Dermal Ulcers Research Articles

Collagen-embedded platelet-derived growth factor DNA plasmid promotes wound healing in a dermal ulcer model.

Gene therapy has shown limited efficacy for treating congenital diseases, partly due to temporary gene expression and host immune responses. Such results suggest that gene therapy is ideal for chronic wound treatment where limited duration of target gene expression is required. This study tested the wound healing effects of topically applied platelet-derived growth factor (PDGF)-A or -B chain DNA plasmids embedded within a collagen lattice. Four 6-mm dermal ulcer wounds were created in the ears of young adult New Zealand White rabbits made ischemic by division of the central and rostral arteries. Wounds were treated with lyophilized collagen containing PDGF-B DNA (1.0-3.0 mg), PDGF-A DNA (1.0 mg), irrelevant DNA (1.0 mg), or collagen alone. Wounds were dressed and harvested after 10 days for measurement of granulation tissue formation, epithelialization, and wound closure. Results were evaluated with a paired two-tailed Student t test, with P values < 0.05 considered significant. PDGF-B DNA increased new granulation tissue (NGT) formation up to 52% and epithelialization 34% compared with controls. Wound closure was increased up to threefold. At 1.0 mg DNA, PDGF-A and PDGF-B stimulated similar responses. No difference in NGT or epithelialization was seen between control groups. PDGF DNA gene therapy is effective at accelerating wound healing in ischemic dermal ulcers and provides a viable alternative to peptide growth factor therapy.

Dermal ulcerations and mortalities of estuarine fishes as indicators of environmental problems

Dermal ulcers appeared in young menhaden Brevoortia tyrannus in 1984. Field sampling showed dermal ulcers in this clupeid and in species of other families of fish from Delaware to Florida. Some mortalities were associated with the lesions. No definitive causative organism or process of lesion development was discovered and the disease was called Ulcer Disease Syndrome (UDS) by some investigators. Because various fungi were found in many of the sores, the disease was termed Ulcerative Mycosis (UM) by others. The epizootic waned around 1989–1990 as did political and scientific interest. Renewed attention, due to outbreaks of ulcers and mortalities of fish attributed to the toxic dinoflagellate Pfiesteria piscicida, revealed that UDS/UM had persisted in many East Coast estuaries. In North Carolina and Chesapeake's Pocomoke River, fish have died and some humans seem to have been affected. River closures resulted. The extent and nature of dinoflagellate and/or fungal involvement in ulcer epizootics of menhaden is under investigation. Unfortunately, ulcerations in other fishes are being largely ignored. Regardless of the principal causative organisms or the detailed processes involved in ulcer initiation and development and associated (?) mortalities, adverse environmental factors seem to have been involved in both epizootics.

Associations of several externally visible lesions in finfishes with contaminated sediments in the lower Chesapeake Bay

Virginia's Elizabeth River, an industrialized tributary of the lower James River, is ideal for studies of effects of pollution. In some locations its sediments and associated waters are heavily contaminated by polycyclic aromatic hydrocarbons (PAHs), among other toxicants. Fishes were trawled from stations along the river during 1982–1984. Controls were from a ‘cleaner’ tributary nearby. Over 94,000 individuals of 49 species came from the Elizabeth while about 17,000 individuals of 20 species came from the Nansemond. Lesions were found among the Elizabeth River samples: none were found in the Nansemond's. Most heavily affected were the ocean-spawning Sciaenidae, Spot, Croaker and Weakfish. To learn whether lesions develop outside the Elizabeth River, a second series of fish samples was collected from stations extending from the Bay mouth into the Elizabeth and from the ‘clean’ York River. A total of 5154 individuals were involved. Of the externally visible lesions seen in both series eye abnormalities (mostly cataracts), fin erosion and dermal ulcerations were the most common. Comparisons of their prevalences by station show a clear positive relationship with PAH-contaminated sediments.

Cladosporiosis in a tomato clownfish (Amphiprion frenatus).

Infection with Cladosporium sp., a deuteromycete, caused a deep dermal ulcer that extended to bone in a cultured tomato clownfish (Amphiprion frenatus). The infection may have been secondary to immunosuppression resulting from transport or confinement-induced stress or may have resulted from chronic exposure to copper. Reports of fungal infections in tropical marine fish are rare.

