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At least 19 recordsLinked to original sources
PubMed2001

Expression of cyclooxygenase isoforms in normal human skin and chronic venous ulcers.

Chronic venous ulcers are an example of abnormal wound healing showing chronic inflammation which together with the underlying vascular pathology results in delayed healing. Prostaglandins are among the most important mediators of inflammation. They have proinflammatory effects, predominantly by affecting the vasculature. Cyclooxygenase (COX) is the rate-limiting enzyme in prostanoid synthesis. It is present in two isoforms: COX-1 (constitutive cyclooxygenase) which is produced in the body to maintain normal haemostatic functions, and COX-2 (inducible cyclooxygenase), which is induced during inflammation in response to cytokines. Using immunoenzymatic labelling and western blot analysis, this study has shown that both COX-1 and COX-2 were up-regulated in chronic venous leg ulcers by comparison with normal human skin. De novo appearance of COX-2 in chronic venous ulcers was demonstrated, which is not seen in normal human skin. The main cellular sources of both COX isoforms are macrophages and endothelial cells. COX-2 is also produced by mast cells and fibroblasts. A COX radioimmunoassay showed up-regulation of COX activity in chronic venous ulcers compared with normal skin (p<0.05). Up-regulation of COX-1 in chronic venous leg ulcers could produce prostacyclin, which contributes to angiogenesis. Thus, inhibition of COX-1 by non-steroidal anti-inflammatory drugs (NSAIDs) could increase the local ischaemia and hypoxia associated with chronic venous ulcers. On the other hand, up-regulation of COX-2 is most likely responsible for the persistent inflammation in chronic venous leg ulcers. COX-2 selective inhibitors could therefore be effective in the treatment of chronic venous ulcers.

Blotting, Western↗
PubMed1999

Recombinant human granulocyte-macrophage colony-stimulating factor applied locally in low doses enhances healing and prevents recurrence of chronic venous ulcers.

BACKGROUND: Chronic venous leg ulcers have a major medical and economic impact on the elderly worldwide. Healing of the large ulcers (>10 cm2) occurs only in two-thirds of the patients and reulceration of healed ulcers recurs in one-third within 1 year. Because both healing and relapse rate influence greatly a patient's quality of life and the overall cost of treatment, every effort should be made to improve these two parameters. OBJECTIVE: To determine the safety and efficacy of topical low-dose recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) for the treatment of venous ulcers, and to document any improvement in healing rates. METHODS: Thirty-eight patients (29 women, 9 men; median age, 74 years) with chronic venous insufficiency were treated with topical rhu GM-CSF (5 microg/mL 0.9% sodium chloride solution), followed by application of a compression dressing. All subjects were treated as outpatients. RESULTS: Complete healing was observed in 47 of the 52 ulcers (90.4%). The average healing time was 19 weeks. No systemic or local side-effects from the therapy were observed. Nine chronic ulcers, previously refractory to conventional treatment (pretreatment for more than 46 weeks), showed the same response rate (9/8, or 88.9%) and healing time (mean, 19 weeks). After 40 months, no reulceration of the healed ulcers was observed, but two patients developed new ulcers on the same leg. Healing remained stable, with excellent cosmetic results. CONCLUSIONS: In this first study, topically applied low-dose rhu GM-CSF was a safe treatment for chronic venous leg ulcers. Healing rates were significantly increased and relapse rates were minimal.

Administration, Cutaneous↗
PubMed2000

Expression of nitric oxide synthase isoforms and arginase in normal human skin and chronic venous leg ulcers.

