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Biomedical subjects

V Falanga

Publications and source records attributed to V Falanga.

At least 55 records · Page 3Linked to original sources
PubMed1997

Pericapillary fibrin cuffs in venous disease. A reappraisal.

BACKGROUND: Over the last several years, a number of hypotheses have been proposed to explain the pathogenesis of venous ulceration. According to an early model suggested by Browse and Burnand, pericapillary fibrin cuffs, developing as a result of venous hypertension and extravasation of fibrinogen, act as a barrier to the diffusion of oxygen and nutrients; ultimately, tissue anoxia, cell death, and ulceration would follow. More recent hypotheses include the idea that macromolecules leaking from the vasculature trap growth factors and adhesion molecules, and the notion that white blood cells adhere to and damage endothelial cells in the microcirculation. OBJECTIVE: To review the available evidence for or against a pathogenic role of fibrin cuffs, and hope to provide a useful perspective for this controversial topic. METHODS: We have reviewed the different hypotheses for venous ulceration and the evidence for and against fibrin cuffs acting as a barrier. CONCLUSIONS: Venous ulceration is likely to be the result of a number of distinct pathogenic events. Pericapillary fibrin cuffs remain a prominent feature, whether they act as a barrier, a marker for endothelial cell damage, or as part of an overall mechanism of macromolecular leakage and trapping.

Capillaries↗
PubMed1997

Initial rate of healing predicts complete healing of venous ulcers.

BACKGROUND: Venous ulcers represent a clinical problem with considerable morbidity, especially in the elderly population. Standard treatment is the use of leg compression bandages to improve the underlying venous hypertension, but not every ulcer heals in a timely fashion with this treatment modality. Methods are needed to predict the outcome of standard treatment as soon as possible to institute alternative therapy. OBJECTIVE: To prospectively study the rate of healing in a group of elderly patients with venous ulcers, based on a previously described equation that takes into account the size and perimeter of the ulcer. METHODS: We studied by computerized planimetry 15 elderly patients with venous ulcers treated with leg compression bandages for up to 24 weeks or until complete healing. We determined weekly healing rate by comparing ulcer size at each visit to initial baseline size (baseline-adjusted healing rate). Also, we used a novel way to calculate the healing rate at a given week by taking the mean of all previous healing rates between each visit (mean-adjusted healing rate). RESULTS: When using the baseline-adjusted healing rate, we noted what we describe as a healing rate instability from week to week, which decreases the ability to predict complete healing. However, the mean-adjusted healing rate allowed us to predict complete healing as early as 3 weeks from starting therapy (P<.001). CONCLUSION: In this prospective study of elderly patients with venous ulcers, we describe a novel and more powerful method for predicting complete healing of venous ulcers with compression therapy alone.

Administration, Cutaneous↗
PubMed1996

Retrovirally mediated gene transfer in a skin equivalent model of chronic wounds.

Given that treatment for chronic wounds is unsatisfactory, it is likely that gene therapy may be tested as a therapeutic modality in this difficult clinical problem. Actively proliferating cells in wounds are also a good target for retroviral transduction, an increasingly useful method for gene therapy. However, it is unclear how gene therapy may best be used in chronic wounds, and experimental models are urgently needed to study and manipulate gene transfer in the context of chronic wounds. In this report, partial- and full-thickness wounds were made in vitro in a human living skin equivalent (LSE) consisting of fully differentiated keratinocytes layered over a collagen matrix seeded with fibroblasts. To mimic a chronic wound situation, we used tissue culture conditions which, as in a chronic wound, allowed fibroblast but not keratinocyte proliferation or migration. The wounded LSE was then placed over a transduced cell line (PA317) which produced a replication defective retrovirus containing as a histological marker the bacterial beta galactosidase gene. Using this close and direct exposure to the virus-producing cell line, distinct staining for beta-galactosidase was observed in partial-thickness wounds, and was limited to fibroblasts away from the upper site of injury and immediately overlying the retrovirus-producing cell monolayer. Expression of beta-galactosidase was uniformly present at the wound edges and along the base of the entire partial thickness wound. These studies demonstrate that, in in vivo conditions mimicking a chronic wound, an intimate apposition of the injured LSE with the virus-producing cell line is needed for gene transfer. Using this in vitro model system, gene transfer protocols may be optimized prior to beginning in vivo studies in chronic wounds.