Viremia-associated ana-aki-byo, a new viral disease in color carp Cyprinus carpio in Japan.

A new virus disease that displays dermal ulceration and high mortality has been occurring since 1996 in color carp Cyprinus carpio reared in warm water in Japan. In histological examinations, initial erosive lesions displayed necrosis, hemorrhage and fibrin deposition in the dermal loose connective tissue and were accompanied by the partial destruction of the epidermis. Developed ulcerative lesions involved the lateral musculature with bacterial invasions. In visceral organs, necrotic cells were observed in the hematopoietic tissue, the spleen and the intestinal tissues as well as in cardiac muscle fibers which showed no signs of bacterial invasion. Electron microscopy revealed corona-like virus particles in these necrotic cells. The necrotic cells of the hematopoietic tissue and the spleen were accompanied by the formation of tubular structures and crystalline inclusions. The putative virus was isolated and cultured in epithelioma papillosum cyprini (EPC) cells. Carp experimentally inoculated with the cultured virus showed virus transmission, and the same pathological signs of the disease and mortalities as in natural infections.

Varracalbmi: a new bacterial panophthalmitis in farmed Atlantic salmon, Salmo salar L.

The present authors report the first description of a bacterial disease, Varracalbmi, recorded sporadically among seawater‐reared Atlantic salmon in northern Norway between 1989 and early 1992. The causative organism, a Gram‐negative, non‐motile, capsule‐forming, oxidase‐positive and facultatively anaerobic rod, has not previously been described. The mean water temperatures during the outbreaks varied from 2.5 to 8 °C. The disease was characterized by haemorrhagic and necrotizing pyogranulomatous inflammation which targeted the eye and resulted in panophthalmitis. Accompanying lesions included deep dermal ulcerations, necrotizing and haemorrhagic pyogranulomatous lesions in the visceral organs, and necrosis of the pseudobranch. The proposed name of the disease, Varracalbmi, is the Lappish name for ‘bloody eye’.

Current therapies for wound healing: electrical stimulation, biological therapeutics, and the potential for gene therapy.

It has long been known that dermal wounds may show The healing of wounds results from a number of temporally impaired healing in patients with peripheral arterial occlusco-ordinated processes that involve several events driven ive disease (PAOD), deep vein thrombosis (DVT), and by locally released mediators.1–11 The first event is immedidiabetes. For example, wounds in diabetic patients heal ate and consists of the activation of the coagulation cascade very slowly or not at all when compared with wounds and the production of a blood clot. After several minutes, in nondiabetics. Despite intense investigation, the precise an acute inflammatory response ensues. Subsequently, molecular mechanisms associated with impaired healing in leukocytes clear the wound of debris and release growth this patient group are poorly understood. A number of factors to initiate the healing process. Then follows the laboratories have shown reductions in the levels of growth first stage of collagen repair involving deposition and the factors and their receptors. These include PDGF recepformation of granulation tissue which becomes a new and tors,20 IGF-I and IGF-II,21 keratinocyte growth factor temporary weak tissue. The third and final process is the (KGF),22 TGFβ and IGF-I,23 TGFβ1,2,3 and receptors.24 second phase of collagen repair resulting in extracellular Consistent with these findings, several groups have shown matrix remodeling, angiogenesis, and the reproduction of that the application of growth factors may induce the full strength tissue comparable to the original skin. Much acceleration of cutaneous wound healing in murine models of the normal healing process is driven by growth factors. of diabetes. These studies are described later. In addition to their role in blood clot formation, platelets generate a number of growth factors that are found in wound fluid, including transforming growth factor α Healthcare burden for the treatment of (TGFα), platelet-derived growth factor (PDGF), epidermal chronic wounds growth factor (EGF), vascular endothelial growth factor (VEGF), transforming growth factor β (TGFβ), and insulinUlcers associated with pressure and arterial and venous like growth factor I (IGF-I).12–15 In the inflammatory diseases response, neutrophil migration is induced by PDGF, Dermal ulcers are a common complication and frequent interleukin 1α (IL1α), IL8, tumor necrosis factor α (TNFα), cause of hospital admission for many patients suffering granulocyte macrophage colony-stimulating factor with diabetes. In 1992, in the UK, 2% of the diabetic (GM-CSF), and granulocyte colony-stimulating factor population were documented as having ulcer history with (G-CSF).16–19 Thus, multiple growth factors and cytokines approximately 0.5% having active ulcers at any one time.25 There is a marked increase in dermal ulcer prevalence play a major role in wound healing. 808

