A review of pharmacogenomics studies assessing the knowledge and attitudes of physicians and pharmacists across the Arab and Middle Eastern Region

The principal goal of pharmacogenomics (PGx) is to achieve the highest drug efficacy while maintaining a low toxicity profile. Historically, health care systems used to target treatment for all individuals with the same diagnosis using a standardized medication or dose that fits all. However, a recent pattern in medicine has emerged focusing on personalized and precision medicine. For effective implementation of PGx, there is a need for more collaborations between all the stakeholders in the healthcare system to integrate the pharmacogenetics concept into practice. When it comes to the knowledge and attitudes towards pharmacogenomics, the majority of medical professionals, including pharmacists and physicians, appear to lack appropriate knowledge and training. Across the Middle East and Arab Region, only few studies have addressed this topic. The current review objective is to shed light on pharmacists’ and physicians’ knowledge and attitudes towards PGx practice in the UAE, Arab and the Middle East region as compared to the rest of the world. Moreover, highlighting the role of the pharmacists in the application of PGx services and the educational challenges that are faced. Proposed solutions to improve the knowledge gaps will also be discussed. We also aim to provide the international readers as well as the local researchers with a summary of the trends and distribution of the results across these countries. (AU)

Camel-related major vascular injuries: A 20-years' experience.

BACKGROUND: Majority of human animal-related injuries in the United Arab Emirates are caused by camels. These may involve major vessels and can be life-threatening. We aimed to study the biomechanism, injured regions, management, and outcome of major camel-related human vascular injuries. METHODS: We retrospectively studied all patients who were admitted to Al-Ain Hospital with camel-related major vascular injury during January 2001 to January 2020. Studied variables included demography, mechanism of injury, injured structures, clinical presentation, vital signs on arrival, associated injuries, surgical management, ICU stay, length of hospital stay, complications, and outcome. RESULTS: Seven patients were studied; all were males having a median age of 26 years. Five out of six bite injuries (83%) occured during the camel rutting season. The injuries were severe and life-threatening. A camel bite causes four small elliptical wounds of the canine teeth which resembles two stab wounds of 8 cm long, penetrating deeply and injuring major vessels. Four involved the carotid artery, one the femoral artery and vein, one the external iliac vein and one the aorta which was due to a fall from a camel. Although the standard of surgical care was high, the outcome was poor. Six patients were admitted to the ICU for a median of 5 days. One patient died, one became vegetative, and one had arm paralysis. CONCLUSIONS: Major camel-related vascular injuries have a poor clinical outcome. This is related to the biomechanism of injury which combines penetrating, crushing and blunt trauma. Neck wounds of camel bites can be closed primarily after debridement.

Management of superficial and deep surgical site infection: an international multidisciplinary consensus.

Surgical site infections represent a considerable burden for healthcare systems. To obtain a consensus on the impact and future clinical and economic needs regarding SSI management in an era of multidrug resistance. A modified Delphi method was used to obtain consensus among experts from five European countries. The Delphi questionnaire was assembled by a steering committee, verified by a panel of experts and administered to 90 experts in 8 different surgical specialities (Abdominal, Cancer, Cardiac, General surgery, Orthopaedic, Thoracic, Transplant and Vascular and three other specialities (infectious disease, internal medicine microbiology). Respondents (n = 52) reached consensus on 62/73 items including that resistant pathogens are an increasing matter of concern and increase both treatment complexity and the length of hospital stay. There was strong positive consensus on the cost-effectiveness of early discharge (ED) programs, improvement of quality of life with ED and association between increased length of stay and economic burden to the hospital. However, established ED protocols were not widely available in their hospitals. Respondents expressed a positive consensus on the usefulness of antibiotics that allow ED. Surgeons are aware of their responsibility in an interdisciplinary team for the treatment of SSI, and of the impact of multidrug-resistant bacteria in the context of SSI. Reducing the length of hospital stays by applying ED protocols and implementing new treatment alternatives is crucial to reduce harm to patients and costs for the hospital.

