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Biomedical subjects

G D Weinstein

Publications and source records attributed to G D Weinstein.

At least 19 recordsLinked to original sources

Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells.

Determination of the cell types proliferating in the dermis of patients with psoriasis should identify those cells experiencing activation or responding to growth factors in the psoriatic dermal milieu. Toward that end, sections of formalin-fixed biopsies obtained from 3H-deoxyuridine (3H-dU)-injected skin of eight psoriatic patients were immunostained, followed by autoradiography. Proliferating dermal cells exhibit silver grains from tritium emissions. The identity of the proliferating cells could then be determined by simultaneous visualization with antibodies specific for various cell types. UCHL1+ (CD45RO+) T cells (recall antigen-reactive helper T-cell subset) constituted 36.6 +/- 3.1% (mean +/- SEM, n = 6) of the proliferating dermal cells in involved skin, whereas Leu 18+ (CD45RA+) T cells (recall antigen naive T-cell subsets) comprised only 8.7 +/- 1.5% (n = 6). The Factor XIIIa+ dermal perivascular dendritic cell subset (24.9 +/- 1.5% of proliferating dermal cells, n = 6) and Factor VIII+ endothelial cells (23.0 +/- 2.3%, n = 6) represented the two other major proliferating populations in lesional psoriatic dermis. Differentiated tissue macrophages, identified by phase microscopy as melanophages or by immunostaining with antibodies to Leu M1 (CD15) or myeloid histiocyte antigen, comprised less than 5% of the proliferating population in either skin type. In addition to calculating the relative proportions of these cells to each other as percent, we also determined the density of cells, in cells/mm2 of tissue. The density of proliferating cells within these populations was increased in involved versus uninvolved skin: UCHL1+, 9.0 +/- 1.7 cells/mm2 versus 1.8 +/- 0.6 cells/mm2, p less than 0.01; Factor XIIIa+, 6.0 +/- 0.7 cells/mm2 versus 1.5 +/- 0.5 cells/mm2, p less than 0.01; Factor VIII+, 5.5 +/- 1.4 cells/mm2 versus 0.0 cells/mm2, p less than 0.05. The presence of preferential active proliferation of a T-cell subset in lesional dermis suggests that activating signals specific for this subset are contained within the psoriatic dermis in vivo. The activation of recall antigen-reactive T cells may be a driving force behind the dendritic cell and endothelial cell proliferation. Alternatively, the selective proliferation and expansion of these two constitutive cell types (Factor XIIIa+ and Factor VIII+) may result in signals that promote activation of UCHL1+ (CD45RO+) T cells.

Cell Division

Specificity of human keratinocyte X HeLa cell hybrid murine monoclonal antibodies.

The immunofluorescent staining patterns of three differentiation-specific monoclonals (HLK3, HLK7, HLK20) that display different immunofluorescent (IF) reactivity in normal and psoriatic epidermis, were examined in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), as well as other human normal epithelial and nonepithelial tissues. Similar staining patterns within epidermis were seen with HLK3 (intercellular) and HLK7 (perinuclear) in psoriasis, SCC, and BCC. HLK20 selectively stained BCC and SCC within epidermis and dermis, and was negative in psoriasis. The monoclonals did not react with nonepithelial tissues, but repetitively displayed positive, granular reactivity with simple epithelia and transitional epithelium. Stratified squamous epithelia showed IF staining similar to normal epidermis for all three monoclonals. These new monoclonal antibodies offer new investigative tools to study abnormalities in keratinocyte differentiation in benign and malignant hyperplastic skin diseases.

Antibodies, Monoclonal

Topical tretinoin for treatment of photodamaged skin. A multicenter study.

The clinical and histologic effects of a new emollient cream formulation of topical tretinoin at concentrations of 0.05% and 0.01% were examined in 251 subjects with mild to moderate photodamaged facial skin in a randomized, double-blind, vehicle-controlled, multicenter study. Seventy-nine percent of the subjects who received 0.05% tretinoin for 24 weeks showed overall improvement in photodamaged skin compared with improvement in 48% of the vehicle-treated control subjects. Significant reductions were found in fine wrinkling, mottled hyperpigmentation, roughness, and laxity after 0.05% tretinoin therapy when compared with controls. In addition, histologic changes of increased epidermal thickness, decreased melanin content, and stratum corneum compaction provide independent evidence supporting clinical improvement. Side effects of erythema, peeling, and stinging were usually mild and well tolerated.

Administration, Cutaneous

Vasoactive pharmacologic responses of human skin xenografts in ciclosporin-treated rats.

Human skin xenografts in ciclosporin-treated rats have been reported to preserve many of the characteristics of normal human skin. This model was used to study the cutaneous responses of human skin xenografts and host rat skin to intradermal injections of vasoactive agents. The xenograft responses to corticosteroids (blanching), nicotinic acid (erythema), histamine HCl (urticaria), and privine (blanching) all paralleled those of the host rat skin. However, when quantitatively compared to the responses reported for human skin in vivo, the xenografts were less sensitive to these compounds. The large variability seen in the xenograft responses may be due to variable graft revascularization and to structural irregularities in the dermis from the recent grafting procedure. It is concluded that the lower sensitivity and variable responsiveness of the xenografts limit the potential usefulness of this pharmacologic model for evaluating vasoactive agents.