Chronic venous insufficiency is associated with increased platelet and monocyte activation and aggregation

Purpose: This study assessed whether the increased numbers of platelet-monocyte aggregates observed in patients with venous stasis ulceration (VSU) represent a response to dermal ulceration or if it is a condition associated with underlying chronic venous insufficiency (CVI). We also analyzed the expression of CD11b in patients with CVI to determine whether leukocyte activation, known to occur in VSU, is a precursor of or a response to ulceration. Methods: Patients with varying classes of CVI (n = 24) and healthy control subjects (n = 15), whose status was documented by means of duplex scanning, stood upright and stationary for 10 minutes. Two aliquots of blood, drawn from a distal leg vein and an antecubital fossa vein, were incubated with either buffer or one of three platelet agonists. After fixation, these samples were further incubated with fluorescent-labeled monoclonal antibodies (f-MoAb) specific for CD14 (monocytes) and CD61 (platelets). The activated leukocyte assay was performed by incubating another aliquot of the blood samples with f-MoAb specific for CD11b and CD14. All samples were evaluated by means of flow cytometry. Results: We observed significantly more platelet-monocyte aggregates throughout the circulation in patients with CVI than in control subjects (29% vs. 8%; P < .0002). Furthermore, patients with CVI formed significantly more of these aggregates in response to all platelet agonists than did control subjects. There were no significant differences between baseline numbers of aggregates or response to agonists in patients who had CVI with (n = 10) or without (n = 14) ulceration. Patients with CVI had more circulating platelet-neutrophil aggregates than control subjects (7.2% vs. 3.6%; P = .05). The addition of platelet agonists to the blood of patients with CVI resulted in more platelet-neutrophil aggregates than in control subjects. Monocyte CD11b expression was higher in patients with CVI than in control subjects (7.5 vs. 3.7; P < .01), with no differences noted in CD11b expression between patients with or without ulceration. Neutrophil CD11b expression was low and similar in control subjects and patients with CVI. Conclusion: All classes of CVI are associated with significantly increased percentages of platelet-monocyte aggregates and increased percentages of platelet-neutrophil aggregates throughout the circulation. The presence of more of these aggregates and the increased propensity to form aggregates in the presence of platelet agonists in all classes of CVI suggests an underlying state of platelet activation and increased reactivity that is independent of the presence of ulceration. The increased expression of monocyte CD11b throughout the circulation in all classes of CVI suggests that although systemic monocyte activation occurs in CVI, its presence is independent of VSU as well. (J Vasc Surg 1999;30:844-53.)

Effects of keratinocyte growth factor-2 (KGF-2) on wound healing in an ischaemia-impaired rabbit ear model and on scar formation.

Keratinocyte growth factor-2 (KGF-2), also described as fibroblast growth factor-10 (FGF-10), is a member of the fibroblast growth factor family. KGF-2 shares 57 per cent sequence homology to previously reported KGF-1 (FGF-7). In skin, both growth factors are expressed in the dermal compartment. KGF-1 and KGF-2 bind to the same receptor with high affinity, the KGFR isoform of FGFR2, which is exclusively expressed by epithelial cells. This study examines the in vivo function of topically applied KGF-2 on wound healing using an ischaemia-impaired rabbit dermal ulcer model, in young and aged animals. Histological analysis of the wounds showed that KGF-2 significantly promoted re-epithelialization in both young and old animals. Similar results have been observed with KGF-1 in this model. In addition, KGF-2 enhanced granulation tissue formation in both young and old rabbits, a biological effect not found with KGF-1, suggesting a possible indirect mechanism which enhances neo-granulation tissue formation. Immunohistological staining of day 7 wounds with proliferating cell nuclear antigen (PCNA) antibody demonstrated a significant increase of dermal cell proliferation in KGF-2-treated wounds compared with placebo wounds. These results suggest a mesenchymal-epithelial interaction that is mediated by a paracrine feedback loop of KGF-2. Because of the wound healing impairment observed with ageing, the wound healing response to KGF-2 was also studied in ischaemic wounds of aged animals. Administration of KGF-2 led to significant stimulation of epithelial growth and granulation tissue formation. The effects seen in the old animals were delayed compared with the young animals. Lastly, the effect of KGF-2 was examined in a rabbit model of scar formation. Quantification of scar elevation index showed no significant differences in scar formation when KGF-2 was compared with buffer placebo. Compared with other growth factors, including KGF-1 and TGF-beta which have previously been examined in these models, KGF-2 is the most effective and causes no obvious scarring.