Assessment of Transdermal Delivery of Topical Compounds in Skin Scarring Using a Novel Combined Approach of Raman Spectroscopy and High-Performance Liquid Chromatography.

Objective: The goal of any topical formulation is efficient transdermal delivery of its active components. However, delivery of compounds can be problematic with penetration through tough layers of fibrotic dermal scar tissue. Approach: We propose a new approach combining high-performance liquid chromatography (HPLC) and Raman spectroscopy (RS) using a topical of unknown composition against a well-known antiscar topical (as control). Results: Positive detection of compounds within the treatment topical using both techniques was validated with mass spectrometry. RS detected conformational structural changes; the 1,655/1,446 cm-1 ratio estimating collagen content significantly decreased (p < 0.05) over weeks 4, 12, and 16 compared with day 0. The amide I band, known to represent collagen and protein in skin, shifted from 1,667 to 1,656 cm-1, which may represent a change from ß-sheets in elastin to α-helices in collagen. Confirmatory elastin immunohistochemistry decreased compared with day 0, conversely the collagen I/III ratio increased in the same samples by week 12 (p < 0.05, and p < 0.0001, respectively), in keeping with normal scar formation. Optical coherence tomography attenuation coefficient representing collagen deposition was significantly decreased at week 4 compared with day 0 and increased at week 16 (p < 0.05). Innovation: This study provides a platform for further research on the simultaneous evaluation of the effects of compounds in cutaneous scarring by RS and HPLC, and identifies a role for RS in the therapeutic evaluation and theranostic management of skin scarring. Conclusions: RS can provide noninvasive information on the effects of topicals on scar pathogenesis and structural composition, validated by other analytical techniques.

Transcatheter aortic valve implantation facilitated by right common carotid cut-down and innominate artery angioplasty with simultaneous right coronary artery vein graft percutaneous coronary intervention in a patient with mid aortic syndrome: a case report.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is most commonly performed via the femoral approach. Small caliber ilio-femoral arteries, severe calcification and tortuosity are often prohibitive reasons for TAVI via the femoral approach. Mid-aortic syndrome is a rare condition describing congenital or acquired coarctation of the abdominal aorta. CASE SUMMARY: To the best of our knowledge, this case report describes the world's first TAVI in a patient with mid-aortic syndrome with challenging vascular access that would preclude conventional TAVI access routes. A 76-year-old woman with intermittent claudication, underwent work-up for axillo-bifemoral bypass, underwent a TAVI for incidental severe asymptomatic severe aortic stenosis via right common carotid TAVI facilitated by innominate artery angioplasty achieved vascular access for TAVI. Percutaneous coronary intervention to a right coronary artery vein graft was simultaneously performed via a left brachial artery cut down. DISCUSSION: We demonstrate that complex angioplasty to coronary artery bypass grafts and the innominate artery alongside TAVI via a variety of arterial access sites is both safe and feasible.

A microbiome and metabolomic signature of phases of cutaneous healing identified by profiling sequential acute wounds of human skin: An exploratory study.

Profiling skin microbiome and metabolome has been utilised to gain further insight into wound healing processes. The aims of this multi-part temporal study in 11 volunteers were to analytically profile the dynamic wound tissue and headspace metabolome and sequence microbial communities in acute wound healing at days 0, 7, 14, 21 and 28, and to investigate their relationship to wound healing, using non-invasive quantitative devices. Metabolites were obtained using tissue extraction, sorbent and polydimethylsiloxane patches and analysed using GCMS. PCA of wound tissue metabolome clearly separated time points with 10 metabolites of 346 being involved in separation. Analysis of variance-simultaneous component analysis identified a statistical difference between the wound headspace metabolome, sites (P = 0.0024) and time points (P<0.0001), with 10 out of the 129 metabolites measured involved with this separation between sites and time points. A reciprocal relationship between Staphylococcus spp. and Propionibacterium spp. was observed at day 21 (P<0.05) with a statistical correlation between collagen and Propionibacterium (r = 0.417; P = 0.038) and Staphylococcus (r = -0.434; P = 0.03). Procrustes analysis showed a statistically significant similarity between wound headspace and tissue metabolome with non-invasive wound devices. This exploratory study demonstrates the temporal and dynamic nature of acute wound metabolome and microbiome presenting a novel class of biomarkers that correspond to wound healing, with further confirmatory studies now necessary.

