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Biomedical subjects

G S Lazarus

Publications and source records attributed to G S Lazarus.

At least 37 records · Page 2Linked to original sources
PubMed1993

Venous leg ulcers: an analysis of underlying venous disease.

Patients with venous leg ulcers have a readily recognized clinical syndrome of shallow ulcers, oedema, leg pain, venous ankle blush, lipodermatosclerosis, varicose veins, hyperpigmentation, and atrophie blanche, and they are assumed to have venous abnormalities. We examined 43 patients with venous leg ulcers, and compared those with obvious venous abnormalities (defined as historical or clinical evidence of deep venous thrombosis or varicose veins) with those with presumed venous abnormalities (defined as lacking any such evidence), to see if they presented with different clinical features. We found that both groups had similar clinical features, with the exception that lipodermatosclerosis was present more frequently in those patients with obvious venous abnormalities (94 vs. 36%, P < 0.001). Most patients with presumed venous abnormalities had musculoskeletal conditions which might cause calf pump dysfunction (91%). Using air plethysmography, we were unable to confirm that all patients with presumed venous abnormalities did have intrinsic venous abnormalities. We propose that ulcers occurring in this clinical syndrome be designated as calf pump dysfunction ulcers (CPD ulcers), rather than venous ulcers.

Arteriosclerosis↗
PubMed1993

Development of pemphigus vulgaris-like lesions in severe combined immunodeficiency disease mice reconstituted with lymphocytes from patients.

Pemphigus vulgaris is an autoimmune blistering disease that is induced by binding of antibodies to a 130/85-kD protein complex on epidermal keratinocytes. An in vivo experimental model of this disease was developed by reconstituting severe combined immunodeficiency (SCID) mice with 1-10 x 10(7) PBL from patients with naturally occurring pemphigus vulgaris. Of 49 reconstituted mice, 34 (69%) produced human IgG levels of > 0.1 mg/ml. Circulating anti-pemphigus antibodies were found in 20 of the 34 successfully reconstituted mice; 44% of these animals had deposits of human IgG in their own skin after it was traumatized by either heat or cold. Spontaneous pemphigus vulgaris-like blisters associated with human IgG deposits were rarely found in mouse skin. By contrast, allogeneic human skin grafted to 10 to 12 mice before reconstitution with patients' PBL developed pemphigus vulgaris-like lesions containing human IgG deposits. These results demonstrate that SCID mice can serve as a model of an antibody-mediated human autoimmune skin disease.

Adult↗
PubMed1993

Differential expression of plasminogen activators and their inhibitors in an organotypic skin coculture system.

Using immunohistochemistry and in situ hybridization, we have characterized the expression and localization of components of the plasminogen activator proteolytic cascade in an organotypic coculture system which consists of a "dermal" portion (human dermal fibroblasts throughout a collagen matrix) and a stratified, well-differentiated epidermal portion. Specifically, the following components were examined: the enzymes urokinase-type plasminogen activator and tissue-type plasminogen activator and their type 1 and type 2 inhibitors. Urokinase plasminogen activator mRNA and antigen were found predominantly in the least differentiated, basal keratinocytes; in some fields there was also faint deposition of antigen beneath the basal cells. The distribution of plasminogen activator inhibitor type 1 was similar to that of urokinase, except that inhibitor type 1 antigen deposition beneath the basal cells appeared more intense and uniform. In contrast to the results with urokinase plasminogen activator and inhibitor type 1, tissue plasminogen activator mRNA and antigen were localized focally in the suprabasal, i.e. more differentiated, keratinocytes. Plasminogen activator inhibitor type 2 mRNA and antigen were detected in most epidermal layers, but were more intense suprabasally and often spared the basal layer. These studies demonstrate that the same type of cell, i.e. the keratinocyte, can express different components of the plasminogen activator cascade depending on its state of differentiation. The change in expression of plasminogen activator cascade components with keratinocyte differentiation suggests distinct epidermal functions for these components, related to cell-matrix interaction and epidermal differentiation.

Cell Differentiation↗
PubMed1992

Alterations in renal function in psoriasis patients treated with cyclosporine, 5 mg/kg/day.

BACKGROUND: Cyclosporine has been used to treat a variety of cutaneous and immune-mediated diseases. Nephrotoxicity is the most common major adverse side effect. OBJECTIVE: The study was designed to investigate the frequency of alterations in serum creatinine in patients with psoriasis receiving 5 mg/kg/day of cyclosporine. METHODS: Sixteen patients with severe refractory psoriasis received cyclosporine, 5 mg/kg/day, for 12 weeks. Serum creatinine was evaluated with respect to each patient's baseline. RESULTS: Serum creatinine levels remained in the normal range, but 10 of 16 patients had a 30% elevation and 5 of 16 patients had a 50% elevation of serum creatinine compared with the patient's baseline value. CONCLUSION: These results indicate that a significant elevation in serum creatinine occurs in many patients who receive cyclosporine for psoriasis.