Vascular endothelial growth factor is more important than basic fibroblastic growth factor during ischemic wound healing.

To test the influence of vascular endothelial growth factor (VEGF) on normal and ischemic wounds in a noncontractive dermal ulcer standardized model in the rabbit ear and to assay the levels of both VEGF and basic fibroblastic growth factor messenger RNA levels in normal and ischemic wounds at different intervals during the healing process. Dermal ulcers were created in the normal and ischemic ears of 20 anesthetized young female New Zealand white rabbits. Either VEGF 121, VEGF 165 (30 microg per wound), or buffered saline solution alone was applied to each wound and covered. Wounds were harvested at day 7 or 10 and evaluated histologically. Twenty-four similar rabbits were wounded in the same manner and their untreated wounds were harvested at 1, 3, 7, and 10 days after wounding. The wounds were analyzed with reverse transcriptase polymerase chain reaction. Histologic specimens were measured for amount of new epithelium and granulation tissue. Reverse transcriptase polymerase chain reaction was used to determine basic fibroblastic growth factor and VEGF messenger RNA expression. Both isoforms of VEGF improved granulation tissue formation in both normal and ischemic wounds with a magnitude similar to other vulnerary agents tested in the past. Vascular endothelial growth factor application had no effect on new epithelium formation. In contrast to basic fibroblastic growth factor, VEGF messenger RNA levels were induced 4 fold by ischemia alone and 6 fold by wounding in both ischemic and normal wounds. Vascular endothelial growth factor seems to be more important than basic fibroblastic growth factor during ischemic wound healing. Treatment of ischemic wounds with VEGF improves the deficit in wound healing produced by ischemia.

Transforming Growth Factor-β1 Fails to Stimulate Wound Healing and Impairs Its Signal Transduction in an Aged Ischemic Ulcer Model: Importance of Oxygen and Age

Clinical trials of exogenous growth factors in treating chronic wounds have been less successful than expected. One possible explanation is that most studies used animal models of acute wounds in young animals, whereas most chronic wounds occur in elderly patients with tissue ischemia. We described an animal model of age- and ischemia-impaired wound healing and analyzed the wound-healing response as well as the transforming growth factor (TGF)-beta1 effect in this model. Rabbits of increasing ages were made ischemic in the ear where dermal ulcers were created. Histological analysis showed that epithelium ingrowth and granulation tissue deposition were significantly impaired with increased age under ischemia. TGF-beta1 stimulated wound repair under both ischemic and non-ischemic conditions in young animals, although it showed no statistical difference in aged animals. Procollagen mRNA expression decreased under ischemic conditions and with aging. Neither TGF-beta1 nor procollagen alpha1(I) mRNA expression increased in response to TGF-beta1 treatment under ischemia in aged animals. Therefore, the wound-healing process is impaired additively by aging and ischemia. The lack of a wound-healing response to TGF-beta1 in aged ischemic wounds may play a role in the chronic wounds.

