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Biomedical subjects

M D Tharp

Publications and source records attributed to M D Tharp.

At least 19 recordsLinked to original sources
PubMed1996

IgG anti-50 kd lymphocyte membrane peptide antibody in patients with Sézary syndrome.

BACKGROUND: Recent evidence suggests that as cutaneous T-cell lymphoma progresses, cell-mediated immunity is reduced and humoral responses are augmented. OBJECTIVE: The present study was designed to compare the IgG response in Sézary syndrome with that in mycosis fungoides. METHODS: The IgG antilymphocyte response was studied in six patients with Sézary syndrome and in 11 patients with mycosis fungoides by means of immunoblot analysis, enzyme-linked immunosorbent assay, immunohistochemistry, and flow cytometry. RESULTS: An IgG antilymphocyte response to a 50 kd peptide was seen in five of the six patients with Sézary syndrome; however, none of the 11 patients with mycosis fungoides expressed this response. CONCLUSIONS: An enhanced IgG immune response to 50 kd lymphocyte peptide may be helpful in identifying disease progression in patients with cutaneous T-cell lymphoma.

Adult↗
PubMed1996

A comparison of twice-daily and once-daily administration of fluticasone propionate cream, 0.05%, in the treatment of eczema.

This multicenter, double-blind, randomized, parallel, four-week, vehicle-controlled study compared the efficacy and safety of once- and twice-daily application of fluticasone propionate cream, 0.05%, over a twenty-eight-day treatment period in 238 patients with moderate-to-severe eczema. Clinical evaluations, which included the physician's gross assessment, the severity of signs and symptoms, and the patient's subjective evaluation, were conducted at baseline and at weekly intervals following initiation of treatment. Both fluticasone QD and BID were found to be superior to vehicle at each evaluation. Application of fluticasone BID was found to be superior to once-daily application at day 22 based on the physician's gross assessment, and at days 15 and 22 based on the patient's subjective assessment. There were, however, no statistically significant differences between QD and BID application at day 8 and at the end of the twenty-eight-day treatment period. The results of this study suggest that QD application may be recommended for the treatment of moderate-to-severe eczema in most patients. As always, treatment effectiveness should be monitored periodically and BID application may be necessary to maximize therapeutic benefits in some patients.

Administration, Topical↗
PubMed1995

Cetirizine and astemizole therapy for chronic idiopathic urticaria: a double-blind, placebo-controlled, comparative trial.

BACKGROUND: Cetirizine and astemizole have been shown to be safe and effective in the treatment of patients with chronic idiopathic urticaria. Cetirizine brings about clinical benefit more rapidly. OBJECTIVE: The purpose of this study was to compare the efficacy of single daily doses of cetirizine and astemizole in relieving the symptoms of chronic idiopathic urticaria, with particular emphasis on the commencement of action. METHODS: Patients with chronic idiopathic urticaria were randomly assigned to relieve either 10 mg of cetirizine, 10 mg of astemizole, or placebo for 4 weeks in a multicenter double-blind trial. Patients rated symptom severity each night, and investigators rated symptoms weekly. RESULTS: One hundred eighty-seven patients were enrolled in the trial; 180 were included in the safety analysis and 177 were included in at least one efficacy analysis. Both cetirizine and astemizole were significantly superior to placebo in relieving symptoms of chronic idiopathic urticaria. Both patients' and investigators' ratings indicated that cetirizine acted more rapidly. Both active treatments were well tolerated, and the incidence of somnolence did not differ statistically between cetirizine (14.5%) and astemizole (10.3%). CONCLUSION: Both cetirizine and astemizole provide effective relief of the symptoms of chronic idiopathic urticaria with similar side-effect profiles. However, clinical benefit occurs significantly more rapidly with cetirizine.

Adult↗
PubMed1994

A role for mast cells in the progression of Duchenne muscular dystrophy? Correlations in dystrophin-deficient humans, dogs, and mice.

Dystrophin deficiency has been shown to be the underlying cause of Duchenne muscular dystrophy. Although dystrophin-deficient homologous animal models have been identified (dog, mouse, and cat), the clinical expression of the biochemical defect is species-specific. Thus, while the genetics and biochemistry of Duchenne dystrophy is understood, the pathophysiological cascade leading to muscle weakness in only humans and dogs remains obscure. To begin to dissect the pathophysiology at the histological level, we undertook a systematic study of mast cells in normal and dystrophin-deficient muscle. Mast cells have been implicated in the development of fibrosis in other disorders, and progressive fibrosis has been hypothesized to mediate the failure of muscle regeneration in human and dog dystrophin deficiency. Our results show a strong correlation between mast cell content and localization, and the clinico-histopathological progression in humans, dogs and mice. The mast cell increases were disease specific: other dystrophic myopathies with normal dystrophin generally did not show substantial increases in mast cell content or degranulation. Our data suggest that mast cell accumulation and degranulation may cause the grouped necrosis characteristic of dystrophin deficiency in all species.

