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Biomedical subjects

G S Lazarus

Publications and source records attributed to G S Lazarus.

At least 19 recordsLinked to original sources
PubMed1998

The effects of a managed care educational program on faculty and trainee knowledge, attitudes, and behavioral intentions.

PURPOSE: To assess the state of managed care knowledge and attitudes and to evaluate the effects of a two-day course on participants' knowledge, attitudes, and behavioral intentions. METHOD: In 1996, the University of California, Davis, Medical School invited all medical students, residents, faculty, and administrators to participate in one of two sessions of a two-day course on managed care. Participants in the first session were given both pre- and post-course questionnaires. Participants in the second session were given only post-course questionnaires. The questionnaires measured objective knowledge, attitudes, and behavioral intentions. Participants (other than administrators) who completed the questionnaires also received a follow-up questionnaire six months after the seminar. RESULTS: The two sessions were attended by 818 UC Davis medical students, residents, faculty, and administrators: after excluding 33 non-physician administrators, 428 completed survey packets (55%) were available for full analysis. Before the course, participants in the first session correctly answered on average only 46% of 32 questions about managed care knowledge. Course attendance was associated with significant gains in knowledge (to 67% correct, p < .001) and a marked increase in appreciation for the cost-control effectiveness of managed care (from 3.35 to 3.98 on a five-point scale, p < .001). Knowledge gains were greatest among medical students; changes in attitudes and behavioral intentions were least among residents. Among respondents to a follow-up survey, the changes were partially sustained six months later. CONCLUSION: Within this academic medical center, baseline levels of managed care knowledge were low among faculty as well as among trainees, and attitudes reflected a blend of negativism and wishful thinking. An intensive two-day educational program effectively increased knowledge and changed selected attitudes among critical academic constituencies. Other academic medical centers may wish to consider presenting similar programs in order to orient their faculties and trainees to the economic realities of the foreseeable future.

Academic Medical Centers↗
PubMed1997

Dominantly inherited epidermal acantholysis in dogs, simulating human benign familial chronic pemphigus (Hailey-Hailey disease).

We report on dominantly inherited epidermal acantholysis in three dogs, a sire and two female offspring. The skin lesions were characterized by hairless, hypertrophic plaques. Histopathologically, these lesions showed epidermal hyperplasia with individual enlargement of keratinocytes, extensive acantholysis and minimal dyskeratosis. Ultrastructural analysis revealed that attachment plaques of desmosomes were still intact while some tonofilaments were detached from them in early lesions; there were well-developed microvilli at dissociated cell surfaces. The data imply that these animals have undergone a process similar to human benign familial chronic pemphigus (BFCP). Immunohistochemical examination revealed that staining for E-cadherin and actin variably remained in dissociated keratinocytes. Focal intracellular staining for desmosomal glycoproteins and desmosomal proteins were observed within the dissociated keratinocytes. This dominantly inherited acantholytic disease in dogs could be a useful animal model for investigating the pathogenesis of BFCP in humans.

Acantholysis↗
PubMed1996

Expression of plasminogen activators in basal cell carcinoma.

The plasminogen activators, tissue type and urokinase type (tPA and uPA, respectively), have been identified in various malignancies and have been implicated in both local growth and metastatic spread. To characterize plasminogen activator expression more fully in human basal cell carcinoma, the localization of uPA and tPA mRNAs was evaluated by in situ hybridization. Nodular basal cell carcinomas demonstrated uPA expression in most cases, whereas the non-nodular subtypes were negative. Message for uPA was identified within tumour islands (11/12 cases), scattered fibroblast-like stromal cells (6/12 cases), and the basal layer of the overlying epidermis (10/12 cases). In addition, signal for uPA was elevated and pronounced in areas where the epidermis merged into invasive basal cell carcinoma in the superficial papillary dermis in some cases. Message for uPA was often associated with ulceration or erosion of the overlying epithelium. Expression of tPA was noted in the epidermis (3/12 cases) and in tumour cells (4/12 cases), but tended to be focal and sparse. These results suggest that complex interactions involving uPA expression occur between the tumour, the stroma, and the overlying epidermis. Both the stroma and the epidermis may contribute to local spread of the tumour through production of uPA and consequent plasmin-mediated activation of collagenases and metalloproteinases.

Basal Cell Carcinoma↗
PubMed1996

Fibrinolytic abnormalities in two different cutaneous manifestations of venous disease.