Wound healing A pilot study using an essential oil-based cream to heal dermal wounds and ulcers

The Wound Heal Formula (containing the “active ingredients” of various aromatic plant extracts and mostly highly polyunsaturated vegetable oils) has been observed to significantly decrease the healing time of a variety of wounds in nursing home residents, as detailed by nursing staff. Such results were most notable in the treatment of very slow healing wounds or wounds in stasis (where the wound remains unchanged for extended periods). Here application of WHF would stimulate the growth of healthy granulation tissue and lead to complete healing, often in relatively short periods of time. Further research on the wound healing properties of essential oils could fruitfully consider these issues: 1. ⊎Is this simply a function of stimulating cell division in the germinative layer of the epidermis and if so, how is this accomplished? 2. ⊎Do essential oils increase angiogenesis (the formation of the blood vessels) within the wound, or otherwise affect the micro-circulation? 3. ⊎Do the antiseptic properties of essential oils also play a role in healing times?

Induction of Collagenase-3 (MMP-13) Expression in Human Skin Fibroblasts by Three-dimensional Collagen Is Mediated by p38 Mitogen-activated Protein Kinase

Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against alpha1 and alpha2 integrin subunits and augmented by activating antibody against beta1 integrin subunit, indicating that both alpha1 beta1 and alpha2 beta1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimensional collagen. Collagen-related induction of MMP-13 expression was dependent on tyrosine kinase activity, as it was abolished by treatment of fibroblasts with tyrosine kinase inhibitors genistein and herbimycin A. Contact of fibroblasts to three-dimensional collagen resulted in simultaneous activation of mitogen-activated protein kinases (MAPKs) in three distinct subgroups: extracellular signal-regulated kinase (ERK)1 and ERK2, Jun N-terminal kinase/stress-activated protein kinase, and p38. Induction of MMP-13 expression was inhibited by treatment of fibroblasts with a specific p38 inhibitor, SB 203580, whereas blocking the ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by PD 98059, a selective inhibitor of MEK1,2 activation potently augmented MMP-13 expression. Furthermore, specific activation of ERK1,2 pathway by 12-O-tetradecanoylphorbol-13-acetate markedly suppressed MMP-13 expression in dermal fibroblasts in collagen gel. These results show that collagen-dependent induction of MMP-13 in dermal fibroblasts requires p38 activity, and is inhibited by activation of ERK1,2. Therefore, the balance between the activity of ERK1,2 and p38 MAPK pathways appears to be crucial in regulation of MMP-13 expression in dermal fibroblasts, suggesting that p38 MAPK may serve as a target for selective inhibition of collagen degradation, e.g. in chronic dermal ulcers.

Surgical Intervention in Venous Ulceration

The purpose of this article is to review surgical management for dermal ulceration that results from chronic venous insufficiency. Efficacy is gauged by freedom from recurrent ulceration, an objective clinical monitor. Accurate preoperative diagnosis and postoperative assessment of the venous circulation is enhanced by reliable non-invasive examinations. A recently developed clinical classification unifies reporting criteria and has been widely subscribed. Standard surgical ablation of incompetent saphenous and other superficial veins significantly improves clinical and hemodynamic outcome. Perforator incompetence alone is rarely the cause of ulcerative disease, but adjunctive ligation of communicating veins is considered important to the effective elimination of chronic venous insufficiency. New endoscopic techniques reduce morbidity associated with long incisions from the open subfascial procedure. In a more advanced role, deep venous reconstruction is infrequently performed, but is quite durable. Free-tissue transfer appears to be effective after 2 years of observation. Post-thrombotic chronic venous insufficiency continues to confer a more severe prognosis, which emphasizes the importance of accurate and precise diagnosis. Investigation of patients with ulcerative chronic venous insufficiency should be actively pursued, since individualized surgical management will effectively reduce recurrence of ulceration.

Surgical intervention in venous ulceration

The purpose of this article is to review surgical management for dermal ulceration that results from chronic venous insufficiency. Efficacy is gauged by freedom from recurrent ulceration, an objective clinical monitor. Accurate preoperative diagnosis and postoperative assessment of the venous circulation is enhanced by reliable non-invasive examinations. A recently developed clinical classification unifies reporting criteria and has been widely subscribed. Standard surgical ablation of incompetent saphenous and other superficial veins significantly improves clinical and hemodynamic outcome. Perforator incompetence alone is rarely the cause of ulcerative disease, but adjunctive ligation of communicating veins is considered important to the effective elimination of chronic venous insufficiency. New endoscopic techniques reduce morbidity associated with long incisions from the open subfascial procedure. In a more advanced role, deep venous reconstruction is infrequently performed, but is quite durable. Free-tissue transfer appears to be effective after 2 years of observation. Post-thrombotic chronic venous insufficiency continues to confer a more severe prognosis, which emphasizes the importance of accurate and precise diagnosis. Investigation of patients with ulcerative chronic venous insufficiency should be actively pursued, since individualized surgical management will effectively reduce recurrence of ulceration.