Chronic venous ulcers, an example of abnormal wound healing, show chronic inflammation with defective matrix deposition which together with the underlying vascular pathology, result in delayed healing. L-arginine is known to be metabolized by one of two pathways: nitric oxide synthase (NOS), producing nitric oxide (NO), or arginase, producing ornithine. NO is involved in many pathological conditions including vascular and inflammatory disorders. This study therefore investigated the distribution, level and activity of NOS and arginase in chronic venous ulcers in comparison with normal skin, using immunocytochemistry, western blotting, and enzyme assays. The results demonstrated an increased distribution of both NOS and arginase in chronic venous ulcer tissue compared with normal skin, with inflammatory cells and vascular endothelial cells as the main sources. These data were confirmed by western blot analysis, which showed increased levels of both enzymes in chronic venous ulcers. Moreover, there was significantly increased activity of both total NOS (p<0.04) and inducible NOS (p<0.05) in chronic venous ulcer tissue compared with normal skin, and significantly increased activity of arginase (p<0.01) in chronic venous ulcer tissue in comparison with normal skin. NO is known to combine with hydroxyl free radicals forming peroxynitrite, a potent free radical which causes tissue destruction. NO overexpression in chronic venous ulcers may be involved directly or indirectly (through production of peroxynitrite) in the pathogenesis and delayed healing of chronic venous ulcers, through its effects on vasculature, inflammation, and collagen deposition. Arginase is known to enhance matrix deposition. Thus, increased levels of arginase in chronic venous ulcers could contribute to the pathogenesis of lipodermatosclerosis associated with chronic venous insufficiency, predisposing to the formation of chronic venous ulcers and also to matrix cuff formation around blood vessels.

Arginase↗
PubMedDate not supplied

Randomized, double-blind, placebo-controlled, dose- ranging study of granulocyte-macrophage colony stimulating factor in patients with chronic venous leg ulcers.

Chronic venous leg ulcers are a common ailment with no ideal treatment. Recent reports have shown granulocyte- macrophage colony stimulating factor to be of use in the healing of these chronic wounds. Therefore, we conducted a double-blind, randomized, placebo-controlled study which enrolled 60 patients with chronic venous leg ulcers, whom we treated with placebo or with 200 or 400 microg of granulocyte-macrophage colony stimulating factor by perilesional injections of the drug in four weekly treatment episodes. Observations were conducted at each treatment visit, at weeks 5, 9, 13, and six months after the inclusion in the protocol. The number of healed wounds in the placebo and the treated arms were significantly different (p = 0.05), with 4 of 21 (19%) in the first group having healed at week 13, as compared to 12 of 21 (57%) and 11 of 18 (61%), in the 200 microg and the 400 microg groups, respectively. There were only minor side-effects attributable to the treatment, and the reobservation at 6 months showed that none of the treated ulcers recurred during that period. We conclude that granulocyte-macrophage colony stimulating factor injected perilesionally may be a useful drug for the treatment of chronic venous leg ulcers.

Adult↗
PubMed2003

Chronic venous ulcer treatment with fascial pedunculated graft.

AIM: Chronic venous ulcer treatment is often time consuming and requires a high degree of compliance from the patient. This derives not only from venous hypertension but also from chronic structural and metabolic changes of underlying tissues which impair the healing process. It therefore becomes necessary to improve the ulcer tissue condition in order to accelerate the healing process. This is obtained mainly with the improvement of local haemodynamics and secondly by direct action on the ulcer. The aim of the study is to evaluate the efficacy of a treatment with a pedunculated flap of fascia as an additional treatment of chronic venous ulcer. METHODS: Four patients classified C6 according to the CEAP classification were treated for chronic venous ulcer with correction of venous hypertension (saphenectomy or ligature of incompetent perforating veins). The patients also underwent rotation of a fascial pedunculated flap transferred from the sural area to the perimalleolar area. After 7-15 days they had a free skin graft in the treated area. RESULTS: All patients were discharged on the 3(rd) postoperative day after the flap rotation. In 3 patients the ulcer healed within 30 days and in a 4(th) patient within 45 days. No recurrence was observed. CONCLUSION: With this method the healing time seems to be shortened compared to the typical evolution in patients treated with only reflux control followed by conservative therapy. Associating fascial flap in the treatment of chronic venous ulcers improves the bed on which the free skin graft is applied. We can also hypothesize that this procedure restores the aponeurotic barrier between deep venous circulation and superficial microcirculation with the ensuing improvement in local venous hypertension.

