg Club model has been established in Australia.

Molecular profiling of exudate from chronic ulcerated wounds

Non-healing wounds represent a significant burden to healthcare systems and societies worldwide. Current best practice treatments of chronic wounds can require patients to undergo extensive periods of therapy without any positive outcome. This consumes substantial healthcare resources and severely impacts patient quality of life. At present, there are no measures to predict a patient's response to best practice care. The hypothesis of this thesis was that biochemical markers could be found within the wound fluid of chronic ulcers and these markers could predict the healing outcome of an ulcer undergoing best practice care. Discovery phase proteomic and mass spectrometry techniques were utilised to determine novel proteins that correlated with the healing outcome of ulcers. These candidate biomarkers could be developed into simple dip-stick tools for use in clinical practice. This would aid clinicians in the choice of effective wound management strategies to address hard-to-heal wounds.

Identifying risk factors and protective factors for venous leg ulcer recurrence using a theoretical approach : a longitudinal study

Background The high recurrence rate of chronic venous leg ulcers has a significant impact on an individual’s quality of life and healthcare costs. Objectives This study aimed to identify risk and protective factors for recurrence of venous leg ulcers using a theoretical approach by applying a framework of self and family management of chronic conditions to underpin the study. Design Secondary analysis of combined data collected from three previous prospective longitudinal studies. Setting The contributing studies’ participants were recruited from two metropolitan hospital outpatient wound clinics and three community-based wound clinics. Participants Data were available on a sample of 250 adults, with a leg ulcer of primarily venous aetiology, who were followed after ulcer healing for a median follow-up time of 17 months after healing (range: 3 to 36 months). Methods Data from the three studies were combined. The original participant data were collected through medical records and self-reported questionnaires upon healing and every 3 months thereafter. A Cox proportion-hazards regression analysis was undertaken to determine the influential factors on leg ulcer recurrence based on the proposed conceptual framework. Results The median time to recurrence was 42 weeks (95% CI 31.9–52.0), with an incidence of 22% (54 of 250 participants) recurrence within three months of healing, 39% (91 of 235 participants) for those who were followed for six months, 57% (111 of 193) by 12 months, 73% (53 of 72) by two years and 78% (41 of 52) of those who were followed up for three years. A Cox proportional-hazards regression model revealed that the risk factors for recurrence included a history of deep vein thrombosis (HR 1.7, 95% CI 1.07–2.67, p=0.024), history of multiple previous leg ulcers (HR 4.4, 95% CI 1.84–10.5, p=0.001), and longer duration (in weeks) of previous ulcer (HR 1.01, 95% CI 1.003–1.01, p<0.001); while the protective factors were elevating legs for at least 30 minutes per day (HR 0.33, 95% CI 0.19–0.56, p<0.001), higher levels of self-efficacy (HR 0.95, 95% CI 0.92–0.99, p=0.016), and walking around for at least three hours/day (HR 0.66, 95% CI 0.44–0.98, p=0.040). Conclusions Results from this study provide a comprehensive examination of risk and protective factors associated with leg ulcer recurrence based on the chronic disease self and family management framework. These results in turn provide essential steps towards developing and testing interventions to promote optimal prevention strategies for venous leg ulcer recurrence.

An Australian native plant: A novel antimicrobial for the treatment of MRSA

Chronic wounds, often associated with venous and arterial ulcers, diabetes and pressure sores, is an area of great concern. In Australia, the cost of treating chronic wounds is conservatively estimated at $285 million/annum for the treatment of pressure ulcers and $654 million annually for the treatment and management of leg ulcers. Current figures indicate that more than seven million people suffer from chronic wounds worldwide with Australians accounting for approximately 600,000 of this number. Bacterial infection of the wound site is a major issue as contamination of a chronic wound with methicillin-resistant Staphylococcus aureus (MRSA) significantly delays wound healing. Further, once systemic, current antibiotic therapies capable of treating the infection are limited. Aboriginal bush medicine has been used for thousands of years for the treatment of wounds and sores. Hence, we selected a native Australian plant to evaluate its bactericidal activity against MRSA.