Epizootic Ulcerative Syndrome (EUS), associated with a fungal pathogen, in Indian fishes: histopathology—`a cause for invasiveness'

A highly invasive fungus is associated with Epizootic Ulcerative Syndrome (EUS) in Indian fishes. The fungal invasion and associated pathology is not confined to the region of dermal ulcers. The fungus invades and proliferates in tissues away from the site of dermal ulcers and even penetrates across the vertebral septum to the contra-lateral side. The fungus readily invades the body cavity and produces mycotic granulomas in all the visceral organs. The invasive ability of the fungus is further demonstrated by its presence in the gizzard, spinal cord and intermuscular bones. The invasive nature of the fungus and associated tissue necrosis observed in a wide range of fresh and brackishwater fish hosts during natural epizootics present a plausible explanation for its high virulence and possible importance in defining the primary etiology of EUS.

Epidemiological study of chronic dermal ulcers in China.

A total of 30,000 hospitalized surgical patients in 15 hospitals were screened for chronic ulcers. A total of 489 patients with chronic dermal ulcers were found with their major causes of ulceration including traumatic wounds, infections, diabetes mellitus, and venous diseases. Patients with chronic ulcers following trauma and infection comprised 67.48% of the total patient population. The incidence of diabetic ulcers and venous ulcers was 4.91% and 6.54% respectively. Sites of ulceration differed with different etiological factors. The percentage of chronic dermal ulcers in the lower extremities, upper extremities, thorax and abdomen, back, and head was 63.10%, 17.93%, 7.76%, 4.83% and 6.38% respectively. Of the 489 patients with chronic ulcers, 183 were farmers (37.42%), and 131 were workers (26.79%). Chronic dermal ulcers were more common in men than in women, but there was no significant difference in the sex-related prevalence. According to these data from different hospitals, the incidence of chronic ulcers in patients hospitalized for surgery was 1.5% to 3.0%. These data have primarily shown the prevalence and clinical characteristics of chronic ulcers in hospitalized patients in China. These data may not be consistent with reports from other countries. Significant differences in etiological factors of ulceration, professional distribution of patients with chronic dermal ulcers, and treatment methods were found when compared with reports of studies conducted in developed countries. Our results will benefit not only additional basic research, but these data will also be useful in preventing and managing chronic wounds in developing countries.

Macrophage Colony-Stimulating Factor Accelerates Wound Healing and Upregulates TGF-β1 mRNA Levels through Tissue Macrophages

Macrophage colony-stimulating factor (M-CSF) is produced by many cell types involved in wound repair, yet it acts specifically on monocytes and macrophages. The monocyte-derived cell is thought to be important in wound healing, but the importance of the role of tissue macrophages in wound healing has not been well defined. Dermal ulcers were created in normal and ischemic ears of young rabbits. Either rhM-CSF (17 μg/wound) or buffer was applied to each wound. Wounds were bisected and analyzed histologically at Days 7 and 10 postwounding. The amounts of epithelial growth and granulation tissue deposition were measured in all wounds. The level of increase of TGF-β1 mRNA level in M-CSF-treated wounds was examined using competitive RT-PCR. M-CSF increased new granulation tissue formation by 37% (N= 21,P< 0.01) and 50% (P< 0.01) after single and multiple treatments, respectively, in nonischemic wounds. TGF-β1 mRNA levels in rhM-CSF-treated wounds increased 5.01-fold (N= 8) over vehicle-treated wounds under nonischemic conditions. In contrast, no effect could be detected in ischemic wounds treated with rhM-CSF, and these wounds only showed a 1.66-fold increase in TGF-β1 mRNA levels when compared to ischemic wounds treated with vehicle alone. GAPDH, a housekeeping gene, showed no change. As mesenchymal cells lack receptors for M-CSF, the improved healing of wounds treated with topical rhM-CSF must reflect a generalized enhancement of activation and function of tissue macrophages, as demonstrated by upregulation of TGF-β. The lack of effect under ischemic conditions suggests that either macrophage activity and/or response to M-CSF is adversely affected under those conditions; this may suggest the pathogenesis of impaired wound healing at the cellular level.