Adult↗
PubMed1992

Urokinase plasminogen activator is immunocytochemically detectable in squamous cell but not basal cell carcinomas.

The presence of plasminogen activators (PA) in a variety of solid tumors appears to correlate, in a number of instances, with enhanced invasive or metastatic capabilities. In the present study, we have immunocytochemically examined basal cell (BCC) and squamous cell carcinomas (SCC) comprising a spectrum of histologic subtypes for the presence of urokinase-type (uPA) and tissue-type (tPA) PA. Neither uPA nor tPA was noted in any BCC, whether of the nodular, infiltrative, morpheaform, or basosquamous variety. uPA but not tPA was seen in 12 of 16 SCC examined; the tumors lacking uPA were all histologically well differentiated. No relationship between uPA expression and depth of invasion was noted, and uPA was not preferentially expressed at tumor borders. We conclude that uPA presence in SCC may relate to the degree of differentiation.

Animals↗
PubMed1992

Treatment of pyoderma gangrenosum with cyclosporine.

BACKGROUND AND DESIGN: Pyoderma gangrenosum is a chronic inflammatory ulcerative skin disease of unknown origin, often associated with various diseases including inflammatory bowel disease, inflammatory arthritis, monoclonal gammopathies, hepatitis, and myeloproliferative disorders. Treatment of associated systemic disorders may improve the ulcers, but lesions may be recalcitrant and persist for months to years. Therapy for pyoderma gangrenosum includes high-dose systemic corticosteroids, sulfa drugs such as sulfasalazine, clofazimine, and immunosuppressive agents such as mercaptopurine and azathioprine; these drugs are sometimes ineffective. RESULTS: We present a series of 11 patients with pyoderma gangrenosum, with a wide range of underlying diseases, whose ulcers were refractory to usual therapy and who were treated with low-dose cyclosporine. Ten of the 11 patients cleared rapidly and completely with cyclosporine therapy. CONCLUSIONS: Cyclosporine should be seriously considered as a primary form of treatment for pyoderma gangrenosum.

Adult↗
PubMed1991

Role of laminin in localization of human dermal mast cells.

Human connective tissue type mast cells (CTMC) are frequently located in close proximity to microvascular and neural basement membranes (BM). We have explored the interaction between human dermal connective tissue-type (chymase positive) mast cells and laminin, a component of BM. In this report, we document that normal CTMC express laminin receptors and are intimately associated with laminin of BM in vivo and pericellular laminin complexes in vitro. Upon degranulation in vitro, CTMC-laminin complexes dissociate and CTMC do not adhere to laminin substrates. In cutaneous mastocytosis/urticaria pigmentosa, CTMC do not express laminin receptors detectable by immunohistochemistry, and are frequently not in close association with laminin of vascular BM. These same features could be induced by degranulation of normal mast cells in organ culture. These findings indicate that CTMC-laminin interactions may be important determinants of mast cell localization in tissue compartments.

Basement Membrane↗
PubMed1990

mRNA for tissue-type plasminogen activator is present in lesional epidermis from patients with psoriasis, pemphigus, or bullous pemphigoid, but is not detected in normal epidermis.

Plasminogen activator (PA), which catalyzes the conversion of plasminogen to the proteinase plasmin, has been implicated in a variety of cutaneous disorders. Lesional epidermis from patients with psoriasis, pemphigus, bullous pemphigoid, and Hailey-Hailey disease contains elevated levels of tissue-type PA (tPA) activity compared to non-lesional epidermis or to epidermis from normal individuals. In the present study, we have used Northern blot analysis to demonstrate that mRNA for tPA is detectable in lesions from patients with psoriasis, pemphigus, and bullous pemphigoid, but is not detectable in normal epidermis. These data strongly suggest that the tPA enzymatic activity present in lesional epidermis results from enhanced synthesis of the enzyme in situ, secondary to elevated steady-state levels of tPA mRNA. Cultured keratinocytes likewise are shown to contain tPA mRNA. Previous investigators have suggested that the phenotypes of keratinocytes in culture, psoriatic epidermis, and epidermis in the process of wound reepithelialization are comparable. Our findings, combined with those of other investigators, suggest that elevated tPA expression may be another common feature of epidermis under these circumstances.

Biopsy↗
PubMed1990

Tissue plasminogen activator in psoriasis.