Culture Techniques↗
PubMed1996

Acute lipodermatosclerosis is associated with venous insufficiency.

BACKGROUND: Acute lipodermatosclerosis is characterized by pain and tenderness in the medial aspect of the leg. It is thought to be the result of venous insufficiency and to be the acute counterpart of chronic lipodermatosclerosis, a hallmark of venous disease. However, there is no direct evidence linking acute lipodermatosclerosis to venous disease. OBJECTIVE: Our purpose was to determine whether acute lipodermatosclerosis is associated with venous insufficiency. METHODS: With air plethysmography, we determined the venous filling index, the ejection fraction, and the residual volume fraction in 15 sequential patients with acute lipodermatosclerosis. RESULTS: Ten of the 15 patients (67%) had at least one abnormal result, eight (53%) had two, and two (13%) had three. In four patients (27%), abnormalities of both reflux and ejection were noted. Duplex venous ultrasonography, in two of the patients with normal results from air plethysmography, showed incompetent perforators at sites of lipodermatosclerosis. CONCLUSION: Acute lipodermatosclerosis is associated with objective findings of venous insufficiency in a high percentage of patients. It is likely that this condition is the result of venous disease.

Acute Disease↗
PubMed1996

Transforming growth factor-beta receptor binding and function are decreased in psoriatic dermal endothelium.

T lymphocyte adhere to dermal microvascular endothelial cells (DMEC.) as the first step in their emigration from the blood vasculature into diseased skin. Earlier studies have shown that the adhesiveness of cultured DMEC. from normal skin for lymphocytes can be blocked by transforming growth factor-beta1 (TGF-beta1). In contrast, TGF-beta1 has no effect on the adhesive properties of DMEC from psoriatic plaques, and this response is attenuated by the addition of interleukin-4 (IL-4). In the present study, we show that both TGF-beta1 and TGF-beta2, and to a lesser extent TGF-beta3 isoforms block the ability of normal but not psoriatic DMEC to bind lymphocytes. Pretreatment with TGF-beta1 selectively inhibited the tumor necrosis factor-alpha(TNF-alpha)-stimulated expression of E-selecting on normal DMEC but had no psoriatic DMEC. Scatchard analysis revealed both low- and high-affinity receptors on normal DMEC. The baseline number of high-affinity TGF-beta receptors was significantly reduced on psoriatic DMEC, whereas IL-4 treatment of DMEC altered the binding affinity but not the number of receptors. The protein and mRNA transcripts of type I and type II TGF-beta receptor genes were detectable in psoriatic DMEC. A reduction in the autophosphorylation the TGF-beta type II receptor protein, a constitutively active serine/threonine kinase, however, was detected in psoriatic DMEC. These in vitro finding suggest that reduction of TGF-beta receptor expression and function may contribute to lymphocyte infiltration into psoriatic plaques in vivo by allowing dermal microvascular endothelium to escape form the negative regulation by TGF-beta.

Blotting, Northern↗
PubMed1996

Topically applied recombinant tissue plasminogen activator for the treatment of venous ulcers. Preliminary report.

BACKGROUND: Increasing evidence suggests that fibrin deposition is an important pathogenic component of venous ulceration and that fibrin removal could accelerate ulcer healing. OBJECTIVE: We sought to determine whether topical application of recombinant tissue plasminogen activator (tPA) compounded in 1% hyaluronate acid (HA) can be used safely in venous ulcers and whether it can accelerate healing. METHODS: Twelve patients were randomized in a double-blind fashion in three sequential groups of four subjects each, so as to receive daily topical application of either placebo (HA alone, one patient) or tPA/HA (three patients) at escalating doses of 0.25, 0.5, and 1.0 mg/ml of tPA for 4 weeks. RESULTS: No safety problems occurred, and we found a close direct correlation between mean ulcer reepithelialization, fibrin removal, and the dose of topically applied tPA (r = 0.991). CONCLUSION: In this first study to examine its usefulness, topically applied tPA appears to be a safe and promising agent for treating venous ulcers.