BACKGROUND: Chronic venous insufficiency may be associated with lipodermatosclerosis or atrophie blanche. Coagulation abnormalities may be related to these cutaneous disorders. OBJECTIVE: Our purpose was to determine whether fibrinolytic abnormalities exist in patients with lipodermatosclerosis or atrophie blanche. METHODS: A case control study of patients with venous disease and atrophie blanche or lipodermatosclerosis was performed. Plasma levels of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) in a resting and venous occluded state were measured. RESULTS: Plasma levels of PAI-1 were different between the two groups of patients. The lipodermatosclerosis group had significantly higher levels of PAI-1 in both the resting and venous occluded states (p < 0.001). Patients with atrophie blanche had milder elevations of PAI-1 in the resting and venous occluded state (p = 0.06). CONCLUSION: Fibrinolytic abnormalities are present in patients with venous disease. These abnormalities are different between patients with lipodermatosclerosis and patients with atrophie blanche.

Aged↗
PubMed1996

Mastocytosis: new understandings in cutaneous pathophysiology.

Human mast cells contain large quantities of chymotryptic and tryptic proteinases. In human skin, mast cells contain both chymase and tryptase, whereas, in the mucosa of the gastrointestinal tract, mast cells contain primarily tryptase. By contrast, submucosal mast cells in the gastrointestinal tract are of the connective tissue type because they contain both chymase and tryptase. Chymase has a broad array of biological functions which include; activation of angiotensin, cleavage of basement membrane through the lamina lucida, activation of IL1 beta, and potentiation of histamine. Chymase may play a significant role in the control of a variety of biological phenomena. Urticaria pigmentosa is a disease characterized by deposition of "normal" connective tissue mast cells within the skin. The source of these mast cells is the bone marrow and mast cells appear to be deposited within other internal organs in almost all cases. Excretion of histamine and prostaglandin metabolites correlates with the deposition of mast cells in extracutaneous sites. High potency steroids under occlusion for six week results in long-lasting clearing of the cutaneous lesions with minimal side effects.

Chymases↗
PubMed1995

Induction of autocrine epidermal growth factor receptor ligands in human keratinocytes by insulin/insulin-like growth factor-1.

Autocrine activation of the epidermal growth factor (EGF) receptor on keratinocytes has been recognized as an important growth regulatory mechanism involved in epithelial homeostasis, and, possibly, hyperproliferative diseases. Insulin-like growth factor (IGF)-1 and insulin have been shown to be paracrine keratinocyte mitogens that bind to the type I IGF receptor which is expressed on actively proliferating keratinocytes in situ. In this report, we demonstrate that IGF-1/insulin induced production of keratinocyte-derived autocrine growth factors that bind to the EGF receptor. Increased steady-state mRNA levels for transforming growth factor alpha (TGF-alpha) and for amphiregulin (AR) were observed upon incubation of keratinocytes with mitogenic concentrations of IGF-1. IGF-1 also induced production and secretion of TGF-alpha and AR proteins as detected by immunoassays. An EGF receptor antagonistic monoclonal antibody abolished the mitogenic effect of IGF-1 on cultured keratinocytes. These results suggest that stimulation of keratinocyte growth of IGF-1 requires activation of an EGF receptor-mediated autocrine loop.

Amphiregulin↗
PubMed1995

Skin abnormalities in mice transgenic for plasminogen activator inhibitor 1: implications for the regulation of desquamation and follicular neogenesis by plasminogen activator enzymes.

Plasminogen activator enzymes have been implicated in the regulation of growth, migration, and differentiation which occur continually in normal epidermis and cyclically in the hair follicle. To elucidate further the importance of plasminogen activation in epidermal physiology, studies were conducted using mice transgenic for human plasminogen activator inhibitor 1 (PAI-1). The epidermis of the newborn (4-7 days) transgenic mice was flaky and showed delayed hair growth compared to that of their control littermates. Histologic analyses revealed a greatly thickened stratum corneum in the transgenics. By 2 weeks after birth, no differences in epidermal morphology were apparent between transgenic and control littermates. Using in situ hybridization, immunocytochemistry, and in situ reverse zymography techniques, epidermal PAI-1 expression was correlated temporally with the aberrant epidermal morphology. These data implicate plasminogen activator activity in the regulation of epidermal shedding and follicular neogenesis.

Animals↗
PubMed1994

Determination of the primary structures of human skin chymase and cathepsin G from cutaneous mast cells of urticaria pigmentosa lesions.