The benefits of a self-management telephone based intervention for promoting exercise and healing rates for venous leg ulcer patients

Venous leg ulcers are a significant cause of chronic ill-health, whilst patients often experience reduced mobility and poor quality of life. This research investigated exercise as a tool for improving outcomes for adults with venous leg ulcers. The results showed that patients who adhere to an exercise program as an adjunct treatment to standard care are more likely to heal than those who do not adhere to an exercise program. This research has the potential to improve the health of venous leg ulcer patients and decrease health care costs.

Plantar pressure in diabetic peripheral neuropathy patients with active foot ulceration, previous ulceration and no history of ulceration: A meta-analysis of observational studies

Aims Elevated dynamic plantar pressures are a consistent finding in diabetes patients with peripheral neuropathy with implications for plantar foot ulceration. This meta-analysis aimed to compare the plantar pressures of diabetes patients that had peripheral neuropathy and those with neuropathy with active or previous foot ulcers. Methods Published articles were identified from Medline via OVID, CINAHL, SCOPUS, INFORMIT, Cochrane Central EMBASE via OVID and Web of Science via ISI Web of Knowledge bibliographic databases. Observational studies reporting barefoot dynamic plantar pressure in adults with diabetic peripheral neuropathy, where at least one group had a history of plantar foot ulcers were included. Interventional studies, shod plantar pressure studies and studies not published in English were excluded. Overall mean peak plantar pressure (MPP) and pressure time integral (PTI) were primary outcomes. The six secondary outcomes were MPP and PTI at the rear foot, mid foot and fore foot. The protocol of the meta-analysis was published with PROPSERO, (registration number CRD42013004310). Results Eight observational studies were included. Overall MPP and PTI were greater in diabetic peripheral neuropathy patients with foot ulceration compared to those without ulceration (standardised mean difference 0.551, 95% CI 0.290–0.811, p<0.001; and 0.762, 95% CI 0.303–1.221, p = 0.001, respectively). Sub-group analyses demonstrated no significant difference in MPP for those with neuropathy with active ulceration compared to those without ulcers. A significant difference in MPP was found for those with neuropathy with a past history of ulceration compared to those without ulcers; (0.467, 95% CI 0.181– 0.753, p = 0.001). Statistical heterogeneity between studies was moderate. Conclusions Plantar pressures appear to be significantly higher in patients with diabetic peripheral neuropathy with a history of foot ulceration compared to those with diabetic neuropathy without a history of ulceration. More homogenous data is needed to confirm these findings.

Characteristics of microbial drug resistance and its correlates in chronic diabetic foot ulcer infections

While virulence factors and the biofilm-forming capabilities of microbes are the key regulators of the wound healing process, the host immune response may also contribute in the events following wound closure or exacerbation of non-closure. We examined samples from diabetic and non-diabetic foot ulcers/wounds for microbial association and tested the microbes for their antibiotic susceptibility and ability to produce biofilms. A total of 1074 bacterial strains were obtained with staphylococci, Pseudomonas, Citrobacter and enterococci as major colonizers in diabetic samples. Though non-diabetic samples had a similar assemblage, the frequency of occurrence of different groups of bacteria was different. Gram-negative bacteria were found to be more prevalent in the diabetic wound environment while Gram-positive bacteria were predominant in non-diabetic ulcers. A higher frequency of monomicrobial infection was observed in samples from non-diabetic individuals when compared to samples from diabetic patients. The prevalence of different groups of bacteria varied when the samples were stratified according to age and sex of the individuals. Several multidrug-resistant strains were observed among the samples tested and most of these strains produced moderate to high levels of biofilms. The weakened immune response in diabetic individuals and synergism among pathogenic micro-organisms may be the critical factors that determine the delicate balance of the wound healing process.

The Queensland high risk foot form (QHRFF): Is it a reliable and valid clinical research tool for foot disease?