Functional Testing of a Skin Topical Formulation In Vivo: Objective and Quantitative Evaluation in Human Skin Scarring Using a Double-Blind Volunteer Study with Sequential Punch Biopsies.

Objective: Many topicals claim an efficacious role in skin scar management with limited evidence. Our aim is to present a clear format for functional testing of a skin scarring ointment, using noninvasive and invasive measurements, categorizing findings under the physiological, structural, and mechanical parameters of a scar. Approach: A double-blinded, randomized volunteer research study of 45 subjects receiving an ointment composing of natural ingredients against a widely used antiscarring topical used as a positive control with temporal sequential punch biopsies (up to 16 weeks) was evaluated using noninvasive quantitative devices and validated by gene and protein studies. Results: Outcome measures included physiological, mechanical, and structural features of scars. Significant non-invasive findings included an increase in skin hydration (p < 0.05) at week (W) 4, 8, and 12, and elasticity (W16; p = 0.009). These findings were validated by immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR). Hyaluronic acid IHC (W4 p = 0.014, W12 p = 0.034, and W16 p = 0.042), qRT-PCR (W16 p = 0.049); Collagen I (W16 p = 0.034, and 0.049) IHC and qRT-PCR, respectively. Collagen III qRT-PCR (W12 p = 0.035, and W16 p = 0.32); elastin IHC (W12 p = 0.044); and fibronectin IHC (W4 p = 0.009, W12 p = 0.038, and W16 p = 0.026). Innovation: Utilizing this model allows for quantitative, objective evaluation of any topical, where previously there has been a paucity of relevant methods to evaluate their effect. Conclusions: The positive effect of a topical formulation with an unknown mechanism of action on early cutaneous scar maturation over progressive sequential time points is now evidenced using noninvasive and invasive techniques with the findings categorized on the basis of scarring parameters.

A Double-Blind, Randomized Trial Shows the Role of Zonal Priming and Direct Topical Application of Epigallocatechin-3-Gallate in the Modulation of Cutaneous Scarring in Human Skin.

BACKGROUND: Epigallocatechin-3-gallate (EGCG), a polyphenol, influences cutaneous wound healing because of its antiangiogenic, anti-inflammatory, and antioxidant properties. We previously showed the role of EGCG in scarring in ex vivo human scar models. Here, we evaluate direct application of topical EGCG compared with zonal priming, a unique concept in the immediate treatment of the zone of injury at the time of wounding before scar formation. TRIAL DESIGN: Double-blind randomized controlled trial. METHODS: We assessed EGCG application compared with placebo over 1-6 weeks in scars created in 62 human volunteers using quantitative noninvasive devices, immunohistochemical analysis, mRNA sequencing, and quantitative real-time reverse transcriptase-PCR of tissue biopsy samples. RESULTS: EGCG reduced mast cells at weeks 1-3, as evidenced by gene and protein analyses (P ≤ 0.01). M2 macrophages were increased with EGCG compared with placebo. EGCG application by zonal priming significantly down-regulated VEGFA and CD31 at week 1 and at 1-2 weeks after direct application (P ≤ 0.01). Direct EGCG application also reduced scar thickness at weeks 1-3 (P = 0.001) and increased scar elasticity at week 4 (P = 0.01). Increased hydration was evident both noninvasively and by increased hyaluronic acid levels (P < 0.01) at week 3. CONCLUSIONS: We show the beneficial role of both zonal priming and direct EGCG application in scar therapy with positive effects on scar thickness, erythema, hydration, and elasticity. Trial register: International standard randomized controlled trial, registration number ISRCTN 18643079; July 16, 2018.