Animals

Identification of differentiation-specific antigens in psoriatic versus normal skin using monoclonal antibodies.

Human cell hybrids derived from fusions between carcinoma (HeLa) and normal epidermal keratinocytes can be used as immunogens to generate monoclonal antibodies against keratinocyte differentiation-specific antigens. We examined the immunofluorescent staining patterns of these monoclonals in normal human and psoriatic (lesional and uninvolved) skin tissue sections. The immunofluorescent staining patterns indicate that the monoclonal antibodies are recognizing a number of different keratinocyte antigens. Three monoclonals (HLK7, HLK3, and HLK20) displayed different immunofluorescent reactivity in these tissues. These new monoclonal antibodies will be useful tools to study the differentiation abnormalities in psoriasis and may serve as a marker of the psoriatic diathesis.

Antibodies, Monoclonal

Ro 20-1724: an agent that significantly improves psoriatic lesions in double-blind clinical trials.

Two double-blind studies comparing the effectiveness of the cyclic nucleotide-altering agent (4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone) (Ro 20-1724) vs vehicle have demonstrated that this compound can improve psoriatic lesions. Although Ro 20-1724 was not as effective as intensive occlusive treatment of psoriatic lesions with 0.025% triamcinolone acetonide, Ro 20-1724 had no adverse systemic or cutaneous effects. Ro 20-1724 and other cyclic nucleotide-altering agents may have therapeutic potential in the future treatment of psoriasis.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone

Abnormal proliferation of uninvolved psoriatic epidermis: differential induction by saline, propranolol, and tape stripping in vivo.

Cell proliferation of the uninvolved psoriatic skin was compared with normal skin of volunteers following stimulation by the intradermal injections of saline or propranolol, or stripping of the stratum corneum with pressure-sensitive tape. Initially, no significant in vivo difference in tritiated thymidine labeling indices were observed between normal and uninvolved epidermal cells. However, 48 hr after each stimulus more DNA synthesizing cells were found in the uninvolved psoriatic than in normal epidermis. Of these 3 stimuli, propranolol was the most effective in distinguishing between uninvolved psoriatic skin and skin from normal control subjects. Thus, uninvolved psoriatic skin appears to possess an abnormal regulation of epidermopoiesis that may be amplified by propranolol injection.

Bandages

Cell proliferation in human cutaneous squamous cell carcinoma.

Squamous cell carcinoma (SCC) of the skin, a fairly slow-growing locally invasive tumor that occasionally matastasizes, was studied in 12 patients in vivo with the use of intralesional tritiated thymidine as a marker for cell proliferation kinetics. Analysis of the cell cycle of the germinative population revealed that the duration of S-phase was 12.5 hours; G1-phase, 28.8 hours; mitotic period (M-phase), 2 hours; G-pahse, 6.9 hours; and the total germinative cell cycle, 50.2 hours. The application of cell kinetics to programming chemotherapy for skin cancer with phase-specific cytotoxins was discussed.

Antineoplastic Agents

In vitro screening of biochemical activity of folic acid antagonists in skin.

Dihydrofolate reductase (DHFR) inhibitors, which differ from the classical folate antagonists in physicochemical and pharmacologic parameters such as lipid solubility and mechanisms of cellular transport, were screened for DHFR inhibitory activity and biologic activity in newborn rat skin. The most effective drugs from this screen were tested for their effects on de novo DNA synthesis in psoriatic epidermis in vitro. Of the 24 compounds studied, methotrexate (MTX) was the most potent inhibitor of rat skin DHFR (I50=8.6 X 10(-9) M). Methotrexate-dimethylester, methasquin-diethylester, DDEP (2,4-diamino-5-(3',4'-dichlorophenyl)-6-ethylprimidine), and Baker's triazine antifolate (NSC 139105), while less effective than MTX as DHFR inhibitors, were more effective than MTX as inhibitors of de novo DNA synthesis in rat skin in vitro. Baker's antifolate was the only compound tested which was considerably more effective than MTX as an inhibitor of de novo DNA synthesis in psoriatic epidermis in vitro.

Animals

Decreased thymidine incorporation in circulating leukocytes after treatment of psoriasis with psoralen and long-wave ultraviolet light.

Tritiated thymidine incorporation, a measure of DNA synthesis, was studied in circulating leukocytes from patients with widespread psoriasis who were being treated with photochemotherapy using oral 8-methoxypsoralen (8-MOP) and high-intensity, long-wave ultraviolet light (UVA). Seven of 13 psoriasis patients treated with photochemotherapy demonstrated a significant (p less than 0.05) reduction in leukocyte incorporation of tritiated thymidine immediately after UVA in comparison to incorporation before UVA. None of 10 control subjects treated with UVA alone demonstrated such reduction in leukocyte tritiated thymidine incorporation. Photochemotherapy thus affects circulating blood cells in some patients with psoriasis in addition to its therapeutic effect on epidermal cells. Further investigations are needed to determine the reasons for the differences in susceptibility to inhibition of leukocyte DNA synthesis among patients and the possible long-term consequences of such inhibition.