Elevated levels of the serine proteinase plasminogen activator are observed in psoriatic lesions. In contrast to normal epidermis, lesional psoriatic epidermis contains primarily tissue type plasminogen activator (tPA) activity and much lower levels of urokinase type plasminogen activator (uPA) activity. Tissue plasminogen activator is also detectable immunocytochemically in lesional psoriatic but not normal epidermis. Similarly, mRNA for tPA is observed in lesional epidermis only. These results suggest that lesional psoriatic epidermis synthesizes enhanced levels of tPA compared to normal. Additional data support the hypothesis that enhanced tPA may be another marker common to psoriatic epidermis, epidermis during wound repair, and keratinocytes in culture. The significance of elevated tPA in psoriatic lesions is presently unclear, but its possible relationship to epidermal proliferation and cutaneous inflammation is under study.

Humans↗
PubMed1989

Reaction of human skin chymotrypsin-like proteinase chymase with plasma proteinase inhibitors.

The ability of plasma proteinase inhibitors to inactivate human chymase, a chymotrypsin-like proteinase stored within mast cell secretory granules, was investigated. Incubation with plasma resulted in over 80% inhibition of chymase hydrolytic activity for small substrates, suggesting that inhibitors other than alpha 2-macroglobulin were primarily responsible for chymase inactivation. Depletion of specific inhibitors from plasma by immunoadsorption using antisera against individual inhibitors established that alpha 1-antichymotrypsin (alpha 1-AC) and alpha 1-proteinase inhibitor (alpha 1-PI) were responsible for the inactivation. Characterization of the reaction between chymase and each inhibitor demonstrated in both cases the presence of two concurrent reactions proceeding at fixed relative rates. One reaction, which led to inhibitor inactivation, was about 3.5 and 4.0-fold faster than the other, which led to chymase inactivation. This was demonstrated in linear titrations of proteinase activity which exhibited endpoint stoichiometries of 4.5 (alpha 1-AC) and 5.0 (alpha 1-PI) instead of unity, and SDS gels of reaction products which exhibited a banding pattern indicative of both an SDS-stable proteinase-inhibitor complex and two lower Mr inhibitor degradation products which appear to have formed by hydrolysis within the reactive loop of each inhibitor. At inhibitor concentrations approaching those in plasma where inhibitor to chymase concentration ratios were in far excess of 4.5 and 5.0, the rate of chymase inactivation by both serpin inhibitors appeared to follow pseudo-first order kinetics. The "apparent" second order rate constants of inactivation determined from these data were about 3000-fold lower than the rate constants reported for human neutrophil cathepsin G and elastase with alpha 1-AC and alpha 1-PI, respectively. This suggests that chymase would be inhibited about 650-fold more slowly than these proteinases when released into plasma. These studies demonstrate that although chymase is inactivated by serpin inhibitors of plasma, both inhibitors are better substrates for the proteinase than they are inhibitors. This finding along with the slow rates of inactivation indicates that regulation of human chymase activity may not be a primary function of plasma.

Chymases↗
PubMed1989

Treatment of cutaneous granulocytic sarcoma in a patient with myelodysplasia.

In this report, we have presented our experience with a patient with a rare cutaneous granulocytic sarcoma. In addition to hematoxylin and eosin, myeloperoxidase stain and specific stains for lysozyme and esterase were helpful in confirming the histologic diagnosis of granulocytic sarcoma. Despite multiple attempts to control this patient's tumor by conservative surgery, radiation therapy, and chemotherapy, we eventually had to resort to limb amputation. This procedure restored a meaningful quality of life to this patient for one and a half years prior to the development of acute leukemia. Treatment with corticosteroids at the time of surgery may have prevented a local recurrence of granulocytic sarcoma despite positive tissue margins. Our experience underscores the importance of directing treatment toward the granulocytic sarcoma whereas the myelodysplasia concurrently present may not require therapy for several years.

Amputation, Surgical↗
PubMed1989

Characterization of keratinocyte plasminogen activator inhibitors and demonstration of the prevention of pemphigus IgG-induced acantholysis by a purified plasminogen activator inhibitor.

To investigate the mechanisms by which cutaneous plasminogen activator (PA) may be regulated, we have tested cultured keratinocytes for the presence of PA inhibitors. Using biosynthetic labeling experiments with 35S-methionine in conjunction with specific antibody precipitation, we have shown that human keratinocytes in culture synthesized and secreted both PA inhibitor 1 and PA inhibitor 2. PA inhibitor 1 was present in conditioned media in the inactive form, but it could be detected with reverse phase autography. PA inhibitor 2 was detected by its ability to form complexes with 125I-uPA. Potential therapeutic relevance for cutaneous PA inhibitor 2 was suggested in skin organ culture experiments which demonstrated that purified PA inhibitor 2 from human placenta was able to prevent the acantholytic changes induced by pemphigus IgG.

Acantholysis↗