Electrical stimulation disrupts biofilms in a human wound model and reveals the potential for monitoring treatment response with volatile biomarkers.

Management of biofilm infections relies on time-consuming laboratory techniques and monitoring treatment by subjective clinical evaluations. Due to these limitations, there is a need to explore alternative strategies. The aims of this study were to assess the feasibility of using volatile organic compound (VOC) biomarkers to monitor treatment response and measure anti-biofilm efficacy of electrical stimulation (ES) in vitro and in human cutaneous wound biofilm models. Staphylococcus aureus (MSSA) and Pseudomonas aeruginosa (PA) biofilms were exposed to ES, ciprofloxacin, or both, with efficacy assessed and quantified by fluorescence staining, enumeration, metabolic assays, and biomass quantification; VOCs were measured by gas chromatography-mass spectrometry. In vitro MSSA and PA and ex vivo PA biofilms exposed to ES showed significantly reduced bacterial viability, metabolic activity, and biomass compared to controls (p < 0.05). There was significant variation in the relative abundance of VOCs in in vitro MSSA and PA and in ex vivo PA biofilms exposed to ES and antibiotic (p < 0.05). 2-methyl-1-propanol was associated with MSSA viability (R = 0.93, p < 0.05), biomass (R = 0.97, p < 0.05), and metabolic activity (R = 0.93, p < 0.05) and 3-methyl-1-butanol was associated with PA biomass (R = 0.93, p < 0.05). We showed that ES and VOC biomarkers are possible options for alternative nonpharmacological antimicrobial management of biofilms and noninvasive monitoring of wound infection treatment responses, respectively.

Validation of biofilm formation on human skin wound models and demonstration of clinically translatable bacteria-specific volatile signatures.

Biofilms are major contributors to delayed wound healing and there is a need for clinically relevant experimental models to assess theranostics. Microorganisms release volatile organic compounds (VOCs) and the ability to identify these in infected cutaneous wounds could lead to efficient non-invasive diagnosis. The aims here were to develop and assess bacterial biofilm formation and identify their VOC profiles in an in vitro model and validate in human ex vivo incisional and excisional cutaneous wound models. Biofilm development was assessed using multiple microscopy techniques with biofilm-forming deficient controls and quantified using metabolic and biomass assays; and VOC production measured by gas chromatography-mass spectrometry. The production of most VOCs was affected by biofilm development and model used. Some VOCs were specific either for planktonic or biofilm growth. The relative abundance of some VOCs was significantly increased or decreased by biofilm growth phase (P < 0.05). Some Staphylococcus aureus and Pseudomonas aeruginosa VOCs correlated with biofilm metabolic activity and biomass (R ≤ -0.5; ≥0.5). We present for the first time bacterial biofilm formation in human ex vivo cutaneous wound models and their specific VOC profiles. These models provide a vehicle for human skin-relevant biofilm studies and VOC detection has potential clinical translatability in efficient non-invasive diagnosis of wound infection.

Volatile organic compound detection as a potential means of diagnosing cutaneous wound infections.

Chronic cutaneous wound infections and surgical site infections (SSIs) present a huge burden on the healthcare system and can lead to increased morbidity and mortality. Current diagnostic methods of identifying and confirming infection involve culture-based and molecular methods. Both techniques are time-consuming and delays commonly lead to untargeted empirical treatment. An ideal diagnostic method would be noninvasive and highly sensitive and detect pathogenic organisms with a high degree of accuracy to allow targeted treatment. Volatile organic compounds (VOCs) are a diverse group of carbon-based molecules produced and released by humans and microorganisms. VOC detection has the potential in aiding cutaneous wound infection diagnostics using noninvasive and time-efficient methods. This review provides a comprehensive update on VOCs produced and emitted by bacteria commonly associated with chronic wounds and SSIs. VOC sampling has the advantage of being painless, time-efficient, noninvasive, and reproducible. VOCs emitted by these organisms are diverse. In vitro studies have identified potential signature volatile profiles, which can be used in detecting these microorganisms. Combining these profiles with volatile profiles emitted from acute, chronic and surgical wounds in vivo could potentially allow identification of bacterial-specific VOCs. VOC detection has the potential for a relatively inexpensive, portable, noninvasive, and reliable clinical diagnostic tool, which could be used in detecting cutaneous wound infections and guiding their optimal management.