Background Foot disease complications, such as foot ulcers and infection, contribute to considerable morbidity and mortality. These complications are typically precipitated by “high-risk factors”, such as peripheral neuropathy and peripheral arterial disease. High-risk factors are more prevalent in specific “at risk” populations such as diabetes, kidney disease and cardiovascular disease. To the best of the authors’ knowledge a tool capturing multiple high-risk factors and foot disease complications in multiple at risk populations has yet to be tested. This study aimed to develop and test the validity and reliability of a Queensland High Risk Foot Form (QHRFF) tool. Methods The study was conducted in two phases. Phase one developed a QHRFF using an existing diabetes foot disease tool, literature searches, stakeholder groups and expert panel. Phase two tested the QHRFF for validity and reliability. Four clinicians, representing different levels of expertise, were recruited to test validity and reliability. Three cohorts of patients were recruited; one tested criterion measure reliability (n = 32), another tested criterion validity and inter-rater reliability (n = 43), and another tested intra-rater reliability (n = 19). Validity was determined using sensitivity, specificity and positive predictive values (PPV). Reliability was determined using Kappa, weighted Kappa and intra-class correlation (ICC) statistics. Results A QHRFF tool containing 46 items across seven domains was developed. Criterion measure reliability of at least moderate categories of agreement (Kappa > 0.4; ICC > 0.75) was seen in 91% (29 of 32) tested items. Criterion validity of at least moderate categories (PPV > 0.7) was seen in 83% (60 of 72) tested items. Inter- and intra-rater reliability of at least moderate categories (Kappa > 0.4; ICC > 0.75) was seen in 88% (84 of 96) and 87% (20 of 23) tested items respectively. Conclusions The QHRFF had acceptable validity and reliability across the majority of items; particularly items identifying relevant co-morbidities, high-risk factors and foot disease complications. Recommendations have been made to improve or remove identified weaker items for future QHRFF versions. Overall, the QHRFF possesses suitable practicality, validity and reliability to assess and capture relevant foot disease items across multiple at risk populations.

Successful topical tacrolimus (FK506) therapy in a child with pyoderma gangrenosum

The inflammatory skin disease pyoderma gangrenosum is characterized by destructive ulceration, typically occurring on the calves and thighs and less commonly on the buttocks and face. Lesions vary in size and may be multiple, often rapidly ulcerating to form deep painful wounds. Ulcers characteristically have ragged purple edges that overhang. In many patients a concomitant condition can be identified such as inflammatory bowel disease, rheumatoid arthritis, chronic autoimmune hepatitis, and various hematologic and solid tumours (1,2). Treatment of these ulcers in the past has been disappointing. The large lesions usually run a chronic course and heal very slowly, with traditional dressings often in combination with systemic steroids or immunosuppressants. Since 1998, a small number of case have been reported of adults with pyoderma gangrenosum whose lesions heal with the use of topical tacrolimus (FK506) (2–4). We report, to the best of our knowledge, the first successful treatment of a child with pyoderma gangrenosum using topical tacrolimus.

Oesophagogastric ulceration in pigs: A visual morphological scoring guide

Objective: To provide a visual guide for oesophagogastric ulcer scoring and recognition of different morphological changes in the pars oesophagea. Design: Pig stomachs were collected at slaughter and visually evaluated and scored for parakeratosis, erosion and ulceration in the pars oesophagea. Results: A visual and descriptive guide is presented that will aid in the objective assessment and scoring of oesophagogastric ulceration in pigs within the pig health monitoring system (PHMS), namely to the four categories of 0 = normal stomach, 1 = parakeratosis and thickened epithelium, 2 = erosions and 3 = developed ulcers with and without stenosis. Conclusion: A visual guide has been developed that illustrates the full range of morphological changes that can occur in the pars oesophagea of the stomach within the few currently recognised stages of the disease.