Animals↗
PubMed1994

Rat mast cell protease I alters cell metabolism.

Rat connective tissue mast cells are known to store significant amounts of mast cell protease I (RMCP I), which suppresses normal cell growth and mediates cytotoxicity against tumor cell lines, including the fibrosarcoma cell line FL. To better define its effects on FL cells, RMCP I was added to FL cultures for 30 min. Analysis of de novo nuclear protein synthesis revealed that RMCP I suppressed the expression of three proteins (41, 46, and 69 kD) and enhanced the expression of two other proteins (25 and 32 kD). Treatment of FL cells with diisopropylfluorophosphate (DFP)-inactivated RMCP I proved that these effects were largely independent of the protease catalytic site. Western blot hybridization, using a monoclonal antibody to phosphotyrosine-containing proteins, revealed that RMCP I inhibited phosphorylation of a nuclear and a cytoplasmic 81-kD tyrosylprotein. Inhibition of nuclear tyrosine kinase activity by RMCP I appeared to be catalytic site dependent, whereas cytoplasmic tyrosine kinase inhibition was independent of RMCP I proteolytic activity. Biotinylated RMCP I was used to identify potential surface-binding proteins. Three specific binding complexes (130, 150, and 210 kD) were detected. The binding of biotinylated RMCP I to these surface proteins was inhibited by excess unlabeled RMCP I, but not by trypsin or chymotrypsin. We speculate that the binding proteins may be critical in initiating RMCP I-induced metabolic changes on FL cells. The ability of RMCP I to alter the metabolism of cells suggests that it may have an important role in regulating their functions.

Animals↗
PubMed1993

Mast cell and myofibroblast in wound healing.

Growing evidence in the literature indicates that mast cells are integrally involved in the process of dermal wound repair. They are resident cells of the normal dermis and have several cytokines stored in their granules that are stimulatory to fibroblasts. They also contain serine proteases that may be involved in remodeling of the extracellular matrix during healing. Mast cells are found in increased numbers in acute wounds and in certain chronic fibrotic diseases. Their influence on fibroblast growth and collagen production may be an important element in fibrosis. The effects of mast cell mediators on dermal fibroblasts are currently being explored by our laboratory and others. Myofibroblasts are implicated in the phenomenon of wound contraction. These phenotypically altered fibroblasts express some features of smooth muscle cells, notably actin filaments, and are abundant in granulation tissue. It has been proposed that they are responsible for wound contraction and possibly certain types of contracture. However, this hypothesis has been challenged by studies demonstrating the presence of myofibroblasts in wounds that do not contract, or the process of contraction in vitro in the absence of myofibroblasts. At this time the issue remains open to debate and further research.

Fibroblasts↗
PubMed1991

Growth of human basal cell carcinomas transplanted to C57/Balb/C bgJ/bgJ nu/nu (beige-nude) mice.

The purpose of this study was to measure growth parameters of transplanted basal cell carcinoma (BCC) to beige-nude mice during a 4-month observation time. Forty male beige-nude mice were transplanted with human BCC with our reported subcutaneous implantation technique. Initial volume and wet weight were determined for each tumor. The tumors were measured every 2 weeks by calipers with a final volume determined at 120 days, at which time the tumors were harvested, weighed, and processed for routine histology. Thirty-two tumor sites were positive for persistent tumor at harvest. Tumor volumes declined by an average of 51% and average tumor weight by 33%. There were increased numbers of mast cells surrounding the BCC tumor lobules. These results indicate that BCC can survive for 120 days in the beige-nude mouse.

Animals↗
PubMed1990

IgE and immediate hypersensitivity.