Cutaneous wound biofilm and the potential for electrical stimulation in management of the microbiome.

Infection contributes significantly to delayed cutaneous wound healing, which impacts patient care. External application of electrical stimulation (ES) has beneficial effects on wound repair and regeneration. The majority of studies to date have explored ES in relation to planktonic microorganisms, yet evidence indicates that bacteria in chronic wounds reside as antibiotic-resistant polymicrobial biofilms, which contribute to impairing wound healing. Culture-independent sequencing techniques have revolutionized our understanding of the skin microbiome and allowed a more accurate determination of microbial taxa and their relative abundance in wounds allowing a greater understanding of the host-microbial interface. Future studies combining the fields of ES, biofilm and microbiome research are necessary to fully elucidate the use of ES in the management of wound infection.

Pre-operative predictors of poor outcomes in patients undergoing surgical lower extremity revascularisation - Retrospective cohort study.

BACKGROUND: Surgical lower extremity revascularisation (LER) can lead to poor outcomes that include delayed hospital discharge, in-hospital mortality, major amputations and readmissions. The aim of this study was to identify pre-operative predictors associated with these poor clinical outcomes. MATERIALS AND METHODS: All patients (n = 635; mean age 69; male 67.4%) who underwent surgical LER over a 5 year period in a single tertiary vascular institution were identified. Patients considered to have suffered a poor outcome (Group A) included all in-hospital mortality and major amputations, delayed discharges with a length of stay (LOS) over one standard deviation above the mean or any readmission under any specialty within 12 months. Group A included 247 patients (38.9%) and the good outcome group included the remaining 388 patients (61.1%) from which a sample of 99 patients were selected as controls (Group B). RESULTS: Mean LOS for the entire study group was 14.4 ± 17.5 days, 12 month readmission rate was 29.1% and in-hospital mortality and major amputation rate was 2.7% and 1.4%, respectively. Pre-admission residence other than own home (OR 9.0; 95% CI 1.2-70.1; P = 0.036), atherosclerotic disease burden (OR 2.2; 95% CI 1.3-3.8; P = 0.003) and tissue loss (OR 3.0; 95% CI 1.6-5.3; P < 0.001) were identified as independent, statistically significant pre-operative predictors of poor outcome. Following discharge, group B patients had a significantly higher rate of amputation free survival and graft infection free survival (P < 0.001) compared to group A. CONCLUSION: Recognition of pre-operative predictors of poor outcome should inform case selection and identify high risk patients requiring intensive perioperative optimisation and post discharge follow up.

Single-Center Experience Following the Introduction of a Percutaneous Endovascular Aneurysm Repair First Approach.

We evaluated our experience following the introduction of a percutaneous endovascular aneurysm repair (pEVAR) first approach using Perclose Proglide assessing efficacy, complications, and identification of factors that could predict failure. A retrospective cohort study on patients over a 2-year period following the introduction of a pEVAR first approach was performed. The primary end point was defined as successful deployment and access site hemostasis. Percutaneous EVAR was technically successful in 41 (77.4%) of 53 patients and 83 (86.5%) of 96 access sites. Factors associated with failure were smaller common femoral artery (CFA) diameter ( P = .045) and CFA circumferential calcification of greater than 50% ( P = .0001). The incidence of access site infection was significantly higher in the failure group ( P = .008) as was procedure duration ( P = .026). Percutaneous EVAR first approach must be introduced with caution. Percutaneous EVAR failure occurs more often in patients with unfavorable access site anatomy. Success rate can be improved with careful patient selection.