Chronic Disease↗
PubMedDate not supplied

Spatial distribution of mast cells in chronic venous leg ulcers.

Chronic venous leg ulcers (CVUs) show chronic inflammation but different pathological changes occur in different parts of the ulcer. There is a lack of re-epithelialisation and defective matrix deposition in the ulcer base but epidermal hyperproliferation and increased matrix deposition in the surrounding skin. The role of mast cells in wound healing, inflammation, fibrosis and epidermal hyperproliferation has been extensively studied but less is known about their role in CVUs. In the present study, we investigated the distribution of mast cells in CVUs with specific consideration of the differences between the ulcer base and the skin surrounding the ulcer. Both histochemical and immunohistological methods were used to detect the mast cell marker tryptase in frozen sections of CVU biopsies. Mast cells were counted in the dermis of normal skin, in the ulcer base and in the skin surrounding the ulcer. Double immunofluorescence staining was used to study the location of mast cells in relation to blood vessels. In normal skin few mast cells were seen in the dermis but none in the epidermis. However in CVUs there was a significant increase in intact and degranulated mast cells in the surrounding skin and ulcer edge (184 per field, p<0.003) of CVUs and a significant reduction in the ulcer base (20.5 per field p<0.05) in comparison to normal skin (61 per field). In CVUs mast cells showed a characteristic location near the epithelial basement membrane whilst mast cell granules and phantom cells (mast cells devoid of granules) were predominantly seen in the epidermis. In the dermis, mast cells were seen associated with blood vessels. The marked increase in mast cells in the surrounding skin of CVUs and depletion of mast cells in the ulcer base could implicate mast cell mediators in the pathological changes in CVUs particularly in the epidermal and vascular changes occurring in the surrounding skin.

Cell Count↗
PubMed1996

Chronic venous insufficiency: a focus on prevention of venous ulceration.

Chronic venous insufficiency of the lower extremities is a common medical problem, with a high prevalence among older persons. Among the costly complications of this disease is venous ulceration, which adversely affects quality of life. As the population of older persons increases, the prevalence of this disease and resulting complications is expected to increase proportionately. Prevention of venous ulcers is key to containing health care costs and improving the overall quality of life for patients affected by chronic venous insufficiency. Armed with an understanding of the pathogenesis of the disease process and its clinical signs, ET nurses and other health care professionals must use their skills to identify and educate patients at risk. Prevention programs should be developed and implemented to prevent venous ulceration among patients with or at risk for chronic venous insufficiency.

Health Care Costs↗
PubMed1991

Epidemiology of chronic venous ulcers.

A metropolitan population of 238,000 in Perth, Western Australia, was screened for chronic ulceration of the leg. Patients with a chronic leg ulcer and a venous abnormality comprised 57 per cent of all patients with a chronic leg ulcer, giving a prevalence of 0.62 per 1000 population. There was an increasing prevalence with age; 90 per cent of patients were 60 years and older. This group comprised 16.7 per cent of the population, and had a prevalence of 3.3 per 1000. Although chronic venous ulcers were more common in women there was no difference in age related prevalence. In 36 per cent of patients with a venous abnormality, there was at least one other aetiological factor contributing to chronic ulceration of the leg; 96 per cent had either a history of deep venous thrombosis or a condition known to predispose to deep venous thrombosis.

Adult↗
PubMed1987

Controlled trial of occlusive dressings in healing chronic venous ulcers.

Fifty-six patients with chronic venous ulcers present for a mean of 2.4 years were randomized to either a new occlusive hydrocolloid dressing (Granuflex, Squibb Surgicare) or a porous non-adherent dressing (N A, Johnson and Johnson). In all patients, dressings were applied beneath a standard graduated compression bandage. There was no difference between the two groups, with complete healing in 21 out of 28 (75 per cent) of occlusive dressing patients and 22 out of 28 (78 per cent) with N A dressings by 12 weeks. Careful graduated compression bandaging achieves healing even in the majority of so-called resistant chronic venous ulcers; there was no additional benefit from applying occlusive dressings which tend to be expensive.