Tissue mast cells play a central role in immediate hypersensitivity reactions. The clinical manifestations of these reactions appear to be dependent, in large part, on the anatomic location of the stimulated mast cells and the type of mediators released. In vivo and in vitro studies indicate that the tissues in which mast cells reside may greatly influence their biochemical composition, expression of surface receptors, and response to potential stimuli. Although all human mast cells in different organs store similar concentrations of histamine, heparin, and tryptase, cutaneous mast cells appear to be the predominant source of mast cell-derived chymase. Furthermore, at the time of stimulation, human skin mast cells predominantly form PGD2, whereas lung and intestinal mast cells generate LTB4, LTC4, and PGD2. Functional studies indicate that human cutaneous mast cells differ from human lung, heart, and intestinal mast cells. Skin mast cells are responsive to a variety of immunologic and nonimmunologic stimuli in vitro, whereas human pulmonary, cardiac, and intestinal mast cells are relatively refractory to many of these stimulatory signals. Taken together, these observations indicate that mast cells may assume different, and possibly specialized, functions within a specific tissue. Such site-to-site variation potentially could have important clinical significance, to the extent that information gained from mast cells in one organ may not be applicable to a mast cell population in a different tissue. Furthermore, these differences among human mast cells may not be confined to their biochemical composition and responses to various stimuli, but also may extend to the effectiveness of different anti-allergic preparations. Therefore, these observations underscore the importance of continued detailed investigation of human mast cells from different anatomic sites.

Humans↗
PubMed1989

The interaction between mast cells and endothelial cells.

Mast cells (MC) are widely distributed throughout different organs with a relative predilection for potential portals of entry into the host. In tissues, MC are generally concentrated around small blood vessels and lymphatics, as well as nerves and glandular tissue. This close association with vascular structures suggests an important interaction between MC and endothelial cells (EC). Tissue MC are known to generate and release a number of mediators including histamine, prostaglandin D2, and leukotrienes that induce vasodilatation and increased vascular permeability. These MC-mediated effects on vessels may enhance responses to tissue injury or infection by facilitating the deposition of plasma components and inflammatory cells into involved sites. Important interactions between MC, EC, and peripheral nerves also occur. MC-derived histamine and possibly other mediators induce axon reflexes in unmyelinated sensory nerves leading to the release of neurotransmitters such as substance P, calcitonin gene-related peptide, and adenine nucleotides. These neurotransmitters exert direct effects on blood vessels, and in some instances, may act as MC stimulators. In vitro studies indicate that MC also affect EC growth and new blood vessel formation. Mast cell-derived heparin has been implicated as an important cofactor in tumor-induced angiogenesis, whereas histamine has been reported to augment human dermal EC growth in culture. The recent identification of a tumor necrosis factor-like peptide in MC and the reported cytostatic effects of TNF on EC suggest that MC may inhibit the proliferation of these cells under certain conditions. Taken together, these observations indicate that the interactions between MC and EC are important in both physiologic and pathologic events.

Animals↗
PubMed1989

Studies of connective tissue mast cell-mediated cytotoxicity.

Although mast cells have been implicated in mediating antitumor activity, the kinetics, mechanism(s), and suspectibility of different tumors to mast cell-mediated cytotoxicity have not been defined. Rat connective tissue mast cells (CTMC) of greater than or equal to 99% purity were investigated in vitro and found to express maximal spontaneous cytotoxicity against the mouse fibrosarcoma cell line WEHI-164 (56.0% +/- 2.1 SEM), the ultraviolet B (UVB)-induced, cutaneous fibrosarcoma 5C25 (34.7% +/- 3.4 SEM), and the human renal cell tumor Currie (26.8% +/- 2.0 SEM) at an effector to target (E:T) ratio of 80:1. Kinetic studies of CTMC-mediated cytotoxicity demonstrated significant detectable lysis against these tumors within 8 h, which was maximal by 16 h. Binding experiments showed that CTMC formed conjugates with all three lytic-sensitive targets; however, CTMC also attached to the lytic-resistant target YAC-1, indicating that conjugate formation alone is not sufficient for mast cell-mediated cytotoxicity. At two different concentrations, mast cell granules (MCG) lysed WEHI-164 (36.5% +/- 6.8 SEM) and 5C25 (34.4% +/- 6.9 SEM), but were only slightly cytotoxic (5.7% +/- 2.9 SEM) against Currie. A potential role for tumor necrosis factor-alpha (TNF-alpha) in CTMC-mediated cytotoxicity also was investigated. Polyclonal antibodies to TNF-alpha greatly reduced CTMC and TNF-mediated lysis of WEHI-164, but only partially inhibited CTMC killing of the slightly TNF-sensitive 5C25 tumors, and had no effect on CTMC cytolysis of Currie. Thus, this study demonstrates that CTMC mediate cytotoxicity in vitro by both TNF-associated and TNF-independent mechanisms. We conclude that CTMC are capable of mediating antitumor activity and that this effect may be important for tumor surveillance in the skin and other sites.