The efficacy of electrical stimulation in lower extremity cutaneous wound healing: A systematic review.

Current gold standard lower extremity cutaneous wound management is not always effective. Cutaneous wounds generate a "current of injury" which is directly involved in wound healing processes. Application of exogenous electrical stimulation has been hypothesised to imitate the natural electric current that occurs in cutaneous wounds. The aim of this extensive review was to provide a detailed update on the variety of electrical stimulation modalities used in the management of lower extremity wounds. Several different waveforms and delivery methods of electrical stimulation have been used. Pulsed current appears superior to other electrical modalities available. The majority of studies support the beneficial effects of pulsed current over conservative management of lower extremity cutaneous wounds. Although it appears to have no benefit over causal surgical intervention, it is a treatment option which could be utilised in those patients unsuitable for surgery. Other waveforms and modalities appear promising; however, they still lack large trial data to recommend a firm conclusion with regards to their use. Current studies also vary in quantity, quality and protocol across the different modalities. The ideal electrical stimulation device needs to be non-invasive, portable and cost-effective and provides minimal interference with patients' daily life. Further studies are necessary to establish the ideal electrical stimulation modality, parameters, method of delivery and duration of treatment. The development and implementation of newer devices in the management of acute and chronic wounds provides an exciting direction in the field of electrotherapy.

Whole genome microarray data of chronic wound debridement prior to application of dermal skin substitutes.

Clinical consensus is that debridement is necessary for successful application of dermal skin substitutes (DSS) to chronic wounds. The aim here was to identify commonly expressed genes associated with wound healing in untreated acute wounds and chronic wounds treated with wound debridement followed by DSS. Cutaneous biopsies were taken at two time points from untreated acute and chronic wounds and from chronic wounds treated with DSS following debridement. Microarray analysis identified significant differences (p < 0.05) related to proliferation (HIPK2, LGR4, FGFR1, SRRT), migration (RHOC, PRPF40A, FGFR1), differentiation (TCF4, COL13A1, GNPTAB, HUWE1, FGFR1), angiogenesis (HIPK2, CASP8), extracellular matrix organization (VWA1), and apoptosis (BBC3, HIPK2, KLF11, PSME3, MSFD10, TOP2A, MLH1, CASP8, PDIA3, XAF1) when comparing untreated chronic wounds to chronic wounds treated with DSS, with similar expression levels compared to untreated acute wounds. Chronic wounds treated with debridement followed by DSS resemble untreated acute wounds at a genomic level. These novel findings, albeit with limited clinical specimen numbers, strengthen the recommendation to transform chronic into acute wounds prior to application of DSS.

The efficacy of electrical stimulation in experimentally induced cutaneous wounds in animals.

BACKGROUND: Complicated cutaneous wounds and their subsequent management can be a clinical challenge in veterinary medicine. There is still an unmet need for an ideal wound healing therapy that is able to stimulate efficiency and quality of repair. Skin wounds generate large and persistent endogenous electric currents and fields termed the "current of injury". The current of injury is involved in numerous processes of wound healing. These observations have led to the hypothesis that applied electrical stimulation (ES) may promote wound healing by imitating the natural electrical current that occurs in cutaneous wounds. OBJECTIVES: This review details the use, effect and mechanism of ES in different preclinical experimental cutaneous wound models and discusses the potential of how ES could be translated into veterinary practice. RESULTS: Studies have found a variable effect of ES on wound healing. Some have been positive with faster rates of wound re-epithelialization, increased wound collagen formation and angiogenesis noted. Other studies have shown no effect or detrimental results. The effects of ES are highly influenced by the ES modality, polarity and parameters. CONCLUSIONS AND CLINICAL IMPORTANCE: Electrical stimulation has the potential to play a significant role in enhancing cutaneous wound healing in veterinary practice. Clinical studies are necessary to corroborate the findings from experimental studies which have shown promise including the use of alternating pulsed and direct current and the use of bio-electric dressings. The ideal ES device would need to be safe, easy to use, portable, noninvasive and aid wound healing by having a beneficial effect on all wound healing stages.

