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Biomedical subjects

V Falanga

Publications and source records attributed to V Falanga.

At least 19 recordsLinked to original sources
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↗
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↗
PubMed1995

Split-thickness skin grafting of leg ulcers. The University of Miami Department of Dermatology's experience (1990-1993).

BACKGROUND: Skin grafting for large and recalcitrant lower extremity ulcers is a commonly used therapy. However, the success rate for grafts performed by dermatologists is largely unknown. OBJECTIVE: To analyze our experience with meshed split-thickness skin grafts for leg ulcers. METHODS: We retrospectively analyzed all hospitalized dermatology patients who underwent meshed split-thickness skin grafting for lower extremity ulceration due to a variety of causes performed by the Department of Dermatology at the University of Miami over a 3-year period (1990-1993). RESULTS: Twenty-nine patients with 36 ulcers were grafted. Greater than 90% of ulcers had initial graft take. At long-term follow-up, 52% of ulcers were healed, 26% were partially healed, and 22% recurred. CONCLUSION: We conclude that meshed split-thickness skin grafting is a safe and effective therapy for recalcitrant lower extremity ulcers.

Adolescent↗
PubMed1995

Enhanced collagen synthesis and transcription by peak E, a contaminant of L-tryptophan preparations associated with the eosinophilia myalgia syndrome epidemic.

The pathogenesis of the eosinophilia myalgia syndrome (EMS) remains unclear. Several abnormal constituents have been found in the L-tryptophan lots responsible for the illness, particularly, 1,1-ethylidenebis[L-tryptophan], also called peak E or EBT, and 3-phenylamino-alanine or peak 5. However, the role of these contaminants in the pathogenesis of EMS and in the development of fibrosis is unknown. We now report that peak E, a dimer of L-tryptophan, is a potent stimulus for human dermal fibroblast DNA and collagen synthesis. Peak E (0.1-1.0 microM) increased DNA synthesis up to four-fold (P = 0.0001) in a dose-dependent manner (r = 0.987). When added to monolayer cultures for 2 to 24 h, peak E (0.5 to 100 microM) caused a progressive, more than threefold increase in alpha 1(I) procollagen mRNA levels and collagenous protein. No increase in procollagen mRNA levels was found after the addition of another major L-tryptophan contaminant, peak 5, or with L-tryptophan itself. Transient transfection with a 2.5-kb alpha 1(I) procollagen promoter-luciferase construct showed that peak E causes a twofold upregulation of promoter activity (P = 0.022). Contraction of collagen gels, consisting of human dermal fibroblasts incorporated into a type I collagen lattice, was enhanced two-fold by exposure to peak E (P = 0.001). We conclude that a major constituent of contaminated batches of L-tryptophan, peak E, is a potent stimulus for fibroblast activation and collagen synthesis. This stimulatory action of peak E may provide a direct mechanism for the development of fibrosis in EMS.

Cells, Cultured↗
PubMed1994

Low oxygen tension decreases receptor binding of peptide growth factors in dermal fibroblast cultures.

We have investigated receptor binding of epidermal growth factor (EGF) and transforming growth factor-beta 1 (TGF-beta) in cultures of human dermal fibroblasts exposed to low (2%, hypoxia) or standard (20%) oxygen tension. Compared to standard oxygen, the binding of both 125I-TGF-beta and 125I-EGF in low oxygen tension was diminished by a mean of 65 and 62%, respectively (P < 0.02), and was reversed by reexposure of cultures to standard oxygen tension. Low oxygen tension decreased the number of binding sites of both EGF (mean = 44%) and TGF-beta (mean = 33%). Preincubation of the media in the two different oxygen conditions showed that alterations in the redox potential of the medium was not responsible for the changes observed in receptor binding. As shown by Northern analysis, diminished TGF-beta receptor binding in hypoxia was accompanied by up to a 10-fold decrease in mRNA levels of TGF-beta type II receptor. We conclude that low oxygen tension decreases EGF and TGF-beta receptor binding and synthesis.

Adult↗
PubMed1994

Dermatologic consultations in the hospital setting.

BACKGROUND AND DESIGN: Dermatologic practice occurs mainly in the outpatient setting. The reasons for, frequency, and impact of inpatient dermatologic consultation are largely unstudied. In this report, we prospectively studied dermatologic consultation in the major teaching hospital complex of a medical school. Over a period of 8 months, we prospectively recorded the demographics of the patients for whom consultation was requested, the provisional dermatologic diagnosis of the referring service, the final diagnosis of the dermatologic service, and the tests necessary to arrive at a final diagnosis. RESULTS: During a period of slightly over 8 months, dermatologic consultation was requested and delivered to 591 patients who were either hospitalized or being evaluated in the emergency department or other urgent care settings. The services requesting consultation most frequently were medicine (39%), pediatrics (14%), surgery (12%), psychiatry (6%), and neurology (3%). In 51% of consultations, the patients were younger than 45 years of age. Diagnostic tests, including Tzanck smear and potassium hydroxide preparation, confirmed the clinical diagnosis in up to 50% of cases. Dermatologic consultation changed dermatologic diagnosis and treatment in more than 60% of the patients. Generally, the dermatologic diagnoses most frequently missed by the referring service were common conditions with established treatment. CONCLUSIONS: Dermatologic consultation in the hospital setting improves dermatologic diagnosis and has an impact on treatment.

Adolescent↗
PubMed1993

The "trap" hypothesis of venous ulceration.

The pathogenesis of venous ulceration is unknown. We propose that macromolecules leaking into the dermis as a result of venous hypertension bind to or "trap" growth factors and matrix material, which then become unavailable for tissue repair and for the maintenance of tissue integrity.

Fibrin↗
PubMed1993

Low oxygen stimulates proliferation of fibroblasts seeded as single cells.

In standard tissue culture conditions (20% oxygen), single human dermal fibroblasts (one cell per well) do not proliferate. We now report that low oxygen tension is a potent stimulus for the proliferation and expansion of human adult and neonatal dermal fibroblasts seeded as single cells. This preferential single-cell proliferation in low oxygen is shown to be also a feature of human lung and dermal rodent fibroblasts, but not of human fibrosarcoma and immortalized 3T3 cells, which proliferate without difficulty in standard oxygen conditions. It is suggested that single-cell proliferation and its dramatic stimulation in low oxygen may represent a fundamental biologic process with an opportunity to better understand mammalian cell growth regulation.

3T3 Cells↗
PubMed1993

Low oxygen tension increases mRNA levels of alpha 1 (I) procollagen in human dermal fibroblasts.

Dermal fibroblasts exposed to low oxygen tension show upregulated synthesis of transforming growth factor-beta 1 (TGF-beta 1), an established stimulatory peptide in the formation of extracellular matrix proteins. In this report, procollagen synthesis was measured in cultures of confluent adult human dermal fibroblasts exposed to either standard (20%) or low (2%) oxygen tension. By Northern blot analysis the steady state levels of alpha 1 (I) procollagen mRNA were increased by 75 to 150% of control (standard oxygen) as early as 12 hours and more than 200% 96 hours after exposure of cells to low oxygen. Similar increases in procollagen mRNA levels were obtained in hypoxic fibroblast cultures in a collagen lattice. The stimulatory effect of hypoxia on procollagen mRNA levels in fibroblast monolayers was diminished by antibodies to TGF-beta, and could not be augmented further by the addition of TGF-beta 1, evidence that hypoxic fibroblasts may already be maximally stimulated by TGF-beta 1. We conclude that low oxygen tension enhances steady state mRNA levels of alpha 1 (I) procollagen, and that this effect is mediated at least in part by TGF-beta 1.

Antibodies↗