Adult↗
PubMed2004

Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial.

BACKGROUND: Chronic venous leg ulceration can be managed by compression treatment, elevation of the leg, and exercise. The addition of ablative superficial venous surgery to this strategy has not been shown to affect ulcer healing, but does reduce ulcer recurrence. We aimed to assess healing and recurrence rates after treatment with compression with or without surgery in people with leg ulceration. METHODS: We did venous duplex imaging of ulcerated or recently healed legs in 500 consecutive patients from three centres. We randomly allocated those with isolated superficial venous reflux and mixed superficial and deep reflux either compression treatment alone or in combination with superficial venous surgery. Compression consisted of multilayer compression bandaging every week until healing then class 2 below-knee stockings. Primary endpoints were 24-week healing rates and 12-month recurrence rates. Analysis was by intention to treat. FINDINGS: 40 patients were lost to follow-up and were censored. Overall 24-week healing rates were similar in the compression and surgery and compression alone groups (65% vs 65%, hazard 0.84 [95% CI 0.77 to 1.24]; p=0.85) but 12-month ulcer recurrence rates were significantly reduced in the compression and surgery group (12% vs 28%, hazard -2.76 [95% CI -1.78 to -4.27]; p<0.0001). Adverse events were minimal and about equal in each group. INTERPRETATION: Surgical correction of superficial venous reflux reduces 12-month ulcer recurrence. Most patients with chronic venous ulceration will benefit from the addition of simple venous surgery.

Aged↗
PubMed2004

Illness behavior and social support in patients with chronic venous ulcers.

Venous ulcers are a chronic and costly condition for providers and payors, as well as for patients, particularly the elderly. To examine the association between chronic venous ulceration, illness behavior, and levels of social support, patients drawn from a separate clinical trial (N = 74) were interviewed using the Illness Behaviour Questionnaire and the Social Support Questionnaire. Results indicate that women had higher hypochondriasis (1.70 versus 1.03, P = 0.19), affective disturbance (2.70 versus 1.42, P = 0.08), and number of supports (Social Support Questionnaire, 2.41 versus 1.81, P = 0.056) than men, although no score achieved a standard level of statistical significance. Patients under 70 years of age had significantly higher hypochondriasis (1.96 versus 1.17, P = 0.021) and irritability (1.38 versus 0.90, P = 0.026) scores than those older than 70 years, although denial was significantly higher in those older than 70 years (3.97 versus 3.46, P = 0.045). The level of satisfaction with social support was significantly higher in those under 70 years of age (5.13 versus 4.97, P = 0.042). These results underscore the psychological and social cost imposed by chronic venous ulceration on older women. They also support previous studies implying a greater psychological burden on younger patients. The association between illness behavior and social support remains unclear, but examining the association between illness behavior and social support among patients with venous ulceration provides an opportunity to increase understanding of the psychological, physical, and social dynamics of this chronic condition.

Activities of Daily Living↗
PubMed1994

Periwound skin microcirculation of venous leg ulcers.