Helicobacter pylori in Vammala, Finland: seroepidemiological studies and a population-based ‘screen-and-treat’ programme

Helicobacter pylorin (helikobakteeri) tartunta saadaan yleensä lapsena ja tauti jää tavallisesti pysyväksi ilman täsmähoitoa. Onnistunut hoito parantaa pysyvästi helikobakteerista aiheutuvan mahan haavataudin ja näyttää ehkäisevän mahalaukun pahanlaatuisten muutosten kehittymistä. Aloitimme Vammalassa terveyskeskuksessa toteutetun kansainvälisesti ainutlaatuisen väestöpohjaisen helikobakteeritulehduksen seulonta- ja hoito-ohjelman pilottitutkimuksella 1994. 1996 kaikki 15-40-vuotiaat ja 1997-2000 15- ja 45-vuotiaat vammalalaiset kutsuttiin verinäyteseulontaan. Yhteensä 4626 henkilöä (75% kutsutuista) osallistui seulontaan. Vasta-ainepositiivisille tarjottiin helikobakteeritulehduksen lopettava lääkekuuri. Toiminnan seurauksena helikobakteeritulehduksen esiintyvyyden laskettiin vähentyneen 12%:sta 4%:iin 15-40-vuotiaiden ikäryhmässä. Tutkimme myös helikobakteerivasta-ainepositiivisten ja -negatiivisten eroja sekä helikobakteeritulehduksen riskitekijöitä kyselytutkimuksella. Lapsuudenkodin asumisahtauden, äidin matalan koulutusasteen, tupakoinnin, alkoholinkäytön, huonojen asunto-olojen ja ylävatsavaivoista johtuvien sairauslomien todettiin liittyvän helikobakteeritulehdukseen monimuuttuja-analyysissa. Tutkimme seulontaohjelmassa käyttämiemme IgG- ja IgA-luokan helikobakteeri-vasta-ainetestien luotettavuutta eri ikäryhmissä ottaen huomioon atrofisen gastriitin esiintyvyyden. 561 kliinisin perustein gastroskopoidun potilaan aineistossa IgG-testi osoittautui erittäin herkäksi kaikissa ikäryhmissä (99%). Tarkkuus oli myös vanhemmissa ikäryhmissä hyvä (97-93%), kun atrofista gastriittia sairastavat suljettiin pois. IgA- ja CagA-helikobakteerivasta-aineiden on todettu liittyvän lisääntyneeseen mahahaava- ja mahasyöpäriskiin. Analysoimme 560 henkilön pariseeruminäytteet, jotka oli otettu kahden vuosikymmenen välein, ja totesimme, että IgA-vasta-aineiden esiintyvyyden lisääntyyminen iän myötä johtuu paitsi syntymäajankohdasta ja uusista infektioista myös IgA-vasta-ainetasojen kohoamisesta helikobakteeritulehduksen aikana. Selvitimme myös CagA-vasta-ainetasojen muuttumista analysoimalla seeruminäytteet, jotka oli otettu kahden vuosikymmenen välein. Totesimme, että samanaikaisesti kun helikobakteerin esiintyvyys väestössä on alentunut, erityisesti CagA-positiiviset infektiot ovat vähentyneet. Tutkimuksemme osoittaa, että Suomessa terveyskeskuksen yhteydessä voidaan toteuttaa näin laajamittainen seulonta- ja hoito-ohjelma, johon suomalaiset osallistuvat aktiivisesti. Nähtäväksi jää, kuinka paljon ohjelma kykeni vähentämään helikobakteeritulehdukseen liittyviä myöhäisseuraamuksia.

Phytochemicals of papaya and its traditional health and culinary uses – A review

This paper reviews the current research on phytochemical composition and non-Western traditional culinary food preparation and health uses of papaya. Only ripe papaya fruit flesh is normally eaten in Western countries. The orange or red flesh is an excellent source of pro-vitamin A and ascorbic acid. In South-East Asia, both ripe and green fruit are used and additionally leaves are popularly consumed either raw in salad or cooked as a green vegetable. The leaves contain alkaloids as well as quercetin and kaempferol as the main phenolic compounds. In contrast to Western use papaya has a reputation as a medicinal plant in tropical countries where it is grown. Different plant parts such as fruit, leaf, seed, root, bark and flowers have been used as health treatments. These have included use as topical dressings for treating ulcers and dermatitis, gastrointestinal uses such as antihelminthic and antibacterial activity treatments and traditional uses for fertility control. The differences in use for food and health illustrate potential applications and nutritional benefits of the plant which require further research. With better verification the health applications of papaya could be more widely adopted into Western culture.