This study establishes the primary structure of human skin chymase and provides further evidence for the presence of a cathepsin G-like proteinase within human mast cells. The amino acid sequence of human skin chymase was established by protein methods and by analysis of PCR amplification products obtained with cDNA-derived from urticaria pigmentosa (UP) lesions. UP is a disease characterized by skin lesions containing high numbers of mast cells. Proteolytic digests of human chymase purified from normal skin yielded 10 resolvable peptides that were sequenced by automated Edman degradation. The amino acid sequences for these peptides combined with the sequence obtained for the protein's NH2-terminal region (35 residues) accounted for 137 residues of the human skin chymase sequence. This partial amino acid sequence corresponded to the sequence of human heart chymase, a proteinase isolated from heart tissue with immunologic and hydrolytic properties similar to skin chymase. PCR amplification of UP-derived cDNA with primers based on the cDNA structure of heart chymase demonstrated a single amplification product of expected size which was subcloned and sequenced. The amino acid sequence (135 residues) deduced from this product was identical to that of heart chymase in the region between the primers. This sequence, along with that established for the purified protein, constituted 99% of the heart chymase primary structure, strongly indicating that human skin and heart chymases have identical primary structures. Amplification of the same UP-cDNA with primers coding for the NH2- and COOH-terminal sequences of human neutrophil cathepsin G also produced a specific amplification product which was sequenced. The deduced amino acid sequence between the primers was identical to that reported for neutrophil cathepsin G, indicating that the protein of cutaneous mast cells previously shown to be immunologically cross-reactive with neutrophil cathepsin G has a comparable amino acid sequence. UP-cDNA demonstrating amplification products for cathepsin G did not demonstrate amplification products for human neutrophil elastase, suggesting that the cathepsin G PCR amplification product was not derived from neutrophils or monocytes possibly contaminating the lesion. These studies provide further evidence that human skin mast cells contain two different chymotrypsin-like proteinases.

Amino Acid Sequence↗
PubMed1994

Managed care in California. Daunting new realities for dermatology and academic medicine.

Managed care is the predominant method of health care delivery in Sacramento, Calif; the effect on our academic medical center is profound. The lessons we are learning in the development of a university-based health care network have applicability to dermatology. The future of dermatology demands that all practicing dermatologists have an understanding of the challenges and that they participate in the design of appropriate cost-effective strategies for the future.

Academic Medical Centers↗
PubMed1994

Expression of plasminogen activator enzymes in psoriatic epidermis.

The plasminogen activators, tissue type and urokinase type (tPA and uPA, respectively) have been identified in human skin under normal conditions and in various inflammatory dermatoses, including psoriasis. By Northern blot analyses, mRNA for uPA, but not for tPA, has been previously identified in epidermal extracts from normal skin, whereas in psoriasis, mRNA for tPA is readily detected. To further characterize uPA and tPA expression in psoriasis, the localization of uPA and tPA mRNAs was evaluated by in situ hybridization. Studies were conducted using lesional and nonlesional skin of patients with psoriasis as well as normal skin. Additionally, in situ zymography using casein gel overlays was utilized to assess enzymatic activity. In psoriatic lesional skin, both uPA and tPA mRNAs were demonstrated by in situ hybridization. Message for tPA was observed throughout the epidermis with areas of accentuation in the superficial stratum spinosum. Message for uPA was more focal and was localized primarily in the basal layer. Zymography showed tPA activity was coordinately increased in psoriatic lesions. Uninvolved skin of psoriatic patients was similar to that of normal skin with respect to expression of plasminogen activators. In normal epidermis, neither tPA nor uPA mRNA could be detected by in situ hybridization. Activity for uPA, but not tPA, was observed by zymography. These studies suggest that alterations in plasminogen activators expression may contribute to the pathogenesis of psoriasis.

Humans↗
PubMed1994

Calcium modulates the expression of urokinase plasminogen activator and plasminogen activator inhibitor 2 by human keratinocytes.

Keratinocytes propagated in low calcium (30 microM CaCl2) serum-free media grow in a monolayer and exhibit morphologic and biosynthetic phenotypes most similar to those of keratinocytes in the basal layer of the normal epidermis. When the calcium in the media is elevated to 1 mM, the cells stratify and differentiate. The effects of calcium on human foreskin keratinocyte expression of urokinase type (uPA) and tissue type (tPA) plasminogen activator enzymes and plasminogen activator inhibitor 1 and 2 (PAI-1, PAI-2) were assessed by Northern analyses. Our data show that keratinocytes, cultured in the presence of low and high CaCl2 concentrations, express transcripts for uPA and PAI-2. Message levels for uPA were dramatically reduced in cultures stimulated with calcium, whereas those for PAI-2 were only slightly decreased. Little PAI-1 mRNA and no tPA mRNA were detected, independent of calcium levels. Actin mRNA levels were not modulated consequent to calcium stimulation. Hybridizations to 28S ribosomal RNA confirmed that equal amounts of RNA were analyzed from cells grown under low and high calcium conditions. These data demonstrate that keratinocytes, propagated in serum-free media under low and high calcium conditions, are similar to normal human epidermis with respect to their expression of regulators of plasminogen activation. Additionally, they suggest that the ratio of PAI-2 to uPA increases with keratinocyte differentiation.

Blotting, Northern↗
PubMed1994

Definitions and guidelines for assessment of wounds and evaluation of healing.

BACKGROUND: Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. OBSERVATION: This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and wound healing end points. CONCLUSIONS: The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.

Acute Disease↗
PubMed1993

Activation of protein kinase C inhibits human keratinocyte migration.