Administration, Cutaneous↗
PubMed1996

Squamous cell carcinoma arising in osteomyelitis and chronic wounds. Treatment with Mohs micrographic surgery vs amputation.

BACKGROUND: Squamous cell carcinoma (SCC) is a rare, but well-documented complication of osteomyelitis and chronic wounds. Treatment of choice for these tumors commonly occurring on the legs has been amputation. Two recent articles have suggested the utility of Mohs micrographic surgery (MMS) as a limb saving procedure. OBJECTIVE: To discuss the process of decision analysis in patients with SCC arising in osteomyelitis and chronic wounds. METHODS: Four patients with SCC (three developing in association with chronic osteomyelitis, one after a burn wound) are presented. RESULTS: Two patients underwent MMS as a limb-saving procedure, while the other two underwent amputation. Only two of our patients were able to have MMS since we were confronted with factors that precluded the use of this technique. These factors included the presence of metastatic disease and the potential for the loss of a functional limb after surgery. CONCLUSIONS: Our series confirms the utility of MMS as a potentially limb-saving procedure in patients with SCC arising in either chronic wounds or in association with osteomyelitis. Despite this, patients with distant spread of their disease or extensive local disease leading to the potential loss of functional stability of the leg postoperatively may not be candidates for MMS and may require amputation.

Aged↗
PubMed1996

UVB therapy decreases the adhesive interaction between peripheral blood mononuclear cells and dermal microvascular endothelium, and regulates the differential expression of CD54, VCAM-1, and E-selectin in psoriatic plaques.

A dermal lymphocytic infiltrate is a characteristic feature of psoriasis, and may be involved in the pathogenesis of the disease. We have previously shown that specialized dermal microvascular endothelial cells (DMEC) in psoriatic lesions promote the selective adherence of the CD4 CD45Ro helper T-cell subset. In this study, we examined the adhesive interaction between peripheral blood mononuclear cells and psoriatic DMEC in patients treated with ultraviolet B light (UVB), and correlated the results with the expression and function of endothelial adhesion molecules on DMEC. Seven psoriatic patients were exposed to one MED of UVB daily for 14 days, and the binding properties of their peripheral blood mononuclear cells (PBMC), and tissue specimens taken from their lesions on days 0, 2, 3, 6, 8, 11 and 14 of UVB treatment, were studied. The ability of psoriatic PBMC to adhere to non-irradiated control or UVB-treated psoriatic plaques was reduced by 70% after treatment with 2-3 MED, and complete inhibition was obtained after 8-11 MED. In contrast, exposure of psoriatic plaques to 2-3 MED had no effect on the capacity of DMEC to support normal PBMC binding, which was only reduced after 8-11 MED. In addition, psoriatic plaques which were shielded from direct UVB exposure also showed decreased PBMC binding, suggesting a systemic effect of UVB treatment. Immunoperoxidase staining revealed that CD54 (ICAM-1) and E-selectin were strongly expressed on dermal vessels in untreated psoriatic plaques. Treatment of patients with 6-8 MED significantly decreased CD54 and E-selectin expression. In contrast, VCAM-1 expression on untreated plaques was weaker than that of CD54 and E-selectin, but was markedly induced following UVB treatment. In functional blocking studies, preincubation of tissue from untreated psoriatic plaques with anti-E-selectin antibody, but not antibodies against CD54 and VCAM-1, significantly inhibited the ability to bind normal PBMC. These observations suggest that UVB treatment interferes with the adhesive properties of both psoriatic PBMC and endothelial cells, and differentially regulates the expression of endothelial adhesion molecules. The study also provided direct evidence for the involvement of E-selectin in the adhesion of circulating lymphocytes to psoriatic endothelial cells.

Adult↗
PubMed1996

Skin grafts as pharmacological agents: pre-wounding of the donor site.