Prognostic value of the clinical examination of the diabetic foot ulcer

To determine the value of the history, physical examination, and magnetic resonance imaging (MRI) in predicting successful primary healing of a foot ulcer in a diabetic patient. Prospective cohort study. Durham (NC) Veterans Affairs Medical Center. Sixty-four consecutive diabetic patients with 78 dermal ulcers through the full thickness of the skin and at or distal to the malleoli of the ankle. A structured clinical history and physical examination were performed by two examiners, a physician participating in the study and the referring physician. Fifty of these patients with 63 ulcers underwent MRI. Patients were followed prospectively for 6 months after enrollment to ascertain healing of the ulcer, amputation, and death. During the 6-month follow-up period, 8 (13%) of the patients died. Seventeen (22%) of the ulcers were amputated, 17 (22%) of the ulcers failed to heal, and 36 (47%) healed primarily. Univariate predictors of healing at 6 months included age less than 65 years, diagnosis of diabetes within the last 15 years, painless ulcer, palpable ankle pulse, anklebrachial index greater than 0.5, and the physician's assessment of the overall likelihood of osteomyelitis. In a multivariable logistic regression model, predictors of healing included the presence of an audible pulse on Doppler examination (p = .01) and a painless ulcer (p = .04). The diagnosis of osteomyelitis on MRI did not predict healing in these patients. Foot ulcers in patients with diabetes frequently have poor outcomes; fewer than half the patients in this study healed their ulcers within 6 months. The vascular components of the clinical examination are the best predictors of healing in patients with a diabetic foot ulcer.

Transforming growth factor beta 3 (TGF beta 3) accelerates wound healing without alteration of scar prominence. Histologic and competitive reverse-transcription-polymerase chain reaction studies.

Transforming growth factor (TGF) beta 3 is a new isoform of the TGF beta superfamily and is presumed to play an important role in wound repair and scarring. To examine the effects of TGF beta 3 on wound healing and on reducing scarring. Dermal ulcers were created on the ears of 75 anesthetized young female rabbits. Either TGF beta 3 or vehicle was applied topically to the wounds. Wounds were bisected and analyzed histologically at postwounding day 7. A second group of wounds was treated with topical TGF beta 3 and TGF beta 2 or vehicle at days 0 and 3 and harvested at days 21 through 42 as an excessive scarring model. The third group of wounds was treated with TGF beta 1, TGF beta 2, and TGF beta 3 and vehicle. The granulation tissue was harvested at day 7, and cellular RNA was extracted for performing competitive reverse-transcription polymerase chain reaction. The amount of new epithelium and granulation tissue was measured in TGF beta 3- and vehicle-treated wounds. The hypertrophic index was calculated for scarring wounds treated with TGF beta 2 and TGF beta 3 or vehicle. Levels of TGF beta 1 messenger RNA were measured in those wounds that were treated with TGF beta 1, TGF beta 2, and TGF beta 3 and in their controls. The use of TGF beta 3 (0.3-0.75 microgram per wound) increased granulation tissue formation by more than 100% (P < .005). Epithelialization showed a biphase, either increasing 30% (P < .04) or decreasing 25% (P < .001) dependent on dose. No significant difference in the hypertrophic index was noted in TGF beta 3-treated wounds compared with controls. Levels of TGF beta 1 messenger RNA increased (7.1- to 14.9-fold) in those wounds treated with TGF beta s compared with controls at day 7. Exogenous TGF beta 3 displays substantial vulnerary properties in wound healing and may be useful in treating nonhealing wounds. However, the observation that TGF beta 3 can reduce scarring was not confirmed in this study, and the messenger RNA level in response to TGF beta 3 suggests that it behaves similarly to TGF beta 1.