The involvement of protein kinase C (PKC) in epidermal growth factor (EGF)-induced human keratinocyte migration was studied with the phagokinetic assay. It was concluded that PKC activation does not mediate, but rather inhibits, EGF-induced keratinocyte migration. The following experimental observations support these conclusions: 1) The PKC inhibitor H-7 did not inhibit EGF-induced migration but instead led to a modest enhancement. 2) PKC activators such as phorbol-12-myristate-13-acetate (PMA), phorbol-12,13-dibutyrate (PDBu), and 1,2-dioctanoly-sn-glycerol inhibited migration, but biologically inactive 4 alpha-PMA had no effect. 3) PMA did not inhibit keratinocyte attachment and spreading but blocked migration almost immediately after addition. 4) Migration of PKC-depleted cells, which were produced by prolonged treatment with PDBu, was enhanced similarly to normal cells by EGF. 5) PKC-depleted cells were not susceptible to the inhibitory effects of phorbol esters on migration. Additional experiments, in which cells were preactivated with EGF, suggested that PKC inhibits the EGF effect at a post-receptor level. The inhibitory effect of PKC on keratinocyte migration was not restricted to EGF-induced migration; PKC activation also inhibited keratinocyte migration induced by bovine pituitary extract, insulin, insulin-like growth factor-1, and keratinocyte growth factor.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Modification of integrin-mediated cell attachment to substrata by serine proteinases in the presence and absence of divalent cations.

The sensitivity to serine proteinases of cellular proteins involved in cell-matrix adhesion was investigated using C32 melanoma cells. Cells dissociated from monolayers by the metal chelator ethylenediaminetetraacetic acid were incubated with proteolytic enzymes, and then attachment was quantified by standard cell adhesion assays. The effect of proteinases was found to depend on the presence of Ca2+ in the incubations. Incubation with 100 nM trypsin or chymotrypsin for 1-2 h (37 degrees C) in the absence of Ca2+ reduced cell attachment to vitronectin (Vn), fibrinogen (Fb), laminin, and fibronectin by approximately 80, 80, 40, and 30%, respectively. Viability studies indicated that such treatment with proteinases was not cytotoxic. Inclusion of 0.1 nM CaCl2 in the incubations prevented the loss in attachment to all substrata. In the case of Fb, proteinase treatment in the presence of Ca2+ had an additional effect; it improved cell attachment to this substratum by about 50%. C32 cells have been shown to express the integrin alpha v beta 3 (Vn receptor) which mediates attachment to Vn and Fb in a GRGDS-sensitive manner. Attachment of C32 cells to Vn and Fb prior to proteinase treatment and after proteinase treatment in the presence of Ca2+ was 90% inhibited by the addition of GRGDS peptide to the attachment assays. These results suggest that the adhesion observed both before and after proteinase treatment was mediated by this integrin. Analysis of the Vn receptor from proteinase-treated cells by immunoblotting of cell extracts and by SDS gel electrophoresis of immunoprecipitated receptor revealed no detectable change in either the alpha v or beta 3 subunit that correlated with loss in attachment. Similarly proteinase treatment in the presence of Ca2+ did not produce detectable alterations in the subunits which might correlate with the improved attachment to Fb. Consistent with these results, an enzyme-linked immunoassay to quantify cell surface receptors revealed little difference in the amount of Vn receptor on cells treated with proteinase in the presence or absence of Ca2+. Degradation of the alpha v subunit was demonstrated, however, at proteinase concentrations higher than those required to affect cell attachment. Thus, treatment of cells with serine proteinases can affect integrin-mediated attachment to matrix proteins in a manner moderated by Ca2+, but the alterations in attachment do not appear to be accompanied by detectable proteolytic modification of the integrin.

Amino Acid Sequence↗
PubMed1993

Planimetric rate of healing in venous ulcers of the leg treated with pressure bandage and hydrocolloid dressing.

BACKGROUND: Venous leg ulcers are a common cause of morbidity, but few predictive parameters exist that can be used to follow their progress. OBJECTIVE: We investigated the use of healing rate as a useful parameter in the treatment of venous ulceration. METHODS: Twenty-seven venous ulcers being treated with a standard regimen were evaluated. We calculated the initial (4-week) and overall healing rates using the Gilman method (delta A/p). RESULTS: The average initial healing rate for all ulcers combined, the healed group, and the nonhealing group was 0.069, 0.087, and -0.005 cm/wk, respectively. Similarly, the average overall healing rate for all ulcers combined, the healed group, and the nonhealing group was 0.062, 0.089, and -0.043 cm/wk, respectively. CONCLUSION: The initial healing rate (delta A/p(0-4)) may be an appropriate end point for clinical investigations comparing therapies for the treatment of chronic venous leg ulcers.

Bandages↗
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↗