Initially thought to act as tissue replacement, cultured epithelial allografts are now known to work by providing a potent stimulus for healing. In a similar fashion, we believe that traditional autografts may also provide a stimulus to help heal chronic wounds, thus acting as pharmacological agents for healing. We attempted to assess the possibility of augmenting the stimulatory properties of donor skin by initiating the healing process in the donor region prior to grafting. This was accomplished by pre-wounding the donor area 3 days prior to harvesting the donor skin. We compared these 'pre-wounded' grafts to those harvested immediately. Two patients underwent punch grafting for chronic leg ulceration. Half of the ulcer was grafted with donor skin harvested from an area that was pre-wounded and the other half from freshly harvested skin. We evaluated each for improvement of granulation tissue and degree of edge effect (migration of the previously dormant wound edges). All the grafts did well. There was marked improvement in granulation tissue in the ulcer bed after grafting, and the obvious presence of an edge effect. The edge effect was increased on the site where the pre-wounded grafts were placed. It may be possible to augment the growth stimulatory properties of donor skin. This may offer therapeutic options in patients with chronic wounds.

Adult↗
PubMed1995

Decreased levels of alpha 1(I) procollagen mRNA in dermal fibroblasts grown on fibrin gels and in response to fibrinopeptide B.

We have investigated human neonatal fibroblast synthetic activity in response to fibrin substrates and components of fibrin formation and degradation. Greater than threefold downregulation of procollagen mRNA levels was seen 24 hours after fibroblasts were grown on fibrin gels as compared to tissue culture plastic. This downregulation occurred in both reptilase-generated fibrin (retention of fibrinopeptide B) and thrombin-generated fibrin (loss of both fibrinopeptide A and B). However, fibroblasts grown on fibrin retained their capacity to respond to the stimulatory action of transforming growth factor (TGF)-beta 1. Fibroblasts seeded on reptilase-generated fibrin displayed an abnormal morphology manifested by dendritic appearance and cell rounding, while fibroblast attachment was enhanced by 30% on thrombin-generated fibrin substrate (P < 0.02). Fibrinopeptides A and B, which are generated during fibrin formation, increased and decreased procollagen mRNA levels, respectively. Tissue plasminogen activator (t-PA) increased procollagen mRNA and TGF-beta 1 levels as early as 6 hours after cells were grown on tissue culture plastic, but this stimulation did not occur in cells cultured on a fibrin substrate. We conclude that alpha 1(I) procollagen mRNA levels in cultures of human dermal fibroblasts are consistently down-regulated by a fibrin substrate and are directly and profoundly influenced by complex interactions between components involved in the formation and removal of fibrin.

Blotting, Northern↗
PubMed1995

Use of a durometer to measure the degree of skin induration in lipodermatosclerosis.

BACKGROUND: Chronic lipodermatosclerosis is characterized by indurated skin on the medial aspect of the leg and is common around venous ulcers. The severity of induration of lipodermatosclerosis has been associated with poor ulcer healing. Clinical assessment of lipodermatosclerosis presently relies on a clinical skin severity score adapted from studies of patients with systemic sclerosis. OBJECTIVE: It would be desirable for prognostic reasons to develop an objective method for measuring skin hardness in lipodermatosclerosis. METHODS: The degree of skin induration at the midpoint between the upper and lower margin of lipodermatosclerosis in 30 sequential nonselected patients with lipodermatosclerosis was assessed by a blinded observer's clinical score and by quadruplicate determinations with a hand-held type O durometer. Skin induration on the medial aspect of the leg was similarly measured in five normal volunteers. Transcutaneous oxygen pressure was measured at the same sites. RESULTS: A direct linear relation (r = 0.962) was found between skin severity scores and durometer readings (p < 0.01). A clinical skin score of 2 reflected a higher durometer reading compared with a skin score of 1 (p = 0.0016) and, similarly, higher durometer readings were found in skin score of 3 compared with score 2 skin (p = 0.0093). Transcutaneous oxygen pressure was uniformly reduced in lipodermatosclerosis (p < 0.02). CONCLUSION: The durometer is a reliable instrument for measuring skin hardness in patients with lipodermatosclerosis. It may be used to test the prognostic value of lipodermatosclerosis on ulcer healing.

Blood Gas Monitoring, Transcutaneous↗
PubMed1995

Stanozolol as a novel therapeutic agent in dermatology.