Anatomic Variation of Rami Communicantes in the Upper Thoracic Sympathetic Chain: A Human Cadaveric Study.

BACKGROUND: Hyperhidrosis is secondary to over activation of the sympathetic nervous system and surgical sympathectomy is the treatment of choice when other modalities have failed. This study investigated anatomic variation in the upper thoracic sympathetic chain and associated rami communicantes among cadaveric specimens. It considers the implications of these findings on surgical techniques to treat hyperhidrosis. METHODS: The upper 4 thoracic sympathetic ganglia, intercostal nerves, and connecting rami were dissected, measured and mapped in 40 sides of 20 adult human cadavers. Ganglia location was recorded. The incidence, orientation, and distance travelled by rami communicantes was compared across different ganglionic levels and between sides. RESULTS: The percentage of ganglia located below their associated intercostal space was 6.25% with stellate ganglions present in 70% of specimens and Kuntz fibers noted in 40%. There was a stepwise reduction in incidence of rami from superior to inferior placed ganglia. The number of rami identified across all levels was significantly greater on the right (P = 0.03). The horizontal distance between the sympathetic chain and union of the rami on the intercostal nerves was significantly greater on the right across all levels (P = 0.04). CONCLUSIONS: There was substantial variation in the rami communicantes across the upper 4 ganglia and between right and left sides. Consideration of this variation should be given when planning surgical sympathectomy for hyperhidrosis particularly to avoid symptom recurrence.

The Role of Neuromediators and Innervation in Cutaneous Wound Healing.

The skin is densely innervated with an intricate network of cutaneous nerves, neuromediators and specific receptors which influence a variety of physiological and disease processes. There is emerging evidence that cutaneous innervation may play an important role in mediating wound healing. This review aims to comprehensively examine the evidence that signifies the role of innervation during the overlapping stages of cutaneous wound healing. Numerous neuropeptides that are secreted by the sensory and autonomic nerve fibres play an essential part during the distinct phases of wound healing. Delayed wound healing in diabetes and fetal cutaneous regeneration following wounding further highlights the pivotal role skin innervation and its associated neuromediators play in wound healing. Understanding the mechanisms via which cutaneous innervation modulates wound healing in both the adult and fetus will provide opportunities to develop therapeutic devices which could manipulate skin innervation to aid wound healing.

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring.

Significance: Cutaneous scarring is an almost inevitable end point of adult human wound healing. It is associated with significant morbidity, both physical and psychological. Pathological scarring, including hypertrophic and keloid scars, can be particularly debilitating. Manipulation of the chemokine system may lead to effective therapies for problematic lesions. Recent Advances: Rapid advancement in the understanding of chemokines and their receptors has led to exciting developments in the world of therapeutics. Modulation of their function has led to clinically effective treatments for conditions as diverse as human immunodeficiency virus and inflammatory bowel disease. Potential methods of targeting chemokines include monoclonal antibodies, small-molecule antagonists, interference with glycosaminoglycan binding and the use of synthetic truncated chemokines. Early work has shown promising results on scar development and appearance when the chemokine system is manipulated. Critical Issues: Chemokines are implicated in all stages of wound healing leading to the development of a cutaneous scar. An understanding of entirely regenerative wound healing in the developing fetus and how the expression of chemokines and their receptors change during the transition to the adult phenotype is central to addressing pathological scarring in adults. Future Directions: As our understanding of chemokine/receptor interactions and scar formation evolves it has become apparent that effective therapies will need to mirror the complexities in these diverse biological processes. It is likely that sophisticated treatments that sequentially influence multiple ligand/receptor interactions throughout all stages of wound healing will be required to deliver viable treatment options.