Chronic venous ulceration has an estimated prevalence of from 0.06 to 1.3% with about 57 to 80% of patients with leg ulcers having demonstrable venous disease. The sequence of events whereby chronic venous insufficiency leads to leg skin ulceration is not yet worked out. Venous hypertension may set the stage for subsequent ulcer development via linkages to observed changes in skin microvessel metrics, morphology, rheology, permeability, hemodynamics, and the interstitium. Periulcer measurements show decreased transcutaneous oxygen and elevated carbon dioxide tensions, yet the skin blood perfusion measured with laser Doppler fluxometry (LDF) is reported to be elevated. This elevated perfusion, (Q), could be due to independent changes in blood velocity (U), and volume (V), with different mechanistic implications depending on the mode. Thus, we sought to determine the relative contributions of these two components with the aim of clarifying the mechanism responsible for the reported skin flow changes. Patients studied (n = 16) had unilateral venous ulcers, an ankle/brachial BP index > 0.8, and venous pathology demonstrated by duplex imaging. Ulcer areas ranged from 0.6 to 76.9 cm2 (mean = 13.7 cm2) and were present for 2 to 144 months, mean = 32. With the patient supine, Q (ml/min/100 g), V (%), and U (mm/sec) were measured by LDF (Vasamedics, BPM403A) at two to three sites on periulcer skin and compared with measurements at corresponding sites on the nonulcerated limb at local skin temperatures of 35 and 44. Results confirm an elevation in basal periulcer flow (7.0 vs 1.8 ml/min/100 g, P = 0.001) and show this to be due to elevations in both circulating blood volume (1.24 vs 0.62%, P < 0.001) and velocity (1.23 vs 0.65 mm/sec, P = .004). Maximal Q, V, and U were also higher on the ulcer leg, being for Q, 11.2 vs 6.42 ml/min/100 g, P = 0.03; for V, 1.49 vs 1.13%, P = .002; and for U, 1.76 vs 1.33 mm/sec, P = 0.020. Expressing each leg's basal values as a percentage of its own maximal response shows the ulcerated leg to have higher values for Q, V, and U, with (ulcer leg/control leg) ratios being 2.5, 1.8, and 1.4, respectively. These findings show that the LDF perfusion increase is due to roughly equal increases in microvessel circulating blood volume and velocity.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2001

Investigation and treatment of chronic venous ulcer disease.

INTRODUCTION: The investigation and treatment of chronic venous ulceration continues to present many difficulties for the clinician. The uncertainties relate to the appropriate use of different forms of investigation and whether conservative treatment or surgical treatment should be used. METHOD: A comprehensive search was undertaken of published literature on venous ulceration. RESULTS: The extent of investigations is largely determined by the type of treatment that the patient is either fit to undertake or is prepared to undertake. When conservative treatment only is to be used, detailed investigation of the venous system is not required. The role of surgery to the veins remains unproven in improving the healing of venous ulcers. Surgery to prevent ulcer recurrence has been demonstrated to be of benefit only in patients who have normal deep veins. CONCLUSIONS: Investigations performed on the venous system should be determined by the planned treatment. Many of the operations that have been performed on the venous system still remain unproven in providing a benefit to the healing of venous ulcers and in preventing venous ulcer recurrence.

Bandages↗
PubMed2005

Distally based sural flap in treatment of chronic venous ulcers.

The treatment of venous ulcers of the leg often fails to heal because venous ulcers are mostly associated with severe lipodermatosclerosis. These complicated ulcers may require correction of local hemodynamics, excision of ulcer with surrounding lipodermatosclerotic skin, and replacement of the defect with healthy tissue. We present our experience with the use of the distally based sural flaps for the reconstruction of soft-tissue defects of the distal region of the lower limb in patients with chronic venous ulcer. Between 2001 and 2003, 12 patients with venous ulceration were treated with distally based sural flaps. At operation, the ulcer and its surrounding lipodermatosclerotic skin were excised. The defects after excision ranged from 3 x 3 to 11 x 17 cm. The distally based sural artery flap was inset within the defect. In all patients, the flap survived completely, and in only 1 patient, distal venous congestion was seen and was treated successfully with leeches. There was donor site skin graft loss in 2 patients. Two flaps had minor local complications that healed with local wound care. No recurrent ulcers were identified after average 19.7 months. In conclusion, the distally based sural flaps can be used reliably for treatment of venous ulcers. Our approach in treatment of chronic venous ulcers improves venous hemodynamics and provides local flap alternative that should be considered prior to a free-flap transfer for closure of the defect.

Adult↗
PubMed2005

The role of nitric oxide in the pathogenesis of venous ulcers.