Anabolic steroids are synthetic derivatives of testosterone that were developed in the 1950s in an attempt to dissociate the anabolic and androgenic effects of testosterone. The anabolic steroid stanozolol has been particularly helpful because it has one of the largest anabolic/androgenic ratios. In addition, stanozolol has substantial fibrinolytic properties. We discuss the safety profile and the use of stanozolol for a variety of clinical applications. Stanozolol is approved for use in the treatment of hereditary angioedema, but numerous reports have detailed the effectiveness of this agent in the treatment of urticaria, Raynaud's phenomenon, and, more recently, cryofibrinogenemia and lipodermatosclerosis. Side effects are mostly dose related and are preventable with appropriate follow-up.

Angioedema↗
PubMed1995

Human dermal fibroblast clones derived from single cells are heterogeneous in the production of mRNAs for alpha 1(I) procollagen and transforming growth factor-beta 1.

Fibroblast clonal heterogeneity has been reported for growth and protein synthesis, but quantitative studies of synthetic phenotype at the pretranslational level have been limited because of difficulty in reliably growing large numbers of clonal cells. We have recently shown a unique stimulatory activity of low oxygen tension in the early phases of clonal growth, which can be used to establish clonal fibroblast cultures suitable for Northern analysis. Using this methodology, we have measured mRNA levels of alpha 1(I) procollagen and transforming growth factor-beta 1 (TGF-beta) both at baseline and after TGF-beta stimulation in a total of 43 clones derived from single cells and from seven different cell strains. We report a remarkable baseline heterogeneity, commonly four- to six-fold, in procollagen mRNA levels among clones and between clones and their parent cultures. Conversely, differences in baseline TGF-beta mRNA levels among clones were either not present or less than onefold. The clonal phenotypic expression of alpha 1(I) procollagen mRNA remained stable after eight additional cell passages. TGF-beta stimulation of itself (autoinduction) was highly variable among clones (range of increases 30% to 150%), and up-regulation of procollagen mRNA levels after TGF-beta stimulation was detected in only 15 (54%) of 28 clonal cultures (range of increases 30% to 353%). A notable lack of correlation was found between baseline mRNA levels of TGF-beta and alpha 1(I) procollagen in clonal cultures. In conclusion, fibroblast clonal populations are remarkably heterogeneous in their baseline procollagen mRNA levels and in their response to TGF-beta.

Adult↗
PubMed1995

Extravasation of macromolecules and possible trapping of transforming growth factor-beta in venous ulceration.

The pathogenesis of venous ulceration is thought to involve formation of pericapillary fibrin cuffs as a result of venous hypertension, and a recent hypothesis suggests that extravasated plasma proteins may bind or trap growth factors. We have compared the tissue distribution of fibrin cuffs, plasma proteins, procollagen, and transforming growth factors (TGF-beta 1 and TGF-beta 2) within venous ulcers and normally healing graft donor sites. In venous ulcers, the papillary dermis and the ulcer bed contained convoluted capillaries with phosphotungstic acid haematoxylin-positive pericapillary fibrin cuffs. By immunohistochemical staining, the cuffs were positive for actin, and contained massively redundant lamellae of basement membrane material which stained positive for type IV collagen. Extravasated factor XIIIa and alpha 2-macroglobulin were present within the fibrin cuffs. Increased numbers of type I procollagen positive fibroblasts, and increased TGF-beta 1 immunoreactivity were present within the fibrin cuffs, but not in the provisional matrix in the ulcer bed around the cuffs. In contrast, in normally healing graft donor sites, tortuous capillaries and fibrin cuffs were absent, factor XIIIa and alpha 1-macroglobulin were restricted to the lumina of vessels, and procollagen and TGF-beta immunoreactivity were present within the granulation tissue and adjacent dermal matrix at the wound margin. These observations suggest that growth factors critical in wound healing, such as TGF-beta, are present within venous ulcers, but are abnormally distributed. Their distribution within fibrin cuffs and co-localization with extravasated plasma proteins, particularly alpha 2-macroglobulin, which is a recognized scavenger molecule for TGF-beta and other growth factors, provides evidence for a possible 'trapping' of growth factors in venous ulcers.

Blood Proteins↗