Cell Line↗
PubMed1988

Ultrastructural morphometric analysis of lesional skin: mast cells from patients with systemic and nonsystemic mastocytosis.

Lesional skin mast cells from some patients with mastocytosis appear morphologically atypical; however, these subjective differences have not been quantified. Herein we describe an objective method for analyzing cutaneous mastocytosis mast cells by a combination of morphometric analysis and electron microscopy. By this technique, lesional mast cells from patients with adult systemic mastocytosis had a significantly larger mean cytoplasmic area (53.3 microns2), nuclear size (20.4 microns2), and granule diameter (0.81 micron) when compared with mast cells from adults with nonsystemic mastocytosis (36.3 micron 2, 15.4 microns2, and 0.67 micron, respectively) and normal age-matched control subjects (34.4 microns2, 14.1 microns2, and 0.67 micron, respectively). Lesional skin mast cells from infants with nonsytemic mastocytosis were very similar to adult nonsystemic mastocytosis mast cells but differed by several parameters from mast cells in adults with systemic involvement. This study demonstrates that there are quantitative differences between lesional skin mast cells from patients with systemic mastocytosis and those with nonsystemic disease.

Adult↗
PubMed1988

Ultrastructural morphometric analysis of human mast cells in normal skin and pathological cutaneous lesions.

Electron micrographs of human mast cells in normal neonatal and adult skin and in cutaneous lesions of basal cell carcinoma (BCC), hemangioma and mastocytosis were assessed by morphometric analysis. Using this quantitative histologic approach, adult skin mast cells were found to be significantly larger (47.7 microns 2 +/- 2.4 SEM vs. 38.3 microns 2 +/- 1.8 SEM, p less than or equal to 0.001) and have larger granules (0.63 micron +/- .02 SEM vs. 0.53 micron +/- .02 SEM, p less than or equal to 0.001) than infant mast cells while both mast cell populations had comparable nuclear sizes (13.7 microns 2 +/- 0.9 SEM vs. 14.3 microns 2 +/- 0.8 SEM) and numbers of cytoplasmic granules (72 +/- 4.0 SEM vs. 66 +/- 4.0 SEM). Morphometric analysis of mast cell infiltrates in the adult skin lesions of BCC and hemangioma revealed that these cells were larger than neonatal mast cells but were similar to normal adult controls. Cutaneous mast cells from 2 mastocytosis patients, however, had significantly larger mean cell surface areas (78.0 microns 2 +/- 3.4 SEM and 70.6 microns 2 +/- 3.2 SEM, p less than or equal to 0.001), nuclear areas (20.8 microns 2 +/- 1.1 SEM and 21.3 microns 2 +/- 1.2 SEM p less than or equal to 0.001) and granule diameters (0.82 micron +/- 0.4 SEM and 0.83 micron +/- .03 SEM, p less than or equal to 0.001) when compared with mast cells in normal adult skin and in the other pathologic lesions. No difference in the total number of cytoplasmic granules was observed in the different mast cell populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Functional heterogeneity of human mast cells from different anatomic sites: in vitro responses to morphine sulfate.

The responses of human cutaneous, pulmonary, intestinal, and cardiac tissue mast cells to the histamine-releasing agent morphine sulfate (MS) were investigated in vitro. Human cutaneous mast cells released significant amounts of histamine in the presence of 1 to 100 mumol/L concentrations of MS. Histamine release was detectable within 5 minutes after challenge and was complete by 15 minutes. A maximal histamine release of 21.6% (+/- 1.4 SEM) was observed after stimulation with 100 mumol/L of MS. This MS effect was inhibited by the opiate receptor antagonist naloxone with a 59% inhibition detected at equimolar concentrations and an 88% inhibition occurring in the presence of a tenfold molar excess of naloxone. Naloxone did not alter the cutaneous mast cell response to the calcium ionophore A23187. Human mast cells derived from pulmonary, intestinal, and cardiac tissues, as well as blood basophils, did not release histamine after stimulation with 1 to 200 mumol/L of MS, whereas each of these cell preparations responded to an IgE-mediated stimulus. The results of this study demonstrate that cutaneous mast cells release inflammatory mediators after stimulation by MS, whereas mast cells residing in lung, heart, and gastrointestinal tissues do not. These observations indicate that human mast cells in different anatomic sites can vary in their functional responses.

Basophils↗