Chronic venous insufficiency frequently leads to ulceration. The exact pathophysiological mechanisms underlying the development of venous ulceration remain to be elucidated. One major etiological factor of the trophic changes is the phenomenon of leukocyte trapping. The aim of the study was to review the pathophysiological events culminating in venous ulceration, focusing primarily on the role of alterations in nitric oxide (NO) production. We establish the hypothesis that venous stasis in the microcirculation reduces the rate of shear stress on the endothelial cells, effectively resulting in a decrease in cellular levels of NO, a key event of enhanced adhesion molecule expression and subsequent massive neutrophil activation. A similar series of events is proposed to explain the ischemic-reperfusion tissue injury. Inducible NO (iNO) produced by the inflammatory cells causes free radical injury seen as a venous ulceration.

Humans↗
PubMed2026

Impact of NR4A3 on wound healing in chronic venous ulcers and its association with the PI3K/Akt signaling pathway.

BACKGROUND: To investigate the role of NR4A3 in chronic venous ulcer (VU) wound healing and to explore its potential regulatory mechanism involving the PI3K/Akt pathway. METHODS: Differential expression and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the GSE174661 dataset. DEGs were filtered by |log2FC| > 1 and adjusted P < 0.05, with KEGG significance set at P < 0.05. NR4A3 was identified as the core gene. NR4A3 knockdown and overexpression were established in HaCaT cells to evaluate proliferation, migration, and inflammatory cytokines. TNF-&#x3b1; was used to mimic the inflammatory microenvironment. Western blotting assessed phosphorylation of GSK3&#x3b2;, mTOR, PI3K, and Akt. PI3K/Akt agonist 740Y-P and inhibitor LY294002 were used in rescue experiments. RESULTS: Bioinformatic analysis revealed that NR4A3 expression was markedly downregulated in chronic venous ulcer (VU) tissues relative to normal skin and ordinary acute wound tissues. Differentially expressed genes were significantly enriched in the PI3K/Akt signaling pathway. TNF-&#x3b1; stimulation significantly upregulated NR4A3 expression and increased phosphorylation of GSK3&#x3b2; and mTOR in HaCaT cells. In cultured HaCaT keratinocytes, NR4A3 knockdown suppressed cell proliferation and invasion, enhanced cell migration, and elevated the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8, CXCL5), accompanied by reduced phosphorylation of PI3K and Akt. Conversely, NR4A3 overexpression promoted cell proliferation and invasion, restrained migration, and dampened inflammatory responses, while increasing PI3K/Akt phosphorylation. Treatment with the PI3K/Akt agonist 740Y-P partially rescued the impaired proliferation, aberrant migration, and excessive inflammation caused by NR4A3 silencing, whereas PI3K/Akt inhibitor LY294002 aggravated pathway suppression. These findings suggest that NR4A3-associated changes in keratinocyte functions and inflammatory reactions are functionally linked to PI3K/Akt pathway activity, and inflammatory stimulation activates GSK3&#x3b2;/mTOR signaling accompanied by compensatory NR4A3 upregulation. CONCLUSION: These findings suggest that NR4A3 is associated with keratinocyte behavior and inflammatory responses via the PI3K/Akt pathway, potentially affecting chronic VU progression and healing. Reduced NR4A3 may impair wound repair through inflammation and abnormal cell migration, while TNF-&#x3b1; induces compensatory NR4A3 elevation.

NR4A3↗
PubMed1989

The bacteriology of chronic venous ulcers treated with occlusive hydrocolloid dressings.

The bacterial flora of chronic venous ulcers treated with an occlusive hydrocolloid dressing were studied over a period of 8 weeks. A novel exudate sampling method was used in an attempt to isolate anaerobic bacteria. The flora was generally stable. Once a species was present, it remained with the exception of Pseudomonas, which appeared to be inhibited by the dressing. Twelve out of 20 ulcers contained anaerobic bacteria and healing did not appear to be impaired by the presence of any particular species of bacteria.

Aged↗