Coumarins

Methotrexate.

The folic acid antagonists, aminopterin and then methotrexate, have been the primary systemically administered drugs for the treatment of severe psoriasis for 25 years. Methotrexate was finally approved by the FDA 5 years ago and was recently estimated to be used for approximately 25,000 psoriatic patients annually. With the small but chronic doses used for psoriasis, methotrexate has been relatively safe, except for a limited occurrence of significant hepatotoxicity. The good to excellent results obtained in most patients must, therefore, be weighted against the small risk of liver damage. Methotrexate has also been used with some effectiveness in several other dermatologic conditions, including mycosis fungoides, dermatomyositis, pityriasis rubra pilaris, and others, although they are not yet FDA-approved indications. The recent successful introduction of photochemotherapy (psoralen and ultraviolet light) for moderate and severely affected psoriatics will probably lead to a substantial decrease in the number of patients requiring methotrexate.

Chemical and Drug Induced Liver Injury

Cell kinetics and programmed chemotherapy for gynecologic cancer. I. Squamous-cell carcinoma.

The results of current investigation into cellular kinetics of both normal and abnormal human genital tissue have stimulated interest in programming chemotherapeutic drug regimens for the treatment of genital cancer. This report outlines the results of cell kinetic studies of normal and abnormal squamous epithelium of the female genital tract and presents preliminary results of a regimen utilizing methotrexate, hydroxyurea, and vincristine in patients with far-advanced squamous-cell cancer of the vulva, vagina, and cervix. A total of 92 patients have received 444 courses of programmed chemotherapy by either pelvic intra-arterial infusion or systemic administration of the drugs. Our results are presented and the theoretical basis of the research is discussed.

Carcinoma, Squamous Cell

Factors affecting human percutaneous penetration of methotrexate and its analogues in vitro.

Factors affecting the percutaneous penetration of methotrexate (MTX) and its analogues through excised human skin were studied. With application of 0.05% MTX solution to the epidermis, 0.07% of the applied dose was recovered in the epidermis and less than 0.005% penetrated completely through the skin. The percent of drug which penetrated remained constant from 0.05% to 2.0% MTX and was also unchanged by increasing incubation temperature from 28 degrees C to 37 degrees C. Cellophane tape stripping of stratum corneum following drug incubation removed essentially all the MTX that had been measured in whole epidermis. Binding of MTX was localized to the outermost layers of the stratum corneum. With removal of the stratum corneum prior to drug incubation, 25% of the applied MTX penetrated through the skin. Various vehicles were tested to determine their effect on MTX percutaneous absorption. Dimethylsulfoxide (80%), dimethylacetamide (25%), or retinoic acid (0.1%) had no effect on penetration. Maximum enhancement of penetration by 25-fold and 143-fold was obtained with retinoic acid (saturated solution in aqueous ethanol) and C-10-methylsulfoxide (2.5%), respectively. The penetration of lipid-soluble derivatives of MTX was also tested. The compound that penetrated best was the dimethyl ester of dichloro-MTX with a 3-fold increase in penetration over MTX.

Acetamides

Cytokinetics and chemotherapy of psoriasis.

The successful treatment of psoriasis with folic acid antagonists during the past 25 years has led to extensive research in the areas of cytokinetics and chemotherapy. In this paper we shall review selected aspects of these topics relevant to the treatment of psoriasis. The effectiveness of methotrexate treatment of psoriasis can be related to both the hyperproliferative cytokinetics of psoriasis and an increased biochemical sensitivity of psoriatic epidermal cells to this drug. Future research goals in chemotherapy of psoriasis include (a) optimizing drug schedules for available drugs; (b) identifying other susceptible biochemical points of selective drug attack; (c) identifying secondary advantages in order to facilitate selective drug action in psoriasis, such as ultraviolet light therapy in combination with a systemic drug; and (d) developing topically effective chemotherapeutic agents. Approaches to research on topical therapy are reviewed with specific reference to animal testing models for psoriasis and percutaneous penetration of topically applied agents.

Administration, Topical

Epidermal activity in annular dermatophytosis.

In five patients with annular tinea corporis, the tritated thymidine labeling indexes were determined in the rim, center, and intermediate areas of the lesion and compared with normal skin. Labeling indexes at the rim were much higher than those of normal skin (mean, 4.2 times). Labeling indexes elsewhere in the lesion were not significantly different from those of normal skin. Histologic examination showed epidermal thickening in all areas of the lesion as compared with normal skin. This study suggests that there is an increased epidermal turnover at the rim of annular dermatophytosis that may be important in the pathophysiology and morphogenesis of such lesions.

Adult